140
CONCUSSIONS
Concussions are a type of mild traumatic brain injury (MTBI) that occurs when the brain is jarred or shaken and are most commonly seen in sports-related brain injury. Sports-related concussion has been described as an epidemic  by the Centers for 
Disease Control and Prevention. Visits to the emergency department for concussions have increased 62% between 2001 and 2009, and it is estimated that up to 250,000 concussions occur each year from high school sports alone. 141 Given the millions of 
young persons involved in high school, collegiate, and older professional players par -
ticipating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from combat-related injuries, concus -
sions have become an important public health concern requiring public education and immediate clinical attention to find an effective treatment. Concussions are the result of biomechanical forces that result in rapid accelera -
tion and decelerations of the brain often involving helmet-to-helmet contact, leading to functional impairments even in the absence of overt structural damage. 142 Football 
is not the only sport that produces concussions; every contact sport such as hockey, 155 DMSO in Basic Neuroprotection
soccer, boxing, and rugby also contributes to this epidemic.143 Concussions can also 
result from the head striking a hard object, as it often occurs in falls, creating a more 
severe acceleration–deceleration of the brain than those seen after football helmet-to-helmet contact ( Figure 8 .4). Concussions have been defined as a temporary impairment of neurological func -
tion that heals by itself over time, and unlike severe, closed head injury, neuroimaging normally shows no gross structural changes to the brain as a result of the trauma. 144
Loss of consciousness is a clinical hallmark of concussion but is not required 
to make the diagnosis. Symptoms include confusion, disorientation, unsteadiness, dizziness, headache, and visual disturbances. 145 These postconcussive deficits occur 
with minimal detectable anatomic pathology and often resolve completely over time, suggesting that they are based on temporary neuronal dysfunction rather than cell death as seen in severe head injury. 146 Neuronal dysfunction can occur due to cere -
bral hypoperfusion, ionic shifts, altered metabolism, impaired synaptic connectivity, or changes in neurotransmission, such as diffuse axonal injury. 147
Repeated concussions, even mild blows to the head from contact sports, can cause 
cumulative pathology on the brain. Successive concussions can have devastating consequences, including progressive decline of memory and cognition, depression, suicidal behavior, poor impulse control, aggressiveness, and, eventually, dementia. 148
The metabolic cascade following this type of injury has been studied extensively 
in animal models as well as humans.149,150 This metabolic cascade immediately after 
biomechanical injury to the brain consists of a sudden release of neurotransmitters involving excitatory transmitters, such as glutamate binding to the NMDA recep -
tor, which leads to further neuronal depolarization with the efflux of potassium and 
influx of calcium into brain cells. 149 These ionic shifts lead to acute and subacute 
changes in cellular physiology, diminished cerebral perfusion, and brain cell energy 
crisis, making the brain less able to respond adequately to a second injury and poten -
tially leading to longer-lasting deficits.151The head strikes a
hard obje ct cr eating
a concussion -type
injury
FIGURE 8.4  Rapid acceleration–deceleration of the brain created by the head striking a 
moving or fixed object.156 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Unfortunately, studies targeting the metabolic cascade have failed to produce a 
viable treatment option given the rapid onset and the shortness of time in reach -
ing a concussed patient in time to stop this cascade from progressing. One option, 
however, is to keep a rapidly acting, safe, and effective agent such as DMSO near the sports facility where games are played and have someone present when players come in contact with each other that can administer DMSO intravenously if it is determined that intervention must be applied. Some studies have shown that cerebral blood flow decreases immediately follow -
ing a concussion, and the amount of time cerebral perfusion remains lowered and seems to depend on the severity of the injury. 152,153
Due to their lack of structural damage, concussion is also referred to as MTBI. More commonly, athletes present with a brief alteration of consciousness, headache, and amnesia and require careful examination and observation before returning to competition. The diagnosis of MTBI is based on subjective findings and subtle changes in mental status. The diagnosis of concussion is largely based on the clinical examination, yet 
certain imaging studies can be considered, such as computed tomography or mag -
netic resonance imaging (MRI), especially if an intracranial bleed is suspected. MTBI requiring urgent neurosurgical attention should be ruled out. 154 Computerized 
tomography and MRI are usually without significant findings in MTBI. Functional magnetic resonance images and positron emission tomographic scans have been used in concussion research but serve no role in the clinical management of concussion. 155
Neuropsychological testing is also very sensitive in the evaluation of brain injuries 
in athletes and may become more clinically useful in the future. Neuropsychological testing may demonstrate areas of deficiencies; however, results may be difficult to interpret because of confounding factors. 156
Complications following MTBI such as second impact syndrome have been 
known to occur, and when this happens, a rapid and effective treatment to counteract the pathologic cascade that follows may be life-saving. The search for an effective and safe concussion treatment when prevention does 
not work is higher now than ever before. A better understanding of the detrimental molecular and cellular effects caused by a concussion is the key to finding a safe, rapid, and effective treatment. Treatment strategies focused on managing the neuroinflammatory responses 
to concussion may prove to be a tangible target since it is hypothesized that these delayed secondary effects may be the primary source of long-term neural damage. There are promising data to suggest that manipulating neuroinflammation can be used as treatment strategies to manage the long-term deficits produced by a concus -
sive injury. 151
However, the use of general anti-inflammatory drugs such as nonsteroidal anti-
inflammatory drugs (NSAIDs) will not serve as a magic bullet  for this type of injury. Rather, it seems that a tailored drug that targets the inflammatory and metabolic 
cascade that follow a concussion when given at particular temporal intervals will 
likely be useful in treating the complexity of the inflammatory response to concus -
sion. DMSO, an efficient anti-inflammatory agent, may become a treatment of choice as we review its properties as a neuroprotective agent.157 DMSO in Basic Neuroprotection
DMSO IN BRAIN CONCUSSION
DMSO may be an ideal agent to treat the metabolic cascade that often follows the 
rapid acceleration and decelerations of brain concussions.155,157
Glutamate is an amino acid in the brain that functions as the principal excit -
atory neuronal neurotransmitter. During excitatory neurotransmission in the healthy CNS, glutamate is briefly released at a high concentration into the extra -
cellular space where normal physiological levels are maintained by reuptake of glutamate through neuronal or glial glutamate transporters. When excessive extracellular glutamate accumulates in the synaptic space after brain traumatic injury, it causes a significant increase in Ca
2+ influx into neurons, thereby trig -
gering neuronal excitotoxicity. Traumatic injury to neurons can produce disas -
trous results when the excessive release of intracellular glutamate concentrations overload the synaptic space. Moreover, many glutamate-induced CNS neurode -
generative disorders, such as epilepsy, amyotrophic lateral sclerosis, brain isch -
emia, and traumatic brain injury, are reported to associate with the dysfunction of glutamate excitotoxicity. 158
When primary hippocampal cell cultures exposed to toxic levels of glutamate 
were given DMSO at clinical doses, DMSO was shown to suppress, in a rapidly reversible manner, excessive calcium influx into cells and channel opening of the ionotropic receptor channels NMDA and AMPA, which are known to be activated by glutamate during brain trauma due to the development of oxidative or metabolic stress. 54
Moreover, this excitotoxic  process by glutamate, which can damage or kill neu-
rons, was reported to be blocked by DMSO.54
The treatment of brain edema after MTBI presents a challenge for many clini -
cians. Considerable animal and human studies indicate that DMSO can quickly lower edema and ICP following severe traumatic brain injury (TBI). 41,43–45,61,159 
These findings suggest that DMSO at lower doses than those used for severe, closed head injury may be beneficial to mild brain trauma. This concussion is supported by the pharmacological properties of DMSO, including its antiedema property, its potent diuretic action, its anti-inflammatory properties, and its increase of cere -
bral perfusion. 160 Moreover, its blocking effect of excessive glutamate, sodium, and 
calcium entry into cells and efflux of potassium ( Figure 8 .3) that can induce cyto -
toxicity demonstrates that it can therapeutically target the biochemical cascade described in animal and human brain following MTBI (concussions) or severe TBI. 50,51,54
DMSO COMBINED WITH A GLYCOLYTIC INTERMEDIATE
Because brain injury can lead to an impairment of mitochondrial oxidative phos -
phorylation with the loss of ATP as well as to the formation of cytotoxic free radicals, 
de la Torre and his group161 reasoned that combining DMSO with an intermediate 
of anaerobic glycolytic metabolism, fructose-1,6-diphosphate (FDP), might be more 
useful than either drug alone in preventing the neuronal and energy compromise associated with severe, concussive head injury in a mouse model. 161158 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
FDP is an intermediate of anaerobic glycolytic metabolism and has been shown to 
restore the activity of the Embden–Meyerhof pathway and oxidative phosphorylation 
when administered during prolonged hypoperfusion states.162 FDP can also inhibit 
oxygen-free radicals, stimulate anaerobic glycolysis, and increase the production of ATP, the main energy fuel of cells and neurons. 163 It is this activity by FDP that may 
limit injury to the brain following ischemic-hypoxia.163
The combination of DMSO + FDP to treat experimental brain trauma in mice thus 
seemed a reasonable option to prevent or restore loss of ATP in ischemic brain cells while simultaneously reducing progressive cerebral edema caused by the injury. 161 
Consequently, it was believed that FDP would act primarily to protect ischemic brain tissue from energy substrate depletion, a common outcome after brain trauma, while DMSO would act to stabilize cell membranes from excess free radical formation and abnormal Ca
+ entry into cells while reducing ICP by improving CBF.160
Both FDP and DMSO have each been reported to be useful when administered in 
head injury42,45,61,163 or cerebral ischemia in animals or humans.159,163,164 FDP has been 
shown to prevent the ischemic-induced loss of ATP and accumulation of intracellu -
lar Ca2+ in experimental animals, possibly by stimulating glycolysis while inhibiting 
gluconeogenesis.164 The administration of FDP during brain ischemia would seem to 
be particularly useful, since it readily crosses the blood–brain barrier (arias) and can yield twice as many moles of ATP as glucose. 164
In an experiment to test the synergic potential of DMSO-FDP, male CD-1 mice 
weighing 22–29 g were restrained and their heads were positioned under a head injury apparatus with their chins resting firmly on a flat surface at the base of the apparatus. 161 The apparatus consisted of a 25 cm long glass shaft held vertically by 
clamps on a ring stand and a tubular lead cylinder weighing 40 g. The lead cylin -
der was allowed to drop 20 cm through the shaft onto the center of the head, thus creating an 800 g/cm force injury on the cranium. An imaginary line was drawn coronally just anterior to the ears in order to create a consistent injury site on the animal’s head. This head injury mouse model has been previously used to screen the effectiveness of potential pharmacological agents after brain trauma. 165 FDP was 
given at 350 mg/kg in a 10% solution, and DMSO was administered at 1 gm/kg in a 28% solution both intravenously via the tail vein. All mice were pretested on the string prior to head injury, and all were able to 
grasp the string for a 90 s trial period and to travel with ease from the center of the string to one of the end posts holding the string. The extent of motor deficits reflected by the reduced ability of mice to remain gripping the string after head injury has been shown to be inversely proportional to the increased severity of the head injury. 166
Following head injury, testing showed 11 of 12 mice treated with DMSO + FDP 
retained sensory function as compared with 5 of 12 mice given vehicle nontreatment, 8 of 12 treated with DMSO only, and 7 of 12 treated with FDP. 161 The combination 
of DMSO + FDP significantly protected mice from motor deficits after injury, as 
indicated by an increased mean grip test score (76.3 s) shown by this group 1 h after 
head injury when compared with vehicle nontreated (5.8 s), FDP-treated (20.8 s), and DMSO-treated (19.6 s) animals. The pattern of protection continued for at least 2 h after head injury, with all groups showing some improvement over the previous grip 159 DMSO in Basic Neuroprotection
test taken 1 h after head injury. However, the only significant protection after 2 h was 
observed in the group treated with DMSO + FDP. Two hours after head injury, the group treated with FDP + DMSO had a mean grip test score of 86.5 s, which was significantly better than from the DMSO only (33.8 s), FDP only (24.3 s), and vehicle nontreated groups (12.2 s). 161
This study was the first to demonstrate that the combined DMSO + FDP given to 
mice that have been subjected to a moderate 800 g/cm concussion head injury can significantly modify the sensory-motor deficits, incidence of mortality, and histopa-thology. DMSO + FDP appeared superior in reducing the trauma-induced neurologi -
cal deficits and fatal outcome to either agent administered alone. Besides the improved sensory-motor function of mice treated with DMSO + FDP, 
a possible fringe benefit to the head-injured brain where inadequate cerebral perfu -
sion is expected may be the ability of these two agents to allow RBCs to maintain their deformability. Under normal conditions, RBCs with a 7–8  µm diameter can 
squeeze through capillaries that are 3–5  µm wide so that oxygen can be delivered to 
the tissues. The RBCs’ viscoelastic properties or deformability is possible because of a spectrin–actin interaction within the erythrocyte, which is dependent on its stored ATP and 2,3-diphosphoglycerate. 167
If 2,3-diphosphoglycerate or ATP stores are reduced by ischemia-hypoxia 
(Heckler/Marcel), it is probable that RBCs will increase their rigidity and thus be unable to adequately perfuse the cerebral microvasculature. This consequence would prevent optimal oxygen delivery to neurons and glial cells, which rely on oxy -
gen for the elaboration of ATP and for their basic cellular metabolism. Infusion of FDP raises the concentration of 2,3-diphosphoglycerate,
168 allowing RBCs to deform 
normally and consequently facilitating oxygen disassociation from hemoglobin169,170 
during ischemia-hypoxia. Conversely, DMSO is reported to promote the formation of ATP from ADP
171 and to preserve mitochondrial oxidative phosphorylation, thus 
ensuring ATP production after experimental brain ischemia172 This activity could 
additionally favor RBC deformability during tissue ischemic-hypoxia, a process that would improve cerebral perfusion. Another advantage of adding FDP to DMSO is that FDP has been shown to be 
effective in preventing ischemic injury to the brain
173,174 ostensibly by inhibiting exci -
totoxic release of glutamate during brain ischemia and preventing ATP loss by sub -
stantially increasing the flux of glucose into the pentose-phosphate pathway. Indirect evidence has also demonstrated that FDP can modulate cerebrovascular tone, myo -
cardial contractility, platelet aggregation, and blood pressure,
175,176 systems that can 
exacerbate damage following severe head injury. The exact mechanism for the synergic activity demonstrated by the DMSO + FDP 
combination has not yet been determined, but it may be assumed to lie in the abil -
ity of each agent to address different but critical metabolic abnormalities associated with the pathogenesis of severe head injury, for example, ATP loss leading to neu -
ronal energy deficiency, metabolic acidosis, abnormal Ca
2+ entry into cells, platelet 
aggregation, inflammatory response, cerebrovascular constriction, glutamate toxic -
ity, ICP increase, and free radical formation. This drug combination is reviewed in terms of its effect on experimental and clinical ischemic strokes in this chapter and Chapter 9.160 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
DMSO IN EXPERIMENTAL BRAIN ISCHEMIA
Stroke is the most fatal neurological disease and the leading cause of long-term dis -
ability in the United States. Stroke is divided into two major types, ischemic stroke, 
where an artery is blocked by a blood clot, and hemorrhagic stroke, where a brain vessel bleeds from a leak or a rupture. About 80% of strokes involve blockage of a major cerebral artery, and this is where most of the animal research in brain isch -
emia is presently focused. 177 A considerable amount in our current understanding of 
cerebral ischemia induced by stroke comes from animal models representing global and focal ischemia. Global ischemia is the product of mild-to-severe reduction of cerebral blood 
flow throughout the brain, which can occur either acutely or chronically. If blood flow  cannot be restored within a given time limit (depending on the cause), 
 permanent damage to the brain or death can result. When blood flow is restored 
after global ischemia, reperfusion injury can occur if the brain is not pharmaco -
logically protected. Many diseases can cause chronic global brain ischemia such as atherosclerosis of a conducting brain artery, diabetes, sickle cell anemia, cardiac arrhythmias, and congenital heart defects, while acute global ischemia can result from a heart attack. 178
Focal brain ischemia is less severe than global ischemia but more common 
both clinically and using experimental animal models. Focal ischemia reduces blood supply to a specific region of the brain where immediate or delayed neuro -
nal death can occur. 178 This area of injury is called the core ischemic zone and is 
marked by severe ischemia with blood flow falling 75%–90% of baseline in con -
junction with the loss of oxygen and glucose, leading to rapid depletion energy stores. 178 Severe focal ischemia can result in brain cell death from the necrosis of 
neurons within the ischemic core, but glial cells may be spared if blood flow is restored early. 179
Surrounding the ischemic core is an area called the penumbra where brain cells 
are kept structurally intact by collateral blood vessels but functionally impaired.180
The ischemic penumbra is a zone where pharmacological therapy could most 
likely be effective in restoring the loss of function.181 The ischemic penumbra blood 
perfusion is generally too low to maintain electric activity but sufficient to preserve ion channels and structural integrity. 180
Research using animal models of stroke have provided not only an understand -
ing of the pathomechanisms underlying injury after ischemic stroke but also a way to develop effective therapy to prevent and arrest the severe pathology associated with stroke. Although many models of stroke have been used for research, includ-ing nonhuman primates, rodents are more often used due to their lower cost, ease of handling, substantial characterization of pathological expectations from previous research, and potential for genetic engineering. Experimental focal ischemia has generally involved occlusion of the MCA that is 
the largest branch of the internal carotid artery (ICA) that supplies a portion of the anterolateral frontal lobe, most of the temporal lobe, and the parietal lobe. Occlusion of the MCA in animals can result in sensory-motor deficits and cognitive impairment 161 DMSO in Basic Neuroprotection
that can be monitored, quantitated, and analyzed by a variety of research tools when 
drug evaluation is done. In the context of cerebral arterial thrombosis, the effects of thrombotic stroke can 
be induced experimentally by cautery or by photothrombosis of the MCA, which differs from those due to cerebral ischemia induced by mechanical ligation or intra -
luminal occlusions of intracranial brain arteries
182 (Figure 8 .5). There are two commonly used surgical approaches to provide direct access to 
the arterial circulation of rodents. The first approach is to perform a craniotomy that allows access to distal branches of the ICA, such as the much used MCA, to be occluded either with a neurofilament or by cautery
183,184 (Figure 8 .5). Other types of 
occlusion to achieve focal ischemia have been reported such as photothrombosis, ligation of an arterial vessel, or drugs to cause local embolism, such as endothelin, a powerful vasoconstrictor. 185
One early report by Tamura and his colleagues186 described an approach that 
occludes MCA proximal to the lenticulostriate arteries and produces the infarction of both the cortex and the lateral part of striatum. Figure 8 .4 shows two popular 
techniques used in rats to induce focal brain ischemia. Rat brain MCA oc clusion
ACA
(a) (b) (c)MCANylon
filamen t Cautery
PCA
ICA
ECA
CCA
FIGURE 8.5  (See color insert.) Normal arteries at the base of rat brain (a) and approaches 
to induce focal brain ischemia using a nylon filament introduced from the ICA to the MCA (b) and thrombotic occlusion (c) of the MCA. Such occlusions of the MCA will mimic human ischemic stroke and involve parts of the cortex and subcortical regions, produc -
ing sensory loss and paresis or paralysis of the contralateral side of the body. See text for details. Key: ACA (anterior cerebral artery), MCA (middle cerebral artery), PCA (posterior 
cerebral artery), ICA (internal carotid artery), ECA (external carotid artery), CCA (common carotid artery).162 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
The intraluminal suture model, developed by Koizumi and his team (koizumi) 
and Longa and his group,187 is undoubtedly the most frequently used focal isch -
emia model in rats and mice but is also one of the trickiest to produce a consis-
tent outcome. This may be due largely to the varied technical approaches, rodent model, rodent age, and gender of rodents. The intraluminal monofilament model of MCA occlusion involves the insertion of 
a surgical filament into the external carotid artery and threading it forward into the ICA until the tip occludes the origin of the MCA, resulting in a cessation of blood flow and subsequent brain infarction in the MCA territory ( Figure 8 .5). The technique has a number of variations and can be used to model permanent 
or transient occlusion. If the suture is removed after a certain interval, controlled reperfusion can be achieved accompanied by an ischemic penumbra, which drug therapy can target. If the filament is left in place over 24 h, the procedure is suitable as a model of permanent occlusion. One useful advantage of the filament occlusion is that it does not require craniectomy or craniotomy, which can result in undesired variables to the experiment. Because the intraluminal suture model occludes the tip of the intracranial ICA, it 
cannot be considered a strict MCA occlusion. 188
For this reason, the filament occlusion technique results in a wider ischemic zone 
and higher mortality than when MCA is directly occluded, especially when permanent occlusion is made. 188 Nevertheless, the filament occlusion technique has become the 
most frequently used method to mimic permanent and transient focal cerebral isch-emia in rats and mice and has also been used in rabbits,
189 gerbils,190 and marmosets.191
However, despite their usefulness in stroke research, these focal ischemic models 
are not consistently reliable. The surgery to access and manipulate the cerebral ves-sels requires skilled and experienced hands, and for practical purposes, the results can vary from one laboratory to another and even within the same laboratory where findings are often highly variable. But the variabilities in stroke research are not due to technical difficulties only. It should be noted that the intensive research done in the past and up to the pres -
ent, using experimental stroke models, displays many technical, behavioral, and pathological shortcomings to mimic human stroke, and a considerable number of pharmacological agents have been seen to dramatically improve or reverse tissue injury after brain ischemia in rodents have failed to be translated into effective clini -
cal use. Many reasons have been suggested for this bench to bedside failure, and some of these reasons have been reviewed elsewhere. 192,193
One obvious reason for the lack of success in translating rodent findings into 
effective human stroke therapy is the basic difference between the rodent cerebral circulation, hemodynamic responses to vascular stress, and relative tolerance to brain ischemia with those of humans. 194 In addition to anatomic and physiological 
differences between rodent and human cerebrovasculature, most human strokes occur in elderly individuals, while a majority of animal stroke models are performed 
on young rodents. 195
This lack of correlation between small mammals such as rodents and human 
brain vasculature has produced no effective treatments in the last century for human 
ischemic stroke other than fibrinolytic therapy. The only FDA-approved therapy for 163 DMSO in Basic Neuroprotection
the treatment of acute ischemic stroke is the thrombolytic tPA,196 and curiously, the 
initial basic research was done in rabbits.197,198
As effective as they are when properly used, fibrinolytics have the limitation that 
makes them ineffective when administered after a 3 h time window following isch -
emic stroke onset.199 This time window is often difficult to obtain due to the onset of 
symptoms in a stroke patient who often waits several or more hours before seeking 
medical help at the emergency department. The effect of the large number of failed human trials that followed dramatic pre -
clinical results obtained primarily from rodent research has visibly reduced current levels of funding among the pharmaceutical industry to invest in research of new neuroprotective agents. 194
Another major reason for the lack of progress in ischemic stroke can be found in 
the difference between human brain and those of smaller mammals such as rodents, marmosets, and rabbits. Human brain is gyrencephalic (cortex convoluted with gyri and sulci), and those of many smaller animals are lissencephalic (smooth cortex). Human cortex and subcortex are highly organized, which includes deep gray nuclei and white matter tracts like the internal capsule. 200 Moreover, human brain lacks the 
collateralization of cerebral vessels found in rodents and other small mammals so their vulnerability to ischemia is enhanced. These species differences between human and rodent brain can be diminished 
when nonhuman primates are used to mimic human ischemic stroke. This has been the recommendation of the Stroke Therapy Academic Industry 
Roundtable (STAIR), a collaborative group made up of industry, academic mem -
bers,
201 and other many independent investigators.202–204
This group met to discuss the failure of finding therapy that could be useful in 
human stroke and came to the conclusion that stroke research would benefit from using an animal with a gyrencephalic brain such as macaque rhesus monkeys. ETHICAL CONSIDERATIONS FOR USING 
NONHUMAN PRIMATES IN CNS INJURIES
The use of macaques and other nonhuman primates comes with the ethical chal -
lenges that need to be considered and that involve the need to eradicate or dimin -
ish pain, emotional stress, and depression associated with the neurological deficits 
following experimental stroke. This can be achieved to some extent by providing proper analgesia during and after surgery and intensive veterinary care to com -
pensate during the recovery period. 205 The trade-off in using a nonhuman primate 
model would likely accelerate the discovery of a treatment that could reverse or significantly limit the neurological and cognitive deficits seen after human or ani -
mal stroke. Another more vulgar consideration in using nonhuman primates is their high 
cost, specialized technical personnel needed, veterinary care, and enriched 
living environment, factors that can discourage most researchers with limited 
research budgets. It should be emphasized that the use of successful therapy against ischemic 
stroke induced in nonhuman primates does not guarantee success in human stroke. 164 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
A number of examples support this conclusion. For example, the experimental radi -
cal trapping agent NXY-059 was used in marmoset monkeys 4 h after permanent 
MCA occlusion and obtained excellent therapeutic results 10 weeks after treatment, resulting in fewer neurological deficits and better neurohistologic picture when com -
pared to saline controls. 206,207 When NXY-059 was tried in human ischemic stroke in 
a randomized, double-blind study comprising 3190 patients, it was found ineffective when given 6 h after stroke onset. 208
Thus, the recommendations of the STAIR group for using nonhuman primates for 
ischemic stroke research have not been validated except for one instance, the use of intravenous DMSO. After canvassing the extensive stroke literature, DMSO appears to be the only agent that has so far shown significant neuroprotection in nonhuman primate ischemic stroke and human ischemic stroke. 209,210 The medical use of DMSO 
in humans is discussed in Chapter 9. ROLE OF DMSO IN EXPERIMENTAL STROKE
The brain region vascularized by the MCA is the most commonly affected area fol -
lowing a cerebral infarction. The reason is due to the large size of the MCA and the direct flow it receives at an angle from the internal carotid artery (ICA) providing the easiest path for thromboembolism. The MCA is therefore a vessel of choice in studying stroke in animals. In nonhuman primates, DMSO was studied in 20 rhesus monkeys ( Macaca 
mulatta ) subjected to ischemic stroke via a transorbital approach to visualize and 
clip the MCA under direct microscopy. 209 The animals were divided into four groups: 
(1) shams, surgery but no occlusion (N = 2); (2) saline controls (N = 8), surgery and clipping of the MCA; (3) clipping of the MCA and treated with 3 mg/kg dexametha -
sone (N = 5); (4) clipping of the MCA and treated with DMSO (N = 5) 2.5 g/kg 50% solution mixed in saline. All treatments were given 4 h after occlusion of the MCA with the clip still in place. The occluding Mayfield clip was removed after 16½ h, and a second intravenous dose of dexamethasone or DMSO was repeated for all treated animals 30 min after clip removal. All animals were given a full neuro -
logical examination daily for 7 days following occlusion of the MCA. After 7 days, animals were killed for neurohistological analysis. Arteriograms were taken in all animals before occlusion, 30 min after occlusion, 16½ h after occlusion, and 30 min following unclipping of the MCA ( Figure 8 .6). Table 8 .2 summarizes the results of 
the neurological examination after 16 h with the MCA clip in place and at 7 days following removal of the clip. 209
Mean average cerebral blood flow measured near the MCA prior to clipping was 
89 mL/100 g tissue/min. This value dropped by 43%–54% after MCA clipping and essentially returned to preocclusion values with no significant group differences fol -
lowing unclipping. Angiographic changes following MCA occlusion can be summa -
rized as follows. ICA narrowing (arterial spasm?) was seen at the level of the siphon 
in all animals 30 min following MCA occlusion ( Figure 8 .6). All animals except 
two saline controls survived the initial MCA clipping. Postmortem tissue weights 
showed DMSO attenuated cerebral tissue edema when compared to dexamethasone or saline controls.165 DMSO in Basic Neuroprotection
After 16½ h and with MCA still occluded, the narrowed carotid was still seen 
in the saline- and dexamethasone-treated groups. No narrowing of the ICA was 
observed in animals treated with DMSO209 (Figure 8 .6). Reperfusion of the posterior parietal and temporal branches of the MCA was 
more pronounced 30 min following unclipping of the MCA in DMSO than in con -
trols or dexamethasone-treated animals. Moreover, brain swelling of the trauma -
tized hemisphere examined at postmortem was moderately high in controls, mildly reduced in the dexamethasone group, and absent in DMSO-treated monkeys. 209
Postmortem histological examination of the ischemic hemisphere revealed less 
structural damage of the inferior thalamic peduncle and fewer chromatolytic and 
Pre-o cclusion
(a) (b) (c)
(d) (e)( f)
(g) (h) (i)Control
DMSO
dxms16½ h po st clip 17½  h po st clip
FIGURE 8.6  Arteriograms of rhesus monkeys showing characteristic vascular response 
after 16½ occlusion and 17  h when MCA was deoccluded. Saline-treated controls (a–c), DMSO treated (d–f), and dexamethasone treated (dxms g–i) before and after deocclusion of the MCAt. Panels (a), (d), (g) show preocclusion vascularization prior to MCA occlusion. Treatments were given 4 h after clipping the MCA and repeated shortly before clip was removed. At 16½ h after clipping, no blood flow is seen filling the MCA or its branches and severe narrowing of the ICA at the siphon is visible in saline controls and dexamethasone treated (b, h arrow), but no narrowing of ICA is observed in DMSO treated (e arrow). After unclipping at 17½ h, ICA narrowing continues in controls (c bold arrow) and dexamethasone (i bold arrow). No narrowing of ICA seen in DMSO (f bold arrow). In addition, the perical -
losal artery and posterior parietal vasculature is absent in saline controls (c double arrows) and significantly reduced in dexamethasone (i double arrows). In DMSO (f double arrows), these vessels are seen to have recovered substantially as compared to preocclusion arte -
riogram. (Adapted from de la Torre, J.C. and Surgeon, J.W., Stroke , 7(6), 577, November–
December, 1976. )166 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
swollen neurons in the pre-occipital cortex and caudate-lentiform region in DMSO-
treated animals when compared to dexamethasone or saline controls. The caudate-lentiform region is an area of the brain supplied by the lenticulostriate branches of the MCA, and because they are end-arteries , the brain regions they feed lack 
a significant collateral blood supply. 209 These end-arteries are not only a common 
site for thrombosis but are also difficult to treat with thrombolytics because they remain localized to the regions where they terminate, such as the caudate-putamen and internal capsule. In addition to light microscopic analysis, selective brain tissue regions from all 
groups of macaque monkeys were examined by electron microscopy on a blind to treatment basis. 47 Brain sections from the nontraumatized hemisphere showed 
no evidence of swelling or distortion of cellular components, including well pres -
ervation of synapses, synaptic vesicles, and unremarkable neuropil. By contrast, the traumatized hemisphere in dexamethasone-treated macaques showed severe swelling of neurons near the MCA occlusion and loss of a clearly delineated plasmalemma. 47
Ribosomes and osmophilic particles were seen to aggregate throughout the fluid-
filled intracellular space, while mitochondria in neurons appeared to be undergoing degenerative changes. Loss of neuronal mitochondria in brain tissue is known to reduce energy synthesis of ATP and make neurons more vulnerable to ischemic damage. Dexamethasone-treated animals also showed swelling of boutons (axon ter -
minals) and considerable loss of synaptic vesicles. These vesicles store neurotrans -
mitters at the axon terminal that are released at the synapse and are essential in propagating nerve impulses between neurons. Brain sections from DMSO-treated macaques showed swelling of some boutons 
and synaptic vesicles within neurons, but the axo-dendritic synaptic contacts revealed TABLE 8.2
Neurological Deficits Observed in Rhesus Monkeys 24 h and 7 Days after 
Occlusion of the MCA and Following No Treatment (Saline Control, N = 8)), Dexamethasone (N = 5), and DMSO (N = 5)
Neurological Status in Monkeys after MCA Occlusion
Treatment24 h Postocclusion 7 Days Postocclusion
A B C D A B C D 
Saline (control) — — — 8 — — — 6
Dexamethasone — — — 5 — — 1 4
DMSO — 4 1 — 2 3 — —
Source:  Adapted from de la Torre, J.C. and Surgeon, J.W., Stroke, 7(6), 577, November–December 1976. Notes:  No neurological deficits (A); contralateral paresis, alert (B); contralateral paresis, lethar gic (C); severe 
lethargy, or coma (D). Two saline-treated monkeys died on the fifth and sixth day postocclusion. Significant improvement was observed in the neurologic status of DMSO-treated animals after 24 h and after 7 days following MCA occlusion as compared to saline controls and dexamethasone-treated animals.167 DMSO in Basic Neuroprotection
good preservation, and little to no damage of neuronal mitochondria or neuropil was 
appreciated.47 There was no expansion of the extracellular space or compression of 
the neuropil as compared to dexamethasone or no treatment animals. These findings showed significantly less subcellular damage after DMSO treatment when compared to dexamethasone or no treatment macaques. In particular, loss of axon terminals and synaptic vesicles in dexamethasone- and saline-treated monkeys, but much lesser after DMSO treatment, implies impairment of synaptic neurotransmission and dys -
function of sensory-motor pathways. 47
The reduction of focal brain edema by DMSO was confirmed in a study using 
ferric chloride injection into rat brain to induce the formation of lipid peroxidation and free radicals. 211 DMSO caused a decreased formation of brain peroxidation at 
the injection site, as measured by the formation of NMDA, and a significant reduc -
tion of tissue edema of the injured cortex when given with or without the antioxidant tocopherol. 211
Another brief study using baboons subjected to MCA occlusion and treated 
with DMSO or DMSO-barbiturate coma appeared less definitive in its conclu -
sions.213 Four baboons underwent 6  h of temporary MCA occlusion and were 
treated with 1 g/kg of intravenous DMSO 30 min and 2 h after occlusion. DMSO infusion was continued for the next 8 h at 1 g/kg. The same DMSO-treated ani -
mals additionally received pentobarbital at a loading of 30 mg/kg begun 4 h after MCA occlusion. Continuous barbiturate infusion was titrated to maintain an isoelectric EEG while 
not allowing a reduction of arterial blood pressure of more than 15%. 212 This group 
was compared to a DMSO-only group of four baboons given similar doses but without pentobarbital therapy. A neurological score was used to assess each of the four baboons treated with DMSO–pentobarbital and DMSO alone resulted in only one baboon of four (25%) with a good survival and few deficits for DMSO alone and with good sur -
vival with mild deficits for one of four baboons given DMSO–pentobarbital. 212 All 
untreated baboons had a high mortality rate and suffered severe neurologic deficits. This study pointed out the success of DMSO in only 1 of 4 baboons subjected to MCA occlusion. Possible reasons for the difference in findings from those using rhesus mon-keys could be the DMSO dose that was twice that used (2.5 g/kg vs. 1 g/kg) and speed of delivery (bolus vs. slow infusion) in the baboon study, as well as the fact that primate brains differ considerably in their vascular anatomy and physiology, including those of baboons and rhesus monkeys. 213
One major difference between baboons and macaque monkeys is the higher vul -
nerability of baboons to MCA occlusion producing marked edema and high risk of death. 214,215 This conclusion is supported by the fact that MCA occlusion in the baboon 
study using DMSO resulted in a 75% mortality regardless of treatment used and 100% mortality or severely poor outcome in 8 untreated baboons. 213 Consequently, 
it is likely that the MCA lesion in this baboon study may have been too severe to adequately test the value of DMSO or any other treatment. A second ischemic stroke study using DMSO was carried out by the de la Torre 
team
48,64 in 45 squirrel monkeys. Survival rate was used to evaluate the efficacy of 
each treatment at the end of 7 days. The left MCA was accessed via a retro-orbital craniectomy and occluded with a small Mayfield clip for 4  h. The animals were 168 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
randomly separated into groups of 5 animals/group except for DMSO only, which 
included 10 animals. The following treatments were given intravenously: Group 1, physiological saline; Group 2, DMSO 1 g/kg in a 50% solution; Group 3, hemodilu-tion (HD) with 6% dextran solution to reduce hematocrit by 50%; Group 4, hyperbaric oxygen (HBO) 2 atmospheres pressure for 4 h; Group 5, DMSO + HBO; Group 6, DMSO + HD. This study was prompted by controversial findings regarding the use -
fulness of HBO and HD in experimental stroke. The results of this study confirmed the potential value of DMSO in cerebral 
infarction. Seven days after each treatment, 8 of 10 DMSO-treated animals were alive with 2 animals showing mild paresis of the contralateral side. Animals treated with DMSO–HD or DMSO–HBO had 50% and 75% survival rate, respec -
tively, with mild-to-moderate neurologic deficits. Animals given single HD or HBO showed 34% and 75% survival rates, respectively, but neurological outcome ranged from moderate-to-severe deficits involving hemiparesis, lethargy, and lack of alerteness. 48,64 Combining DMSO to HBO or to HD did not appear to improve 
neurologic outcome after MCA occlusion when animals were examined at the end of 7 days. Using only HBO or HD suggested that these therapies by themselves were not 
helpful in providing neuroprotection to the brain tissue after infarction of the MCA. The lack of neuroprotection by these agents was evident despite the increased oxy -
genation to brain cells presumably offered by HBO and increased cerebral blood flow ostensibly provided by HD as suggested by previous studies. We now know that while HBO is known to increase oxygen to tissues includ -
ing brain, it reduces CBF by reducing the powerful vasodilator nitric oxide while increasing hyperoxic vasoconstriction. 212a Conversely, HD increases CBF but reduces 
oxygen delivery to brain by lowering the number of red cells in the circulation.212b
In the early 1980s when the squirrel monkey study was performed,64 HD was a 
technique believed to be beneficial as a treatment for acute ischemic stroke. It con -
sisted mainly of administering low-molecular-weight dextran in order to increase cerebral blood flow by dropping the hematocrit and hemoglobin levels by about 25%–50%. However, randomized multicenter studies have since shown no benefit for this approach when applied to ischemic stroke in humans. 216 Similarly, HBO was 
theorized to be beneficial in stroke patients whose blood supply was compromised by the ischemic injury, and consequently, it was thought that increasing the sup -
ply of oxygen would reduce the extent of damage to the brain by limiting hypoxia. However, a systematic review of the evidence now indicates that this technique has not been shown to be of benefit in stroke patients. 217
These findings suggest that a subtle balance between CBF and oxygenation is 
critically required of an agent to counteract hypoxia and ischemia seen after a stroke. That balance between CBF and oxygenation of organ tissue may be provided by DMSO, which is reported to increase both CBF and oxygen delivery. 41,118,137,136,209
It is not surprising therefore, in reviewing the use of DMSO combined with HD 
or with HBO, that no synergism was observed when these combined treatments were compared to DMSO given alone following MCA occlusion in squirrel monkeys. 64 
In fact, the combination of DMSO with HBO or HD may have fallen a notch or two from the effectiveness of DMSO given alone. Nevertheless, the treated animals 169 DMSO in Basic Neuroprotection
showed less paresis when compared to untreated animals and were more alert follow -
ing recovery from stroke but only when DMSO was added to either HBO or HD.63,64
The Mongolian gerbil is an animal that has been used in ischemic stroke research 
because it lacks a posterior communicating artery in the brain that makes up part 
of the circle of Willis. The function of the circle of Willis is to supply blood to the brain and surrounding structures by creating a loose ring of collaterals to the cerebral circulation from the two ICAs and one basilar artery. Lacking the pos -
terior communicating artery means that unilateral ligation of a common carotid artery can result in an ipsilateral brain infarction of the entire hemisphere. About 300 of these gerbils were used to test whether DMSO could protect the brain from ischemic infarction following ligation of the common carotid artery. The results of this immense study showed that DMSO treatment significantly lowered the cerebral infarct volume as revealed by trypan blue staining when compared to saline-treated controls. 218
Reduction of infarct volume following DMSO treatment was confirmed by 
Shimizu and his colleagues219 using the filament occlusion method for the MCA to 
create a focal brain infarction. DMSO at doses of 0.1–1.0 mL injected intraperitone -
ally 30 min prior to infarction resulted in significantly less infarction volume than untreated controls. 219
Further support for reduced infarct volume with DMSO therapy was obtained in 
rats by Bardutzky and his colleagues.220 This study was unique in the sense that it 
examined different time points of drug administration relative to ischemia onset in the same experimental setting. Moreover, it determined whether DMSO increases cerebral blood flow to prevent injury after focal brain ischemia. It then evaluated the surviving rats for neurological status in treated and untreated animals. Thus, the study evaluated the effects of DMSO on the spatiotemporal evolution of the ischemic lesion using quantitative perfusion and MRI and examined the influence of DMSO on cerebral blood flow mechanics. 220 Permanent focal cerebral ischemia was induced 
using the intraluminal filament occlusion technique in the MCA. It was found that DMSO given at 1.5 g/kg resulted in a highly significant reduction in infarct size when the infusion was initiated 20 h before or 1 h after MCA occlusion. DMSO was also effective in reducing infarct volume at a dose of 0.75 g/kg initiated 1 h after occlusion, but the extent of neuroprotection was less robust compared with the higher dose of 1.5 g/kg. 220
The neurologic scores 24  h after MCA occlusion were significantly improved 
when DMSO was given 20 h prior to occlusion compared to the no treatment group.220 
As well, DMSO given 1 h after occlusion was also improved over the controls.220
Neuroprotection by DMSO was shown in the 3-day survival group with 50% of 
the untreated animals dying prematurely between 48 and 72 h after MCA occlusion, but no rat died prematurely in the DMSO group given 1.5 g/kg DMSO starting 1 h after MCA occlusion. 220
Cerebral blood flow in the ischemic hemisphere that was reduced to an aver -
age of 36% compared to the nonischemic hemisphere in untreated control animals remained constant in both control and DMSO groups without significant differences. This study demonstrated robust neuroprotection using DMSO in a widely used 
and established model of permanent focal cerebral ischemia. 220 The neuroprotective 170 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
effect by DMSO was shown in vivo  by diffusion and perfusion imaging, by neu -
rologic scoring, and at postmortem by the volume of tetrazolium staining of the 
infarcted region. The effective doses of DMSO used were also clinically relevant and shown to be well tolerated in humans. 220
The effect of DMSO on energy metabolism and function following brain ischemia 
and reoxygenation had not been studied in detail until 1991. A study by Gilboe and colleagues
221 reported the following metabolic and functional effects of DMSO dur -
ing a 14 min period of reoxygenation of the ischemic isolated dog brain. Blood gases, EEG, auditory-evoked potentials, cerebral metabolic rate for glucose (CMRglc), and cerebral metabolic rate for oxygen (CMRO
2) were monitored throughout the 
experiment.221
At the end of the study, brain samples were taken to measure brain tissue high-
energy phosphates, carbohydrate content, and thiobarbituric acid-reactive material (TBAR is an indicator of lipid peroxidation). After 60 min of reoxygenation in the nontreated 14 min ischemic brains, markers of tissue damage, including lactate, ade -
nosine monophosphate (AMP), creatine (Cr), intracellular hydrogen ion concentra -
tion (iH+), and TBAR values were significantly higher than noninjured brain tissue, and energy molecules ATP, creatine phosphate (PCr), CMRglc, CMRO
2, and energy 
charge (EC) values were significantly lower when compared to normoxic brain con -
trol samples.221 In brains exposed to DMSO, TBAR values were near control lev -
els and marked recovery of EEG and auditory-evoked potentials was observed in brains treated with DMSO. Restoration of auditory-evoked potentials and EEG sug -
gests that DMSO is involved in the preservation and restoration of cell membrane structures within the brain subjected to ischemia. 221
DMSO treatment also significantly increased ATP, CMRO2, and PCr values in 
postischemic brains and lowered noxious lactate and creatine when compared to untreated brains. 221 These findings indicated that DMSO appears to come close to 
normalizing brain metabolism during postischemic reperfusion, a finding that could explain in part its benefit following ischemic insults to the brain. This effect may not be totally due to free radical scavenging by DMSO since reducing free radicals alone following ischemia does not improve recovery of brain metabolism. A more likely explanation for the neuroprotective action of DMSO has to do with partially restoring to normal the energy metabolism of ischemic brain cells before bioener -
getic failure has taken hold. This outcome is supported by evidence showing the effect of DMSO in increasing the energy fuels, ATP and PCr, while reducing cellular oxygen consumption and synaptic dysfunction. 222,223 In this regard, DMSO has been 
reported to increase the latency of anoxic depolarization of neurons after acute brain ischemia. 50
It is important to point out that when bioenergetic failure occurs for any reason, 
brain cell metabolism rapidly diminishes and the cell begins a process leading to necrosis and death. When cerebral ischemia occurs, the source of ATP in the form of oxygen and glucose can rapidly diminish due to inadequate delivery of cerebral 
blood flow, a process that leads to depletion or cessation of oxidative phosphorylation. Oxidative phosphorylation is the metabolic pathway within the mitochondria of 
brain cells where the citric acid cycle takes place, where enzymes and energy are 
released by the oxidation of nutrients to generate ATP. ATP is the molecule that 171 DMSO in Basic Neuroprotection
supplies energy to cells and allows cellular metabolism to function. Once mito -
chondria, or the process that catalyzes the synthesis of ATP, is irreversibly dam-
aged, as can happen in ischemic stroke, no neuroprotective agent or intervention can reverse neuronal death. What is important about this simple concept is the erroneous impression some investigators distill from studies where a lethal lesion is created, irreversible neuronal death is obtained, treatment of a putative neuroprotective agent is given, failure to reverse neuronal death and its consequences is observed, and a conclusion about the failure  of the agent is assumed. Under unusual circumstances, the neuroprotective agent can  only  prevent the 
brain injury from expanding or potentially protect the injured brain cells from dying, as may be the case in the ischemic penumbra where neurons may lie dormant until revival or death. A case in point is the relative efficacy of tPA, the only FDA-approved treatment 
for ischemic stroke. Studies have shown that within the 3–4½ h time window where tPA is most effective, 26% of patients return to normal spontaneously without treat -
ment, while an additional 13% return essentially to normal if treated with tPA. 224 
This finding indicates that even when part of the brain is still thought to be salvage -
able after an acute ischemic stroke, the chances for returning the patient to a preoc -
clusion status following the best treatment available at the present are limited indeed. The potential harm of tPA thrombolysis is another consideration of the potential for neuroprotection by a pharmacological agent. There has also been considerable con -
cern that tPA can harm patients. For example, the percentage of patients who develop symptomatic intracerebral hemorrhages was reported increased by tPA therapy from 0.6% in placebo-treated patients to 6.4% in tPA-treated patients. 225
This may be the reason why some experiments testing the potential ability of 
DMSO in a variety of injuries to the brain and spinal cord show partial or incomplete success in preventing or reversing the damage caused by the lesion. The success and benefit of such treatments should be weighed in terms of the gravity of the injury, the relative benefit of a placebo or no treatment, and the safety of the experimental agent. In this sense, DMSO’s ability to prevent lipid peroxidation and increase high-
energy phosphates such as ATP and PCr in the face of brain tissue headed for bio -
energetic failure constitutes a dramatic advancement in the field of neuroprotection that mandates further exploration. Examination of another property by DMSO that seems to be the basis of action for 
thrombolytics like tPA, acetylsalicylic acid (aspirin), and clopidogrel bisulfate (Plavix) is their action in inhibiting platelet aggregation, a condition that generally results from prolonged cerebral ischemia. Multiple studies have shown that thrombosis of the brain is the major cause of stroke. Cerebral thrombosis can occur when a blood clot blocks a cerebral vessel either partially or completely. The clot or thrombus is caused by an inap -
propriate activation of the hemostatic process in an uninjured or mildly injured brain vessel through the aggregation of platelets that form a platelet plug. The clot can adhere to the vessel wall and impede or completely cut off cerebral blood flow, resulting in 
tissue death. Treatment of cerebral thrombosis can be started as soon as a diagnosis is 
confirmed. These consist of using thrombolytics such as tPA, clopidogrel, and aspirin to break up the clot made up of mostly aggregated platelets. Blood thinners (anticoagu -
lants) can be given after platelet deaggregation to prevent further clots from forming.172 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
DMSO when given at 2 g/kg 6 h after embolic stroke has been shown to prevent 
thrombosis in mongrel dogs subjected to an embolus introduced into the MCA. The 
DMSO-treated animals were observed to have normal behavior and no neurologi -
cal deficits following the experimental embolization.226 By contrast, three of nine 
control animals died after embolization, showing large infarctions of the thalamus, internal capsule, and piriform cortex, while the survivors showed contralateral hemi -
plegia and impaired consciousness. 226 The authors of this study postulated that the 
positive actions of DMSO in the postischemic period may have been due to its action as a platelet deaggregator. This idea seemed reasonable because previous studies had shown that agents, such as methohexital and in this case DMSO, are able to protect the endothelial membrane in ischemic blood vessels, thus allowing prosta -
cyclin to be released from endothelial cells at the site of ischemia to inhibit platelet aggregation. 227 This notion is the basis for using tPA to dissolve cerebral vessel clots 
made up of platelet aggregates and clopidogrel or aspirin to prevent further platelet aggregation. The assumption that DMSO could function as a platelet deaggregator was con -
firmed in a later study in rats whose carotid arteries had been occluded. Dujovny and his team
102 examined experimentally occluded carotid arteries using 
scanning electron microscopy and observed within these vessels heavy deposits of platelets, red cell clumps, fibrin, and endothelial flattening in untreated control ani -
mals. Animals treated with intravenous DMSO (2 g/kg) given 1 h prior to carotid occlusion revealed endothelial preservation and no platelet or fibrin clumping. 102
The findings by Dujovny et al.102 suggested that the beneficial action of DMSO in 
experimental brain trauma and cerebral ischemia may have been due, at least partly, to the protective effects by DMSO on the microcirculation by decreasing platelet aggregation and thus preventing the evolution of postischemic reperfusion injury. This effect on platelets by DMSO seems entirely plausible from the point of view 
that present therapy for arterial thrombosis consists of administering platelet deag -
gregators such as cyclooxygenase inhibitors (aspirin), ADP receptor inhibitors (clop -
idogrel, ticlopidine), adenosine reuptake inhibitors (dipyridamole), PDE inhibitors (cilostazol), and glycoprotein IIb/IIIa receptor antagonists that can block the plate -
let receptor for fibrinogen (tirofiban). What class of antiplatelet drugs DMSO might belong to remains to be determined. DMSO IN MISSILE INJURY TO THE BRAIN
From a historical point of view, one of the more wretched creations introduced to society is the invention of the pistol not for hunting or target practice but for the sole purpose of killing people. Since the 1970s, firearm deaths have increased dramati -
cally in the United States every year. Statistics indicate that in 1988, there were about 34,000 gunshot deaths in the United States and many of these were cranial gunshot wounds. By comparison, Canada statistics show 1450 deaths from gunshot wounds 
around the same period. 228 In large U.S. cities, gunshot wounds to the head rank as 
the highest cause of all trauma to the brain. Bullets fired from guns tend to be classified as low velocity (<300 m/s) or high 
velocity (>300 m/s), but this is a technicality since both high- and low-velocity bullets 173 DMSO in Basic Neuroprotection
act similarly in creating their pathology. High- or low-velocity missile wounds to the 
head tend to result in a temporary cavity that produces bursting injuries of the tissue, including blood vessels. When key blood vessels are damaged and bleeding cannot be stopped, the patient will likely die from blood loss at the site of injury. The trajectory of a bullet through the brain carries a major significance as it 
crushes structures along its track. Bullets that cut through the brainstem, or the ven -
tricular chambers where spinal fluid is located, are especially lethal. Gunshot wounds to the head are nearly always fatal and, in the best-case scenario, 
can leave the victim with severe neurological disability. It is estimated that two-thirds of the victims shot in the head die before reaching a hospital. When a high-velocity bullet hits the head, the skull often shatters into small 
pieces, creating not only more wounds to the brain but also a source for infection. Gunshot wounds to the head are classified as penetrating, where the bullet remains lodged in the brain, or perforating where the bullet exits the brain. If the patient with a gunshot wound to the head reaches the hospital, a number of 
critical systems must be addressed if the patient is to survive. These include treating high ICP, low oxygenation, hypertension, falling cerebral blood flow, and rising cere -
brovascular resistance that must be treated aggressively if the patient is to survive with a good outcome. If a hematoma is confirmed by CT scan, a craniotomy and surgical evacuation of the clot can be performed, but high ICP may persist. The high pressure in the brain may respond to mannitol treatment but a rebound effect where ICP returns higher than before mannitol treatment is often seen. 229
When patients are deeply comatose and there is minimal evidence of brainstem 
function in the absence of an intracranial hematoma that might be causing the coma, a fatal outcome is nearly always certain. An important study was reported by Brown and his colleagues
230 from the 
Division of Neurosurgery at the University of Chicago Hospitals and Clinics, a hos -
pital which is classed as a level 1 trauma center. Trauma centers are designed to take care of severe injuries such as car crashes, explosions, and gunshot wounds. The study by Brown and his associates
230 was prompted by the horrific rate of 
deaths due to gunshot wounds to the head seen in many large U.S. cities, including Chicago, in the 1980s, which dismally continue to this day. The objective of the study was to find out the clinical usefulness of mannitol as a treatment for a mis -
sile injury simulating a gunshot wound to the head and to compare this osmolyte to untreated controls. In addition, because DMSO had already been shown to be effective in nonhuman primate brain trauma, and in focal ischemic brain injury, the effects of mannitol were also compared to animals treated with DMSO. Seven rhesus monkeys were included in the study. After anesthesia, monkeys were 
monitored for ICP, cerebral blood flow, CPP, cerebrovascular resistance, blood pressure, and cerebral metabolic rate of oxygen consumption, along with blood gases and hema -
tocrit. 230 A BB pellet missile was fired at a velocity of 90 m/s through a burr hole made 
in the right cerebral hemisphere. Animals received either mannitol (0.05 g/kg, 25% solu -
tion) or DMSO (0.05 g/kg in a 50% solution) as an intravenous bolus 1 h following injury, and these doses were repeated when ICP rose above 20 mm Hg pressure. All parameters were measured 1 h after treatment was initiated. Animals were killed 6½ h after the last measurements were made. The results are summarized in Figures 8 .7 through 8.10.174 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
The ICP rose in all animals 1 min after injury and fell significantly 1 h following 
DMSO, reaching pre-injury levels after 6 h.230
In untreated animals, mean arterial pressure briefly rose after injury and decreased 
progressively for the next 6 h until death. DMSO dramatically reversed the hypoten -
sive process 1 h following injury230 (Figure 8 .7). DMSO was able to stabilize mean arterial pressure, cerebral blood flow, CPP, and 
metabolic rate of oxygen consumption 1 h following treatment. ICP was also reduced 
to preinjury levels by DMSO.230100
50
0
11 03 0* p<0.05mm Hg
MinutesUntreate d
DMSO
Hours12 46**
*
FIGURE 8.7  Mean arterial pressure plunged 1 h after injury in untreated controls (dark 
circles) but remained stable following DMSO (triangles) treatment beginning 1 h after treat -
ment. (Adapted from Brown, F.D. et al., Ann. NY Acad. Sci., 411, 245, 1983.) 40
3020mL/100 g tissue/min10
11 03 0
Minutes*p<0.05Untreate d
DMSO
Hours12 46
FIGURE 8.8  Cerebral blood flow dropped to more than 50% after injury and rose after 1 h 
following DMSO (triangles) as compared to untreated controls (dark circles). (Adapted from 
Brown, F.D. et al., Ann. NY Acad. Sci., 411, 245, 1983. )175 DMSO in Basic Neuroprotection
Cerebral blood flow rose markedly after DMSO ( Figure 8 .8), and this rise par -
alleled those seen for the cerebral metabolic rate of oxygen ( Figure 8 .9) and CPP 
(Figure 8 .10) as compared to significant decreases in untreated animals.230
CPP is the difference between the mean arterial pressure and the ICP and repre -
sents the vascular pressure gradient across the cerebral beds.
Dimethyl_Sulfoxide_(DMSO)_in_Trauma_and_Disease_[2015].txt
Summarize the following text section accurately and concisely. Maintain specific details and numerical information, and use anti-repetition mechanisms:

        140
CONCUSSIONS
Concussions are a type of mild traumatic brain injury (MTBI) that occurs when the brain is jarred or shaken and are most commonly seen in sports-related brain injury. Sports-related concussion has been described as an epidemic  by the Centers for 
Disease Control and Prevention. Visits to the emergency department for concussions have increased 62% between 2001 and 2009, and it is estimated that up to 250,000 concussions occur each year from high school sports alone. 141 Given the millions of 
young persons involved in high school, collegiate, and older professional players par -
ticipating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from combat-related injuries, concus -
sions have become an important public health concern requiring public education and immediate clinical attention to find an effective treatment. Concussions are the result of biomechanical forces that result in rapid accelera -
tion and decelerations of the brain often involving helmet-to-helmet contact, leading to functional impairments even in the absence of overt structural damage. 142 Football 
is not the only sport that produces concussions; every contact sport such as hockey, 155 DMSO in Basic Neuroprotection
soccer, boxing, and rugby also contributes to this epidemic. 143 Concussions can also 
result from the head striking a hard object, as it often occurs in falls, creating a more 
severe acceleration–deceleration of the brain than those seen after football helmet-to-helmet contact ( Figure 8. 4). Concussions have been defined as a temporary impairment of neurological func -
tion that heals by itself over time, and unlike severe, closed head injury, neuroimaging normally shows no gross structural changes to the brain as a result of the trauma. 144
Loss of consciousness is a clinical hallmark of concussion but is not required 
to make the diagnosis. Symptoms include confusion, disorientation, unsteadiness, dizziness, headache, and visual disturbances. 145 These postconcussive deficits occur 
with minimal detectable anatomic pathology and often resolve completely over time, suggesting that they are based on temporary neuronal dysfunction rather than cell death as seen in severe head injury. 146 Neuronal dysfunction can occur due to cere -
bral hypoperfusion, ionic shifts, altered metabolism, impaired synaptic connectivity, or changes in neurotransmission, such as diffuse axonal injury. 147
Repeated concussions, even mild blows to the head from contact sports, can cause 
cumulative pathology on the brain. Successive concussions can have devastating consequences, including progressive decline of memory and cognition, depression, suicidal behavior, poor impulse control, aggressiveness, and, eventually, dementia. 148
The metabolic cascade following this type of injury has been studied extensively 
in animal models as well as humans. 149,150 This metabolic cascade immediately after 
biomechanical injury to the brain consists of a sudden release of neurotransmitters involving excitatory transmitters, such as glutamate binding to the NMDA recep -
tor, which leads to further neuronal depolarization with the efflux of potassium and 
influx of calcium into brain cells. 149 These ionic shifts lead to acute and subacute 
changes in cellular physiology, diminished cerebral perfusion, and brain cell energy 
crisis, making the brain less able to respond adequately to a second injury and poten -
tially leading to longer-lasting deficits. 151The head strikes a
hard obje ct cr eating
a concussion -type
injury
FIGURE 8. 4  Rapid acceleration–deceleration of the brain created by the head striking a 
moving or fixed object. 156 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Unfortunately, studies targeting the metabolic cascade have failed to produce a 
viable treatment option given the rapid onset and the shortness of time in reach -
ing a concussed patient in time to stop this cascade from progressing. One option, 
however, is to keep a rapidly acting, safe, and effective agent such as DMSO near the sports facility where games are played and have someone present when players come in contact with each other that can administer DMSO intravenously if it is determined that intervention must be applied. Some studies have shown that cerebral blood flow decreases immediately follow -
ing a concussion, and the amount of time cerebral perfusion remains lowered and seems to depend on the severity of the injury. 152,153
Due to their lack of structural damage, concussion is also referred to as MTBI. More commonly, athletes present with a brief alteration of consciousness, headache, and amnesia and require careful examination and observation before returning to competition. The diagnosis of MTBI is based on subjective findings and subtle changes in mental status. The diagnosis of concussion is largely based on the clinical examination, yet 
certain imaging studies can be considered, such as computed tomography or mag -
netic resonance imaging (MRI), especially if an intracranial bleed is suspected. MTBI requiring urgent neurosurgical attention should be ruled out. 154 Computerized 
tomography and MRI are usually without significant findings in MTBI. Functional magnetic resonance images and positron emission tomographic scans have been used in concussion research but serve no role in the clinical management of concussion. 155
Neuropsychological testing is also very sensitive in the evaluation of brain injuries 
in athletes and may become more clinically useful in the future. Neuropsychological testing may demonstrate areas of deficiencies; however, results may be difficult to interpret because of confounding factors. 156
Complications following MTBI such as second impact syndrome have been 
known to occur, and when this happens, a rapid and effective treatment to counteract the pathologic cascade that follows may be life-saving. The search for an effective and safe concussion treatment when prevention does 
not work is higher now than ever before. A better understanding of the detrimental molecular and cellular effects caused by a concussion is the key to finding a safe, rapid, and effective treatment. Treatment strategies focused on managing the neuroinflammatory responses 
to concussion may prove to be a tangible target since it is hypothesized that these delayed secondary effects may be the primary source of long-term neural damage. There are promising data to suggest that manipulating neuroinflammation can be used as treatment strategies to manage the long-term deficits produced by a concus -
sive injury. 151
However, the use of general anti-inflammatory drugs such as nonsteroidal anti-
inflammatory drugs (NSAIDs) will not serve as a magic bullet  for this type of injury. Rather, it seems that a tailored drug that targets the inflammatory and metabolic 
cascade that follow a concussion when given at particular temporal intervals will 
likely be useful in treating the complexity of the inflammatory response to concus -
sion. DMSO, an efficient anti-inflammatory agent, may become a treatment of choice as we review its properties as a neuroprotective agent. 157 DMSO in Basic Neuroprotection
DMSO IN BRAIN CONCUSSION
DMSO may be an ideal agent to treat the metabolic cascade that often follows the 
rapid acceleration and decelerations of brain concussions. 155,157
Glutamate is an amino acid in the brain that functions as the principal excit -
atory neuronal neurotransmitter. During excitatory neurotransmission in the healthy CNS, glutamate is briefly released at a high concentration into the extra -
cellular space where normal physiological levels are maintained by reuptake of glutamate through neuronal or glial glutamate transporters. When excessive extracellular glutamate accumulates in the synaptic space after brain traumatic injury, it causes a significant increase in Ca
2+ influx into neurons, thereby trig -
gering neuronal excitotoxicity. Traumatic injury to neurons can produce disas -
trous results when the excessive release of intracellular glutamate concentrations overload the synaptic space. Moreover, many glutamate-induced CNS neurode -
generative disorders, such as epilepsy, amyotrophic lateral sclerosis, brain isch -
emia, and traumatic brain injury, are reported to associate with the dysfunction of glutamate excitotoxicity. 158
When primary hippocampal cell cultures exposed to toxic levels of glutamate 
were given DMSO at clinical doses, DMSO was shown to suppress, in a rapidly reversible manner, excessive calcium influx into cells and channel opening of the ionotropic receptor channels NMDA and AMPA, which are known to be activated by glutamate during brain trauma due to the development of oxidative or metabolic stress. 54
Moreover, this excitotoxic  process by glutamate, which can damage or kill neu-
rons, was reported to be blocked by DMSO. 54
The treatment of brain edema after MTBI presents a challenge for many clini -
cians. Considerable animal and human studies indicate that DMSO can quickly lower edema and ICP following severe traumatic brain injury (TBI). 41,43–45,61,159 
These findings suggest that DMSO at lower doses than those used for severe, closed head injury may be beneficial to mild brain trauma. This concussion is supported by the pharmacological properties of DMSO, including its antiedema property, its potent diuretic action, its anti-inflammatory properties, and its increase of cere -
bral perfusion. 160 Moreover, its blocking effect of excessive glutamate, sodium, and 
calcium entry into cells and efflux of potassium ( Figure 8. 3) that can induce cyto -
toxicity demonstrates that it can therapeutically target the biochemical cascade described in animal and human brain following MTBI (concussions) or severe TBI. 50,51,54
DMSO COMBINED WITH A GLYCOLYTIC INTERMEDIATE
Because brain injury can lead to an impairment of mitochondrial oxidative phos -
phorylation with the loss of ATP as well as to the formation of cytotoxic free radicals, 
de la Torre and his group161 reasoned that combining DMSO with an intermediate 
of anaerobic glycolytic metabolism, fructose-1,6-diphosphate (FDP), might be more 
useful than either drug alone in preventing the neuronal and energy compromise associated with severe, concussive head injury in a mouse model. 161158 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
FDP is an intermediate of anaerobic glycolytic metabolism and has been shown to 
restore the activity of the Embden–Meyerhof pathway and oxidative phosphorylation 
when administered during prolonged hypoperfusion states. 162 FDP can also inhibit 
oxygen-free radicals, stimulate anaerobic glycolysis, and increase the production of ATP, the main energy fuel of cells and neurons. 163 It is this activity by FDP that may 
limit injury to the brain following ischemic-hypoxia. 163
The combination of DMSO + FDP to treat experimental brain trauma in mice thus 
seemed a reasonable option to prevent or restore loss of ATP in ischemic brain cells while simultaneously reducing progressive cerebral edema caused by the injury. 161 
Consequently, it was believed that FDP would act primarily to protect ischemic brain tissue from energy substrate depletion, a common outcome after brain trauma, while DMSO would act to stabilize cell membranes from excess free radical formation and abnormal Ca
+ entry into cells while reducing ICP by improving CBF. 160
Both FDP and DMSO have each been reported to be useful when administered in 
head injury42,45,61,163 or cerebral ischemia in animals or humans. 159,163,164 FDP has been 
shown to prevent the ischemic-induced loss of ATP and accumulation of intracellu -
lar Ca2+ in experimental animals, possibly by stimulating glycolysis while inhibiting 
gluconeogenesis. 164 The administration of FDP during brain ischemia would seem to 
be particularly useful, since it readily crosses the blood–brain barrier (arias) and can yield twice as many moles of ATP as glucose. 164
In an experiment to test the synergic potential of DMSO-FDP, male CD-1 mice 
weighing 22–29 g were restrained and their heads were positioned under a head injury apparatus with their chins resting firmly on a flat surface at the base of the apparatus. 161 The apparatus consisted of a 25 cm long glass shaft held vertically by 
clamps on a ring stand and a tubular lead cylinder weighing 40 g. The lead cylin -
der was allowed to drop 20 cm through the shaft onto the center of the head, thus creating an 800 g/cm force injury on the cranium. An imaginary line was drawn coronally just anterior to the ears in order to create a consistent injury site on the animal’s head. This head injury mouse model has been previously used to screen the effectiveness of potential pharmacological agents after brain trauma. 165 FDP was 
given at 350 mg/kg in a 10% solution, and DMSO was administered at 1 gm/kg in a 28% solution both intravenously via the tail vein. All mice were pretested on the string prior to head injury, and all were able to 
grasp the string for a 90 s trial period and to travel with ease from the center of the string to one of the end posts holding the string. The extent of motor deficits reflected by the reduced ability of mice to remain gripping the string after head injury has been shown to be inversely proportional to the increased severity of the head injury. 166
Following head injury, testing showed 11 of 12 mice treated with DMSO + FDP 
retained sensory function as compared with 5 of 12 mice given vehicle nontreatment, 8 of 12 treated with DMSO only, and 7 of 12 treated with FDP. 161 The combination 
of DMSO + FDP significantly protected mice from motor deficits after injury, as 
indicated by an increased mean grip test score (76. 3 s) shown by this group 1 h after 
head injury when compared with vehicle nontreated (5. 8 s), FDP-treated (20. 8 s), and DMSO-treated (19. 6 s) animals. The pattern of protection continued for at least 2 h after head injury, with all groups showing some improvement over the previous grip 159 DMSO in Basic Neuroprotection
test taken 1 h after head injury. However, the only significant protection after 2 h was 
observed in the group treated with DMSO + FDP. Two hours after head injury, the group treated with FDP + DMSO had a mean grip test score of 86. 5 s, which was significantly better than from the DMSO only (33. 8 s), FDP only (24. 3 s), and vehicle nontreated groups (12. 2 s). 161
This study was the first to demonstrate that the combined DMSO + FDP given to 
mice that have been subjected to a moderate 800 g/cm concussion head injury can significantly modify the sensory-motor deficits, incidence of mortality, and histopa-thology. DMSO + FDP appeared superior in reducing the trauma-induced neurologi -
cal deficits and fatal outcome to either agent administered alone. Besides the improved sensory-motor function of mice treated with DMSO + FDP, 
a possible fringe benefit to the head-injured brain where inadequate cerebral perfu -
sion is expected may be the ability of these two agents to allow RBCs to maintain their deformability. Under normal conditions, RBCs with a 7–8  µm diameter can 
squeeze through capillaries that are 3–5  µm wide so that oxygen can be delivered to 
the tissues. The RBCs’ viscoelastic properties or deformability is possible because of a spectrin–actin interaction within the erythrocyte, which is dependent on its stored ATP and 2,3-diphosphoglycerate. 167
If 2,3-diphosphoglycerate or ATP stores are reduced by ischemia-hypoxia 
(Heckler/Marcel), it is probable that RBCs will increase their rigidity and thus be unable to adequately perfuse the cerebral microvasculature. This consequence would prevent optimal oxygen delivery to neurons and glial cells, which rely on oxy -
gen for the elaboration of ATP and for their basic cellular metabolism. Infusion of FDP raises the concentration of 2,3-diphosphoglycerate,
168 allowing RBCs to deform 
normally and consequently facilitating oxygen disassociation from hemoglobin169,170 
during ischemia-hypoxia. Conversely, DMSO is reported to promote the formation of ATP from ADP
171 and to preserve mitochondrial oxidative phosphorylation, thus 
ensuring ATP production after experimental brain ischemia172 This activity could 
additionally favor RBC deformability during tissue ischemic-hypoxia, a process that would improve cerebral perfusion. Another advantage of adding FDP to DMSO is that FDP has been shown to be 
effective in preventing ischemic injury to the brain
173,174 ostensibly by inhibiting exci -
totoxic release of glutamate during brain ischemia and preventing ATP loss by sub -
stantially increasing the flux of glucose into the pentose-phosphate pathway. Indirect evidence has also demonstrated that FDP can modulate cerebrovascular tone, myo -
cardial contractility, platelet aggregation, and blood pressure,
175,176 systems that can 
exacerbate damage following severe head injury. The exact mechanism for the synergic activity demonstrated by the DMSO + FDP 
combination has not yet been determined, but it may be assumed to lie in the abil -
ity of each agent to address different but critical metabolic abnormalities associated with the pathogenesis of severe head injury, for example, ATP loss leading to neu -
ronal energy deficiency, metabolic acidosis, abnormal Ca
2+ entry into cells, platelet 
aggregation, inflammatory response, cerebrovascular constriction, glutamate toxic -
ity, ICP increase, and free radical formation. This drug combination is reviewed in terms of its effect on experimental and clinical ischemic strokes in this chapter and Chapter 9. 160 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
DMSO IN EXPERIMENTAL BRAIN ISCHEMIA
Stroke is the most fatal neurological disease and the leading cause of long-term dis -
ability in the United States. Stroke is divided into two major types, ischemic stroke, 
where an artery is blocked by a blood clot, and hemorrhagic stroke, where a brain vessel bleeds from a leak or a rupture. About 80% of strokes involve blockage of a major cerebral artery, and this is where most of the animal research in brain isch -
emia is presently focused. 177 A considerable amount in our current understanding of 
cerebral ischemia induced by stroke comes from animal models representing global and focal ischemia. Global ischemia is the product of mild-to-severe reduction of cerebral blood 
flow throughout the brain, which can occur either acutely or chronically. If blood flow  cannot be restored within a given time limit (depending on the cause), 
 permanent damage to the brain or death can result. When blood flow is restored 
after global ischemia, reperfusion injury can occur if the brain is not pharmaco -
logically protected. Many diseases can cause chronic global brain ischemia such as atherosclerosis of a conducting brain artery, diabetes, sickle cell anemia, cardiac arrhythmias, and congenital heart defects, while acute global ischemia can result from a heart attack. 178
Focal brain ischemia is less severe than global ischemia but more common 
both clinically and using experimental animal models. Focal ischemia reduces blood supply to a specific region of the brain where immediate or delayed neuro -
nal death can occur. 178 This area of injury is called the core ischemic zone and is 
marked by severe ischemia with blood flow falling 75%–90% of baseline in con -
junction with the loss of oxygen and glucose, leading to rapid depletion energy stores. 178 Severe focal ischemia can result in brain cell death from the necrosis of 
neurons within the ischemic core, but glial cells may be spared if blood flow is restored early. 179
Surrounding the ischemic core is an area called the penumbra where brain cells 
are kept structurally intact by collateral blood vessels but functionally impaired. 180
The ischemic penumbra is a zone where pharmacological therapy could most 
likely be effective in restoring the loss of function. 181 The ischemic penumbra blood 
perfusion is generally too low to maintain electric activity but sufficient to preserve ion channels and structural integrity. 180
Research using animal models of stroke have provided not only an understand -
ing of the pathomechanisms underlying injury after ischemic stroke but also a way to develop effective therapy to prevent and arrest the severe pathology associated with stroke. Although many models of stroke have been used for research, includ-ing nonhuman primates, rodents are more often used due to their lower cost, ease of handling, substantial characterization of pathological expectations from previous research, and potential for genetic engineering. Experimental focal ischemia has generally involved occlusion of the MCA that is 
the largest branch of the internal carotid artery (ICA) that supplies a portion of the anterolateral frontal lobe, most of the temporal lobe, and the parietal lobe. Occlusion of the MCA in animals can result in sensory-motor deficits and cognitive impairment 161 DMSO in Basic Neuroprotection
that can be monitored, quantitated, and analyzed by a variety of research tools when 
drug evaluation is done. In the context of cerebral arterial thrombosis, the effects of thrombotic stroke can 
be induced experimentally by cautery or by photothrombosis of the MCA, which differs from those due to cerebral ischemia induced by mechanical ligation or intra -
luminal occlusions of intracranial brain arteries
182 (Figure 8. 5). There are two commonly used surgical approaches to provide direct access to 
the arterial circulation of rodents. The first approach is to perform a craniotomy that allows access to distal branches of the ICA, such as the much used MCA, to be occluded either with a neurofilament or by cautery
183,184 (Figure 8.
A type of mild traumatic brain injury (MTBI) that occurs when the brain is jarred or shaken, often resulting in functional impairments.
What is a concussion?
Up to 250,000
What is the estimated number of concussions that occur each year in high school sports alone?
The blockage of a major cerebral artery, which can lead to a lack of oxygen and glucose delivery to the brain.
What is the primary cause of stroke, according to the text?
To provide a more accurate model for human stroke research, as they have a brain structure similar to humans and can be used to test the effectiveness of potential treatments.
What is the significance of using nonhuman primates in stroke research?
The potential for a subtle balance between cerebral blood flow and oxygenation, which is crucial for maintaining cell viability and preventing further damage.
What is the primary concern when using DMSO in the treatment of stroke or traumatic brain injury?