Although intravenous urea still remains one of the most reliable drugs to combat 
acute brain swelling, another osmotic agent, mannitol, has shown fewer complications 135 DMSO in Basic Neuroprotection
in treating head injuries, but its action is half as short as that of urea (about 4 h), plus, 
it does not improve brain tissue pO2 in severe head trauma and its effect is not as 
dramatic when brain edema is severe.16
A fundamental guide to emergency department management of head injuries at 
the present time is ensuring adequate CPP, adequate oxygenation, and preventing even brief or transient episodes of hypotension, hypoxia, seizures, hyperglycemia, and hypocapnia. 17 CPP is a function of ICP and systemic blood pressure, and it must 
be monitored and controlled at all times to prevent further structural and functional damager. 18
When severe brain tissue trauma occurs, brain cells respond in a typical manner. The anatomic changes in neurons following trauma have been well studied and con -
sist of cytoplasmic swelling secondary to sodium influx and a failure of membrane ionic regulation. 19 This is followed by characteristic cytoplasmic eosinophilia, severe 
loss of the endoplasmic reticulum and Golgi apparatus, chromatin clumping, nuclear shrinking with peripheral shifting, and disappearance of axonal microtubules, a phe -
nomenon that generates synaptic dystrophy and neurotransmission failure. 20
Depending on its location and severity, a focal traumatic insult to the brain will 
destabilize ischemic neurons by inducing hypoxia, glutamate excitotoxicity, a mas -
sive and disruptive intracellular rise of Ca2+, mitochondrial energy loss, formation 
of oxygen and nitric oxide free radicals, and impairment of adenosine triphosphate (ATP) synthesis that fuel all brain cells. 21 The biochemical cascade associated with 
anatomic changes in ischemic neurons and glial cells is the product of irreversible oxygen–glucose deprivation resulting from the severe ischemia that leads inevitably to ATP production failure and a neurometabolic energy crisis in adjacent hypoper -
fused neurons. 22
The reduced mortality and improved outcome for patients with severe traumatic 
brain injury in the past decade has been attributed to the partial but incomplete success of trying to squeeze oxygenated blood through a swollen brain. This plan requires quantification of cerebral perfusion by monitoring the ICP and by prompt treatment of cerebral hypoperfusion to lower the incidence of secondary injury. Although this plan can mean the difference between good survival and incapacitat -
ing, long-lasting neurological deficits or death, it is not generally possible to achieve due to the absence of an agent that can address cerebral hypoperfusion, brain edema, excitotoxic release of glutamate and cytokines, ionic cell shifts involving sodium and calcium channels, and free radical formation. Is there an agent that can address the pathologic cascade results from severe brain trauma and clinical success and improved outcome? SECONDARY INJURY AND ISCHEMIC PENUMBRAL NEURONS
Because traumatic brain injury results in irreversible damage at the site of impact and initiates cellular and molecular processes that lead to secondary neural injury 
in the surrounding tissue, understanding the pathophysiology of secondary injury is 
critical to the development of effective therapy. Adding to the cell and molecular damage that results at the site of trauma, sec -
ondary injury to the surrounding brain tissue also undergoes electrophysiological 136 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
changes without the anatomic necrotic changes to neurons described earlier. The  s econdary injury primarily involves reduced cerebral perfusion, inflammatory 
changes, lowered cerebral energy metabolism, release of excitatory neurotransmit -
ters, and oxidative stress.23,24 These cell and molecular abnormalities not only add to 
the site of injury but can give rise to an area of the brain adjacent to the injury core 
where a ring of ischemic penumbral neurons can accumulate. In his classic paper describing the ischemic penumbra, Astrup and his colleagues25 
recognized two stages where penumbral neurons can experience functional impair -
ment and irreparable degenerative damage, usually with the former stage preceding the latter. However, irreparable damage to penumbral neurons is not always the case, and 
it is clear that at least in embolic stroke, these neurons are salvageable with the proper treatment, for example, using intra-arterial thrombolytics such as the tissue plasminogen activators (tPAs). These clot busters are able to accelerate the conver -
sion of plasminogen to plasmin, the major enzyme that catalyzes clot breakdown. However, one of the disadvantages of tPA therapy is that it must be administered as quickly as possible after an embolic stroke, usually within 4½ h after the onset of symptoms. 26
This brief window of opportunity means that only 3% of persons qualify for treat -
ment with tPAs since most patients wait beyond this time period to seek medical help after the onset of stroke symptoms. Another serious disadvantage of tPAs is the risk of hemorrhage in the brain, worsening the primary damage from stroke. Due to the bleeding risk, tPA has not been assessed in any traumatic brain injury 
trial that we are aware of, but other agents have been used to address the disturbances in platelet function, leading to hyperaggregability following a head injury. 27
Neurons in the ischemic penumbra are formed as a result of critically subnor -
mal brain perfusion following a stroke or local brain trauma.28 These penumbral 
neurons retain their structural integrity but lose their ability to function normally.29 
The penumbral region is therefore a functionally silent population of neurons. The physiological outcome of penumbral neurons is dependent on the degree and dura -
tion of ischemia. 30 It has been reported that an ischemic penumbra results when local 
cerebral blood flow dips between 12 and 18 mL/100 g tissue/min following brain trauma. 31 Below 12 mL/100 g tissue/min, the tissue becomes irreparably damaged 
and soon dies.31
The penumbral neurons are more likely to die if normal cerebral perfusion is 
not quickly restored. However, the grace time before penumbral neurons die from a reduced blood flow supply is variable and dependent on the type of injury involved, severity, region of the brain affected, and many other constants. Penumbral neu -
rons have been reported to remain viable for hours, days, months, or even beyond a year. 32–34 During traumatic brain injury, astrocytes become reactive and increase 
proinflammatory cytokines to produce excitotoxicity through the excessive pro -
duction of extracellular glutamate. This results in brain edema and swelling, a 
 condition that promotes neuronal death from the activation of reactive oxygen 
 species (ROS). In addition, the activation of Janus kinase and signal transducer and activator of 
transcription signaling pathway is one of the most important transducing signals 137 DMSO in Basic Neuroprotection
from the cell surface to the nucleus in response to cytokines, particularly the 
 proinflammatory interleukin-6 cytokine family.36 The Janus kinase and signal trans -
ducer and activator of transcription signaling pathway is the focus of much research 
at the present time due to studies that report its involvement in the pathophysiology of brain ischemia, brain trauma, and spinal cord injury (SCI). 37,38
It is clear that when primary traumatic brain injury cannot be prevented, secondary 
injuries must be restricted with appropriate neuroprotective strategies. Nevertheless, present drug treatments are not generally able to do that consistently or effectively. 39
The ability of pharmacotherapy to rescue salvageable neurons following brain 
trauma and arrest or reverse the quantitative damage that results from such injuries remains elusive and extremely limited. A recent Cochrane Database of Systematic Reviews and Cochrane Injury Group 
conducted an exhaustive literature search analyzing drug therapeutic studies dealing with severe head injury. The search concluded that the majority of these clinical tri -
als included only a modest number of patients largely due to the uncertainty of the trial drug effectiveness. 40 Not surprisingly, the quality of these clinical trials was 
regarded as more or less questionable.40
For this reason, there is an expectation that the effects of dimethyl sulfoxide 
(DMSO) used to treat brain trauma, stroke, Alzheimer’s disease (AD), and SCI will receive the clinical attention it deserves. When brain trauma, stroke, AD, and SCI are combined, it represents a block of disorders that affect 8% of adult Americans and more than 15 million individuals in the United States alone. The findings reviewed here will reveal a very unusual molecule possessing a num-
ber of biological actions that may explain its positive therapeutic effects following traumatic brain injury and other CNS insults. DMSO IN EXPERIMENTAL BRAIN TRAUMA
The mechanism of action(s) exerted by DMSO in improving the outcome of trau -
matic brain injury remains unknown. However, DMSO is reported to display a range of properties, which may be useful in the management of the brain trauma patient or animal. For example, DMSO increases cerebral blood flow without altering blood pressure,
41,42 quickly reduces ICP without a rebound effect,43–46 is a potent diuretic 
that does not affect cardiac rate or output,41,42 reduces cerebral edema,47,49 blocks 
sodium channel activation,50,51 is a powerful free radical scavenger,52,53 prevents glu -
tamate excitotoxic neuron death,54 lowers the Janus kinase and signal transducer 
and activator of transcription signaling pathway whose activation can be induced by excitotoxic cytokines following brain ischemia,
55 and suppresses NMDA-
AMPA-induced (NMDA, N-methyl- d-aspartate; AMPA, alpha-amino-3-hydroxy-5-  
methylisoxazole-4-propionate) ion currents and excessive calcium influx known to damage and kill neurons. 54,56 Additionally, DMSO has a protective and stabilizing 
effect on cell membranes57–59 and inhibits inflammation, a reaction that is generally 
associated with moderate-to-severe brain trauma.60–62
The biological actions listed earlier for DMSO are relevant to our review of the 
cellular–molecular events associated with CNS injuries, including traumatic brain injury, stroke, or neurodegenerative conditions since these events generally involve 138 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
sodium channel activation, free radical formation, and glutamate excitotoxic signal -
ing involving NMDA-AMPA-induced ion channels and calcium signaling in cell-
death pathways.50,51,54,61 These cellular–molecular actions modified by DMSO will 
be discussed in detail in this section of this chapter and in Chapter 9. Chapter 9 will detail how the basic research of DMSO in cerebral injuries has been successfully applied to humans sustaining a variety of insults to the brain. It is important to point out that the cellular and subcellular biological actions of 
DMSO with the exception of lowering brain edema after trauma are not known to be associated with mannitol, a drug commonly used for the treatment of head injuries. This may be one of the reasons why DMSO treatment has been shown to be more efficacious and safer than mannitol when used in patients with severe, closed head injury. 44,45
The initial studies with DMSO were first carried out in the early 1970s in the 
Division of Neurosurgery at the University of Chicago by a team of investigators led by Jack de la Torre. How DMSO was chosen to be tested against an animal model of head injury among dozens of other potentially worthwhile compounds is worth men-tioning. At that time, about a dozen head injury centers existed in the United States funded by National Institutes of Health (NIH) and most of these centers were des -
perately seeking new agents to address the rising incidence of head trauma. These head injuries occurred from falls, especially in children and the elderly. Automobile accidents were also high on the list of head injury causes. Since seat belts were not in common use in the early 1970s, about 50,000 deaths 
per year were recorded from acceleration–deceleration brain damage sustained mainly from falls and car crashes. Most of these deaths occurred from complications that followed injury to the brain, generally within several days following hospital admissions. The frustration from personnel working in the emergency room after admitting a severe head-injured patient, whether the patient was a child or an adult, was the inconsistent nature of the treatments available at the time, which sometimes worked, but more often did not. At the research meeting held every other week in the Division of Neurosurgery 
at the University of Chicago in 1971, DMSO was proposed by a member of the fac -
ulty, Jack de la Torre, as a possible agent to test in experimental animals with severe head injury. When asked by Sean Mullan, the chief of neurosurgery, for the reasons behind this proposal, de la Torre pointed out DMSO’s unique properties as a power -
ful diuretic, anti-inflammatory, and cell membrane protector from freezing dam -
age, properties, he argued, that could potentially counteract cerebral edema buildup resulting from increased ICP. The research project was approved, and the first series of experiments involving traumatic brain injury in rhesus monkeys were scheduled soon after. A vivid account by Jack C. de la Torre described in a letter to a colleague what happened on the very first experiment following a single, acute intravenous dose of DMSO as the primary treatment for this devastating brain insult. I remember it was bitterly cold in Chicago that March morning of 1971. Tucked away 
on a corner of the second floor of Billings Hospital, my technician and I struggled with 
a myriad of cables, wires and electronic monitors set up to detect any changes in the brain-injured animal lying on the table. I was a newly appointed Assistant Professor 139 DMSO in Basic Neuroprotection
to the Division of Neurosurgery at the University of Chicago, the lowest professorial 
rank in academics. The academic trail for me would involve over 200 publications, six books and hundreds of international medical conferences where I would lecture about injuries to the brain and spinal cord. However, that March morning, only one thing was on my mind. Will the animal survive a severe brain trauma when given a new drug that had never been tested for that purpose? The odds were not good. We had already tested, as part of being one of seven Head Injury Centers in the U.S., dozens of worthless treatments reputed to benefit this usually lethal injury. And, we would keep on searching when…on that morning, “looky, looky, look at that…! !” my technician’s eyes rolled off the animal as I finished my intravenous administration of the drug. She pointed excitedly to the monitoring charts. The charts were going crazy, instead of cardiac collapse, respiratory arrest, a flat EEG and sure death, the heart rhythm stabi -
lized, breathing returned, at first in gigantic gasps, then in steady, normal, breathing pattern. The electroencephalogram, monitoring brain cell activity, returned in full force and blood flow to the brain, which had ceased in the final stages of the injury, began flowing again and reviving the almost dead brain. It was, as if the hand of God had 
somehow touched the animal’s forehead. ‘I don’t believe it’, I   stammered. But it w as 
true. I felt a tingling in my spine because this reawakening of a virtually dead animal had all the markings of a medical breakthrough. The drug was dimethyl sulfoxide or DMSO for short, used years earlier as a pain lotion and anti-inflammatory agent. What we would discover and publish about dimethyl sulfoxide in the next 8 years at the University of Chicago laboratories, would be pharmacological actions of a simple molecule that should have sent shock waves through the field of medical therapeutics as one of the most important drug discoveries of the century in treating devastating brain and spinal cord trauma. Instead, the discovery, the potential for saving lives and the continued research that should have uncovered other uses for dimethyl sulfoxide and similar agents was quietly laid to rest in the coffers of forgotten medicine. It was a baffling paradox that defied a reasonable explanation and to this day still remains unclear to me. The model to simulate acute head injury in rhesus monkeys employed in some head injury centers’ research laboratories consisted of an intracranial balloon inserted extradurally via a cranial burr hole near the temporoparietal region to produce pro -
gressive brain compression and increased ICP. This injury simulated and provoked an expanding extradural hematoma, common in acceleration–deceleration injuries from motor vehicle accidents. This type of slowly evolving compression injury is also commonly seen in falls, aggression, and sports-related injuries. Once in place in the extradural space, the balloon was slowly expanded with 0.2 mL water incre -
ments until respiratory arrest was reached. One hour after each treatment, the bal -
loon was decompressed. 63 We were later to discover that no other agent tested for 
head injury in our laboratories, including steroids and hypertonic agents, had the dramatic effects seen with DMSO. In the initial experiments by de la Torre,
63 40 monkeys were divided into three 
groups ( Table 8 .1). Group 1 received 1 g/kg urea; Group 2, 2 g/kg of a 50% solution 
of DMSO; and Group 3, physiological saline at the same volume as the experimental 
treatments. All drugs were given intravenously at the rate of 8 mL/min. The results 
using DMSO or urea on brain swelling secondary to an expanding extradural lesion in monkeys showed that 10 of 15 urea-treated monkeys survived (33% mortality) and 140 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
the examination of these animals after 24 h showed 4 survivors sustained right-side 
paresis, uneven pupil size (anisocoria), and general lethargy.63
Of the DMSO-treated monkeys, 14 survived (7% mortality) and 1 survivor showed 
mild right-side paresis only. In the monkeys treated with physiological saline, 9 of 10 animals died (90% mortality) within an hour after injury, a lone survivor showed severe neurological deficits and died the following day. 63 Respiration, systemic arte -
rial pressure, carotid blood flow, ICP, and electroencephalography (EEG) were sig -
nificantly modified during the endpoint of brain compression but returned to baseline in the surviving monkeys that were free of deficits upon recovery. On the average, cortical blood flow as seen through a pial window installed in 
every animal prior to injury returned to normal 23 min after treatment with DMSO and 45 min after treatment with urea. Copious volumes of urine were excreted from all monkeys within an hour after the administration of DMSO and considerably less after urea treatment. 63,64
All neurological deficits seen in the monkeys treated with either urea or DMSO 
were temporary, and recovery was observed from 1 to 5 weeks after the experimen -
tal head injury.63,64 This remarkable study in nonhuman primates indicated that a 
promising new agent, DMSO, was significantly more effective than urea, the clinical drug of choice at the time and used even presently for severe, closed head injury
63,64 
(Table 8 .1). As we will review here and in Chapter 9, further studies confirmed and 
extended these observations that a safe and highly effective agent called DMSO had been found that could manage severe trauma to the brain. As will be seen and fully discussed in Chapter 9, the results obtained with DMSO 
treatment of rhesus monkeys subjected to brain compression resulting in consequen-tial brain swelling were applied to humans sustaining severe closed head injuries in several pilot clinical trials. The findings from these trials clearly indicated that lives were spared and neurological deficits minimized in many patients treated with DMSO. Thus, the experimental brain trauma induced in the experimental rhesus monkeys was a price that paid off, considering the potential of saving millions of 
lives who have sustained a severe, closed head injury, using DMSO when it is finally 
approved by regulatory agencies. Handling and storing pure 100% DMSO for intravenous injections in animals 
allowed some useful recommendations to be made for future work. 64 One observation TABLE 8.1
Epidural Balloon Compression 
Treatment Number Survivors % Mortality
Saline (untreated) 10 0 100
Urea 15 10 33
DMSO 15 14 7
Notes:  Results of epidural balloon compression simulating epidural hematoma in rhesus monk eys. Mortality refers to 24 h survival following trauma. Neurological deficits were seen in 4 urea- and 
1 DMSO-treated animals. All other survivors recovered uneventfully over 2 weeks.141 DMSO in Basic Neuroprotection
related to the arterial catheters and needle hubs used during experiments. For exam -
ple, arterial catheters made of polycarbonate, polystyrene, styrene acrylonitrile, and 
polyvinyl chloride needed to be avoided because DMSO could partly dissolve or chemically leach these products. DMSO was found safe to use with conventional or linear polyethylene, polyvinyl chloride, polypropylene, and teflon catheter systems, and products using these plastics also included hubs in disposable needles. 64
One question that arose from these studies was the potential of DMSO to dissolve 
plastics. In the United States, most intravenous bags and tubing are made of polyvinyl chloride, which are safe to use with DMSO. The preliminary reports on DMSO published by the University of Chicago neu -
rosurgery team were sufficiently encouraging to try and extend those findings by targeting other CNS injuries, as we will review in the following text. These findings also stimulated other independent groups to examine DMSO’s potential in other types of brain injuries. When a drug is experimentally tested against a primary drug of choice for a 
clinical condition and is reported to be superior to the standard treatment, a flurry of extracurricular research studies by other investigators usually follows to verify or not the merits of the new drug. This flurry of research studies on DMSO by other investigators exploring possible brain injury treatments was soon to confirm the data reported by the University of Chicago investigators. First, a three-part study from the University of California, San Diego, was under -
taken to test DMSO in the control of lethal ICP and subsequent brain edema using a rabbit model. 42 All animals were monitored for EEG activity, ICP, central venous 
pressure, systemic arterial pressure, and water content in the brain. Animals had a circular area of the parietal cortex frozen for 90 s using a probe previously cooled in liquid nitrogen. This lesion created a consistent localized area of necrosis and hem -
orrhage at the surface and a few millimeters below the cortex. When animals were injected with Evans blue, the dye was observed to extravasate just beyond the lesion site only in the cryogenic lesion group, allowing the measurement of the dye spread following each treatemnt. 42 It was found that EEG activity after 1 g/kg of a 10% 
DMSO solution given 24 h after the cryogenic lesion was an improvement in volt -
age and the number of slow waves in five of six animals treated when compared to untreated lesioned animals. The ICP was significantly reduced 5 min after DMSO with no changes seen in the central venous pressure, which rose only in untreated lesioned animals. Brain water content was significantly reduced after DMSO in both hemispheres 
and was increased in the untreated cryogenic lesioned animals. This study concluded that after a cryogenic lesion, DMSO stabilized systemic arterial pressure, water con -
tent in the brain, and central venous pressure and reduced ICP while increasing cerebral perfusion when compared to untreated lesioned animals. 42
This cryogenic lesion study led to a second study by the San Diego group to 
further test DMSO’s ability to reduce toxic brain edema at variable doses that 
could be effective and still maintain electrolyte and fluid balance.43 The same rab -
bit model and cryogenic lesion was used, and the findings suggested that a 1 g/kg 
of a 10% DMSO solution given as an intravenous bolus was as effective in reducing ICP as a 1 g/kg of a 40% DMSO bolus, a dose that could create red cell hemolysis. 142 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
These authors found that while a 10% bolus of DMSO would avoid red cell hemo -
lysis, it would also increase central venous pressure and fluid overload. However, 
the authors determined that the central venous pressure increase and fluid overload side effects could be avoided when 2 g/kg of a 20% DMSO infusion was given continuously over 1 h. This approach seemed as effective as the 10% bolus injec -
tions. 65 Since the study was terminated 1 h following all treatments, it was hard 
to judge whether a bolus or slow infusion was preferable in a patient developing a rapid extradural hematoma following a closed head injury. The optimal dose of intravenous DMSO would become a controversial stumbling block in subsequent clinical and experimental studies examining how best to treat a brain injury. This impasse of DMSO given as an intravenous bolus or slow infusion at an opti -
mal concentration was finally solved, as we shall see in Chapter 9, in two clinical pilot trials performed by Turkish investigators treating severe closed head injury patients using DMSO. 44,45
The third study carried out by the San Diego researchers43a focused on extending 
the infusion time of DMSO from 1 to 3 h using the same cryogenic rabbit model of brain trauma used in the first and second studies. This experiment examined whether DMSO at a dose of 2 g/kg 20% infusion given 24 h after the cryogenic lesion would still lower ICP and reduce other side effects when given over 3 h rather than over 1 h as reported in the second study. The results indicated that DMSO infused over a 3 h period was able to signifi -
cantly lower ICP from 12.9 mm Hg before treatment to 7.3 torr after 45 min and to 4.2  mm torr after 3  h. Systemic arterial pressure and central venous pressure remained unchanged during and after DMSO infusion. 43a Brain electrolyte levels of 
sodium and potassium showed a reduction of both electrolytes in the lesioned and unlesioned contralateral hemispheres after DMSO, which was similar to untreated lesioned animals. The San Diego studies determined an optimal dose of DMSO at 2 g/kg in a 20% 
solution given over a 3 h period as a more optimal approach to lessen DMSO possible side effects such as volume overload, a rise of potassium brain levels, and red blood cell (RBC) hemolysis. 65 We now know that the optimal dose of DMSO in human 
patients sustaining a severe brain injury is 1 g/kg in a 28% solution mixed with 5% dextrose in water. 44,45
It should be noted that the gross hemolysis seen after a rapid bolus of high intra -
venous doses of DMSO has been shown to be a temporary side effect that does not involve organ damage, including the kidneys. 66 Hemolysis after high rapid doses 
of DMSO is a reaction that always disappears after the discontinuation of DMSO. This was demonstrated in a pathologic study monitoring blood chemistry, hema -
tology, urine, ocular, neurological, and cardiovascular systems in rhesus monkeys given repeated high doses of DMSO (3 g/kg 40%) for 9 days and followed up for 4  months. 65 At the end of the study, all animals underwent postmortem analyses, 
including gross and microscopic pathological examinations. No significant or long-
lasting changes were recorded in any of the parameters studied when these data were 
compared to those animals given normal physiological saline.66
The three-part study by the San Diego group also showed that DMSO could sig -
nificantly reduce ICP without affecting systemic pressure or central venous pressure 143 DMSO in Basic Neuroprotection
while lowering the brain water content in the lesioned hemisphere. These studies 
also suggested that a slow infusion of 2 g/kg of a 20% DMSO solution over a 3 h period was as effective in lowering ICP as 1 g/kg of a 40% DMSO bolus but without the gross hemolysis seen with the bolus. 42–44
Although this conclusion is probably valid for a cryogenic lesion to the cortex 
where local necrosis and hemorrhage develop immediately and remain a nonexpand -
ing lesion, it is not the case with a relatively slower-building epidural hematoma (also called extradural hematoma) that results from a severe blunt trauma to the skull and meninges. An extradural or epidural hematoma occurs when there is a rupture of a blood 
vessel, usually an artery, which then bleeds into the space between the dura mater and the inner wall of the skull. An epidural hematoma is generally an expanding mass that can reach its peak in 4–8 h and is capable of stripping the dura apart and threatening the formation of malignant brain edema as well as inducing secondary brain damage and death. This means that a brain trauma patient’s arrival at the emer -
gency department requires quick evaluation and if an expanding epidural hematoma is found, rapid surgical evacuation is mandatory. Drug treatment is generally con -
sidered when refractory high ICP is detected. 67,68 This implies that if brain edema is 
present, rapid intravenous infusion (fast drip or bolus) of an antiedema drug should be applied to control rising ICP and failing cerebral perfusion. 66
The cryogenic lesion model was again used by the San Diego researchers who 
compared the acute effect of DMSO and pentobarbital, an agent used to reduce ICP often by creating barbiturate coma, on the development of brain edema in rabbits. 69 
DMSO was given 1 mg/kg in a 10% solution by intravenous bolus, and pentobarbi -
tal 40 mg/kg was administered intravenously over a 30 min infusion. It was found that ICP was quickly lowered by both DMSO and pentobarbital with central venous pressure unchanged. Where the treatments differed was in the lowering of systemic arterial pressure by pentobarbital but not by DMSO, an outcome that likely produced a reduction in cerebral perfusion by the barbiturate. To find out the physiological basis for DMSO’s action in lowering ICP and reduc -
ing brain edema after a cryogenic brain lesion in rabbits, cerebral blood flow was measured before and after 2 g/kg/h DMSO 20% infusion for 2 h or 1 g/kg DMSO bolus preceded by a bolus of 20 mg indomethacin, a nonsteroidal anti-inflammatory agent and a nonselective prostaglandin (PG) synthase inhibitor. 65 The results sug -
gested that following the DMSO bolus injection in the absence of indomethacin, an immediate rise in cerebral blood flow was followed by a decrease 30 min later despite a constant lowering of ICP. These rise and paradoxical dip of cerebral blood flow were not observed when 
DMSO was given as a slow infusion where ICP was still lowered and cerebral blood flow rose consistently throughout the infusion. When indomethacin was given 15 min prior to DMSO infusion, cerebral blood flow failed to increase immediately until 60 min had passed, an action not observed when indomethacin was admin-
istered prior to a DMSO bolus. The authors concluded that the action of reducing 
ICP immediately after DMSO infusion may have been due to the ability of DMSO to extract brain water rapidly and lower brain pressure as a result. The decrease of cerebral blood flow induced for 60 min after a bolus of DMSO in animals receiving 144 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
indomethacin implies that ICP was quickly lowered and was not a factor in affecting 
cerebral blood flow levels.65
Another explanation may be that indomethacin’s inhibition of the cyclooxygenase 
pathway controlling the synthesis of PGs may temporarily block DMSO’s ability to stimulate vasodilating PGs such as E
1 or I2 in cerebral endothelium to increase 
cerebral blood flow.70–72
FREE RADICALS IN BRAIN INJURY
Free radicals are atoms that contain an unpaired electron in its outer orbit, making this atom highly reactive. This highly reactive process takes place by the free radical stealing an electron from a healthy molecule in order to become stable. Instead, the original free radical creates a new free radical, resulting in a chain reaction. Free radicals can be generated during the production of ATP in mitochondria. These free radicals can leak from the mitochondria to form ROS, including super -
oxide anion and hydroxyl radicals. Free radicals use a number of biological pathways to create cell damage. For example, free radicals attack the nitrogenous bases of cell DNA where damaging mutations can result and prevent oxidative phosphoryla -
tion from taking place, thus preventing the cell from making ATP to fuel its energy metabolism. Repair of cell damage in the presence of decreased energy production following mitochondrial dysfunction aggravates cell damage by promoting second -
ary damage. 73
Secondary injury following brain trauma in humans or animals is characterized 
by a host of pathophysiologic cascades that can additionally damage more brain mitochondria. These cascades include exposure of neurons to excitotoxic levels of excitatory neurotransmitters with intracellular calcium influx, of ROS, of production of peptides that participate in programmed cell death, and of glutamate generation, a primary mediator of mitochondrial dysfunction and delayed cell death. 74
Excessive free radical production can react with cell membranes, lipids, and 
nucleic acids in a site-specific fashion that can unbalance proteins in healthy cells and damage or kill these cells. 75
Although free radicals perform some beneficial functions within the immune sys-
tem, their excess production can cause deadly toxic oxidation or oxidative stress.76 
The brain is particularly vulnerable to oxidative stress following injury, and hence, much research has focused on how to arrest or reverse free radical damage after a traumatic or ischemic brain injury. The role of toxic free radicals in brain trauma has been the object of numerous 
studies in the past, and many therapies have been introduced to neutralize the pri -
mary and potentially secondary damages caused by these reactive molecules. However, therapeutic strategies to control secondary damage following brain 
trauma by focusing on blocking free radicals that generate oxidative products remain ineffective. 77
Nevertheless, studies carried out in preclinical models of traumatic brain injury 
using DMSO have provided information that free radicals appear to be intimately involved in producing devastating brain cell damage and that blocking their chain reaction can lead to preserving brain tissue from further damage.145 DMSO in Basic Neuroprotection
A study by Ikeda and his colleagues,78 from Johns Hopkins University, looked at 
the effects of DMSO and other hydroxyl radical scavengers such as dimethylthiourea 
and deferoxamine in cats. A standard cortical freezing method for the production of vasogenic brain edema was used. The authors found a reduction in brain edema that correlated with a reduction of hydroxyl radicals in animals treated with DMSO and deferoxamine. 78 These results could be partly explained by the scavenging proper -
ties of DMSO when chain-propagating radicals such as the superoxide anion are present. 79,80
Superoxide has been associated with the pathophysiology of many diseases 
including brain trauma, ischemic stroke, and inflammatory reactions. Superoxide can leak from brain mitochondria in response to these insults and convert to hydro -
gen peroxide, an important contributor to oxidative damage. 81
One study that supports the antioxidant-related damage caused by some mole -
cules that commonly develop after trauma showed DMSO’s antioxidant properties in rat brain homogenates were able to reduce both lipid peroxidation and protein oxida-tion induced by ferrous chloride/hydrogen peroxide. 82
The brain is a highly oxidative organ consuming 20% of the body’s oxygen even 
though it represents only 2% of the total body weight. For this reason, oxidative activity involving ischemia or hypoxia resulting from brain trauma or stroke can have devastating effects on brain function if left untreated or when treatment is delayed. 83
Oxidative stress from ROS has been associated with the onset of systemic inflam -
mation, and it is generally recognized that increased oxidative activity plays an impor -
tant role in pathological process of brain tissue damage.84 The presence of excessive 
free radical, ROS, and release of local inflammatory mediators, including cytokines, are a characteristic initiator of pathologic cascades following traumatic brain injury. 85,86
These inflammatory cytokines include inteleukin-6, nitric oxide, and tumor 
necrosis factor-alpha (TNF- α). They can lead to complications affecting immuno -
suppression and result in severe, systemic inflammation with multiorgan damage, causing death within days or weeks following brain trauma. 87 As discussed earlier 
(see also the section “Anti-Inflammatory” in Chapter 2), DMSO has been shown to significantly decrease the levels of nitric oxide, IL-6, and TNF- α in injured rats,
21,36,37 
as well as the oxidative stress marker malondialdehyde (see the section “Burns and Scar Tissue” in Chapter 2). NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a pro -
tein complex that controls the transcription of DNA and modulates a large number of normal cellular processes, such as immune and inflammatory responses. DMSO has been shown to suppress the effects of activation of NF- κB immunoreactivity, which 
is exerted by decreasing the production of TNF- α and inhibiting the transcription of 
critically important adhesion molecules. 88
Finding a neuroprotective agent that can reduce systemic inflammation, cytokine 
production, and free radicals after brain trauma is the task of numerous investigators that continues to this day. As seen in Figure 8 .1, DMSO appears to fulfill many of 
these requirements based on the research of this compound dating back to the early 1970s. This research will be reviewed in this section of this chapter beginning with a primary understanding of how cerebral blood flow behaves normally and after brain injury.146 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
CEREBRAL HEMODYNAMIC FUNCTION IN BRAIN INJURY
Traumatic brain injury is known to impair cerebral hemodynamic function. Understanding and correcting hemodynamic dysfunction has become an impor -
tant therapeutic target in arresting or reversing secondary damage resulting from brain trauma, ischemia, or neurodegeneration from worsening or becoming irreversible. Restoring cerebral blood flow to preinjury levels is a key therapeutic target 
because when trauma, ischemia, or neurodegenerative damage occurs, nutrient delivery to the brain, including oxygen and glucose, which are the primordial mol -
ecules necessary for maintaining normal brain cell function, can fail to supply brain cells’ demand to carry out all metabolic activities. Since most of the energy of the brain is obtained exclusively from aerobic meta -
bolic processes, a low supply and high demand for energy nutrients in the presence of trauma not only creates a neuronal energy crisis from the uncoupling of cerebral blood flow and metabolism but also ensures that motor, sensory, and cognitive func -
tions remain impaired or irreparably lost. Additionally, the brain cannot manufac-ture or store energy nutrients such as glucose and is totally dependent on optimal cerebral blood flow to deliver these nutrients as needed. 89
We will see in the “Cerebral Hemodynamic Function in Brain Injury” section 
how brain trauma, stroke, and neurodegenerative conditions such as vascular demen -
tia (VaD) and AD can uncouple cerebral blood flow and metabolism by involving a multifactorial list of factors that can act independently or as part of a pathologic cascade to alter blood flow to the brain. This analysis is relevant in attempting to 
Prevents glutamate e xcitoxicity
Free radical sca venger
Suppresse s
tissue facto r
Blocks NMDA r eceptors
Blocks Na+,Ca+ cell in/f_l ux
Inhibit s toxic c ytokinesDimethyl sulfo xide
in CNS injuryAnti-in/f_lammato ry
Incre ases CBF
(via prostaglandins)
Reduces brain edema
Platele t deagg regato r
Vascular smooth muscle
cell rel axant
FIGURE 8.1  Reported biological activity for DMSO in central nervous system (CNS) 
injury. Most of the molecular and cellular factors listed in this illustration result from physical and physiological damages to the brain, but the chronology and the degree of damage caused by many of these factors on brain tissue have not been entirely clarified.147 DMSO in Basic Neuroprotection
understand the role DMSO plays when used therapeutically to improve the outcome 
following primary injuries to the brain. The most common factors influencing cerebral blood flow are cardiac output, 
ICP, blood gas content, vasoactive substances such as nitric oxide, PGs, endothelins, thromboxane A
2, endothelial-derived hyperpolarizing factor, adenosine, and K+ and 
H+ ions.34
CPP is the driving force that moves blood flow through the cerebral circulation. Cerebral blood flow varies directly with CPP, which is defined as the difference between mean arterial and ICPs, and inversely with cerebrovascular resistance. Normally, CPP can be considered equal to mean arterial pressure. Immediately after brain trauma, two compensatory mechanisms to counter low CPP from vessel stenosis or vessel obstruc -
tion (e.g., platelet aggregation) can be activated: autoregulation and oxygen extraction fraction. As CPP falls, cerebral blood flow is maintained by the vasodilation of resis-tance arterioles, which results as reflex autoregulation is activated. 90
If cerebral blood flow falls beyond the autoregulatory range, oxygen extraction 
factor kicks in order to maintain oxygen levels, but up to a point.91 When CPP falls 
beyond the point where neither autoregulation nor increases in oxygen extraction fraction can compensate, ischemia resulting in an insufficient delivery of oxygen to meet metabolic demands will occur with almost certain damage to the brain. Cerebrovascular resistance results mainly from the friction caused by the blood 
on the vessel wall and is determined by vessel length, which does not vary signifi -
cantly in normal physiology, and from blood viscosity, which normally stays within a small physiological range. Blood viscosity, however, increases with blood loss, with ischemia, or with the inability of RBCs to deform in tight capillary lumens. 92 Blood 
viscosity depends on hematocrit, erythrocyte aggregability, and plasma viscosity.93
When blood viscosity increases, cerebral blood flow decreases, and inversely, 
when viscosity is decreased, cerebral blood flow is increased. This occurs because resistance arterioles regulate the amount of blood flow supplied to the brain by changing their diameters according to the viscosity and the friction of the blood passing through them, also called shear stress. Consequently, the most important aspect of resistance in regulating brain blood flow is the diameter of the vessel whose main activator is blood viscosity. There is a vasomotor duality that produces either vasodilation or vasoconstriction 
of brain arterioles, and it is thought to occur from endogenous arteriolar generation of either 20-hydroxyeicosatetraenoic acid (20-HETE), a powerful vasoconstrictor derived from arachidonic acid (AA), or from conversion of AA to the vasodilator epoxyeicosatrienoic acid. 94
Normal cerebral blood flow (CBF) in adult humans is about 60 mL/100 g/min 
and, regionally, about 70 mL/100 g/min in gray matter, and 20 mL/100 g/min in white matter. These values normally decrease with age by an estimated rate of about 0.5% per year. 95 Between the ages of 20 and 65, normal CBF generally declines 
about 15%–20%.96,97 It is generally accepted that when CBF reaches 30 mL/100 
g/min following brain injury, neurologic symptoms can appear and when CBF falls to 15–20 mL/100 g/min, electrical failure or irreversible neuronal damage can occur even within minutes. Neuroimaging studies show that vascular disturbances can reduce CBF to generate ischemic neurons (<12 mL/100 g/min), penumbral neurons 148 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
(12–22 mL/100 g/min), or hypoperfused neurons (>22 mL/100 g/min. Penumbral 
neurons are functionally impaired but, unlike ischemic neurons, lack structural damage, while hypoperfused neurons may or may not exhibit anatomic or functional changes for extended time periods. 27
Penumbral and hypoperfused neurons therefore may be salvageable following 
brain trauma in the event that a safe and effective treatment can be found. Such a treatment should address most if not all of the following factors:
 1 . I nhibit platelet aggregability
 2 . B lock vasoconstrictors including thromboxane A2, endothelins, and 20-HETE
 3 . S uppress tissue factor to prevent thrombosis
 4. B lock Na+ and Ca+ intracellular influx
 5 . B lock glutamatergic activation of NMDA receptors
 6 . S uppress inflammation
 7 . I nhibit free radical formation
 8 . R educe brain edema
 9 . S tabilize cell membrane from damage
 1 0. I nhibit toxic cytokines
 1 1. I ncrease cerebral blood flow by (a) activating smooth muscle cells in brain 
to increase vasodilation and (b) stimulating PG vasodilators E1 and prosta -
cyclin (I2)
These factors that are linked with injuries to the brain and spinal cord and the role DMSO plays in their activation are reviewed in the following text and summarized in Figure 8 .1. PROSTAGLANDINS
Concussive brain trauma is often accompanied by platelet aggregation and platelet dysfunction in pial arteries and arterioles due to coagulation disturbances caused by the sudden trauma. 98,99
In brain trauma patients, early coagulopathy is common on hospital admission 
with the coagulopathic process beginning at the time of trauma.100 As discussed 
in the section “Cerebral Hemodynamic Function in Brain Injury” in this chapter, blocked or obstructed brain vessels can lead to energy delivery disturbances whose outcome is brain cell damage or death. For this reason, traumatic brain injury has been the focus of treatments using antiplatelet aggregators such as prostacyclin, a potent vasodilator and platelet deaggregant. 101
Although microcirculation is improved following prostacyclin treatment after 
brain trauma,101 brain edema and cerebral blood flow do not necessarily improve. This limitation has discouraged the use of prostacyclin and other antiplatelet aggre -
gators both in basic and clinical strategies in treating brain trauma. DMSO has been consistently reported to be an effective platelet deaggregator101–103 
and, unlike prostacyclin, has been shown, following severe insults to the brain, to improve brain edema, cerebral blood flow, CPP, and electroencephalographic activ -
ity, while lowering ICP and cerebrovascular reactivity. 41,47–49149 DMSO in Basic Neuroprotection
The first step in the PG synthesis is the release of the substrate fatty acid, such as 
AA, from the cellular phospholipids, by the action of the enzyme phospholipase A2 
(Figure 8 .2). There are three ways that PGs can be elaborated. The monoenoic pathway forms 
PGE1 and PGE1-alpha from dihomo-y-linolenate. The bisenoic pathway leads to the 
elaboration of the endoperoxides (PGG2 and PGH2), which are the controlling agents 
in subpathways producing PGI2, TXA2, and PGE2 (Figure 8 .2). It can be seen from Figure 8 .2 that PGI2 (prostacyclin) and, to a lesser extent, PGE2 
act as potent vasodilators and platelet deaggregators. The antiplatelet aggregation 
activity by PGI2 and PGE2 results from their increase of cAMP levels in platelets.104,105
The other products, especially TXA2, are potent vasoconstrictors and platelet 
aggregators. There is a third trienoic pathway derived from eicosapentaenoic acid, which originates with the membrane-bound fatty acid, but little is known about the effects of its products, TXA
3 and PGI3, on the cerebral vascular bed. However, it is 
of interest that the vascular-platelet action of PGI3 is similar to that of PGI2, although 
TXA3 is not considered analogous to TXA2 since the latter can increase the levels of 
cAMP in platelets, thus neutralizing their potential aggregation.105,106
Formation of PGE2 can stimulate the levels of adenosine diphosphate (ADP), a 
mild platelet deaggregator and antagonist of noradrenaline production.107Cellular phospholipids
Arachidonic acid
Cyclooxygena seIndomethacin blo cks
Aspirin blo cks
Prostaglandin H2
Thromboxane A2
Vasoconstr iction
Platel et aggr egation
Inflammation
Bronch oconstrictionVasodila tion
Platel et deaggr egation
Anti-inflammation
BronchodilationProstaglandin E2
BlocksIncre ase cAMPProstaglandin E1Prostaglandin synthesis and DMSO actions
Stimulates
StimulatesStimulates
DMSO
DMSO(Prosta cyclin syntha se)
Prosta cyclin (I2)Phospholip ase A
FIGURE 8.2  Simplified scheme of prostaglandin biosynthesis, which starts with the 
release of a fatty acid nearly always derived from the 2-position of a membrane phospho -
lipid. Arachidonic acid is created from diacylglycerol via phospholipase-A2 and then brought 
to either the cyclooxygenase pathway where either prostaglandins (PG) or thromboxane is formed from synthases that yield prostacyclin (PGI
2) and PGE2 or thromboxane A2. PGE1, 
PGI2, and PGE2 are vasodilators, anti-inflammatory, and platelet deaggregators, while throm -
boxane A2 acts as a vasoconstrictor, inflammatory, and platelet aggregator. DMSO is reported 
to block thromboxane A2 and promote the release of PGE1, PGI2, and PGE2 either directly or 
via cAMP stimulation.150 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Vascular constriction and platelet clumping can be antagonized if PGI2 is released 
from endothelial cells in the microvasculature.104 PGI2 appears to do this by stimu -
lating adenylate cyclase in many tissues including peripheral neurons leading to an 
increase in cAMP levels in platelets.108 An increase in PGI2 synthesis or availability 
at the vessel wall would have a positive and direct effect on cerebral ischemia by antagonizing platelet aggregation and vasoconstriction ( Figure 8 .2). DMSO also has a direct effect on platelet cAMP levels. It increases cAMP pre -
sumably by inhibiting phosphodiesterase (PDE)
109,110 although an indirect action 
on PG12-induced elevation of platelet cAMP by DMSO can also be considered 
(Figure 8 .2). Research has revealed that of the 60 different platelet isoforms described in mam -
malian species, platelets are known to possess three main PDEs: PDE2, PDE3, and 
PDE5.111,112 Despite many studies carried out in the past four decades examining the 
role of DMSO in PG synthesis, it remains unclear which of these PDEs DMSO tar -
gets for the inhibition of platelet aggregation. Platelet function is, to a large extent, dependent on PDEs, because their inhi -
bition can dampen platelet aggregation by increasing cAMP and cyclic guano -
sine 3 ′-5′-monophosphate (cGMP), an action that limits the levels of intracellular 
nucleotides.113
Cyclic AMP is a powerful platelet deaggregator, and evidence exists that DMSO 
can increase the levels of cAMP in various biological preparations108,110,114,115 
(Figure 8 .2). Increasing cAMP by DMSO suggests that DMSO can manipulate signal 
transduction mediated by second messenger molecules such as cAMP. This means that the inhibition of platelet signal transduction by DMSO may suppress platelet acti -
vation regardless of the initial stimulus. 111 The mechanism that would allow DMSO 
to directly inhibit platelet-activating second messengers like cAMP and cGMP is by its interaction with intracellular signalling pathways. In addition, DMSO may act indirectly on the endothelium-derived PGI
2, which is known to increase intracellular 
platelet cAMP through the activation of membrane adenylate cyclase, a process that begins when PGI
2 binds to its receptors on the platelet surface.111
The role of DMSO in PG biosynthesis remains partly theoretical, but a number of 
intriguing findings lend support to the specific actions by DMSO on PG activity and their catalytic enzymes ( Figure 8 .2). For example, studies have reported that DMSO can increase the synthesis of PGE
1, 
a moderate vasodilator.71,72 PGE1 can reduce platelet aggregation by increasing cAMP 
levels, and this PG also inhibits the calcium-induced release of noradrenaline in nerve terminals, an effect that may antagonize vasoconstriction following tissue trauma with the resulting effect of preventing cerebral blood flow reduction
116 (Figure 8 .2). An increase in PGI2 synthesis or availability at the vessel wall would have a posi -
tive and direct effect on ischemia by antagonizing platelet aggregation and vasocon -
striction, thus allowing better blood perfusion of the hypoperfused tissue. DMSO may also antagonize the synthesis or release of thromboxane A
2117,118 and thus indi -
rectly counteract platelet aggregation and vasoconstriction. The presence of TXA2 in 
blood will cause strong vasoconstriction and platelet aggregation, while the forma -
tion of PGF2α will also negatively affect the vascular and platelet systems, but the 
reaction will not be as severe as with TXA2.111151 DMSO in Basic Neuroprotection
Theoretical considerations to explain platelet deaggregation by DMSO appears to 
involve PG synthesis in the brain.118
One study has shown evidence that DMSO has the ability to block the prothrom -
botic release of thromboxane A2.119 Although the exact mechanism of DMSO’s 
blocking action of thromboxane A2 to reduce platelet aggregation has not been clari -
fied, it may possibly mimic the action of hydralazine or dipyridamole since DMSO 
shares a number of similar biochemical features with these agents, specifically their increase of cAMP levels. 109,118
The actions of DMSO on the biosynthesis of specific PGs may have clinical appli -
cation not only in cerebral ischemia secondary to traumatic brain injury but also in conditions where inflammatory cytokines, platelet aggregation, and vasospasm result from disease and physical injury. DMSO is reported to exert protective activity on tissue factor expression in human 
endothelial cells in response to TNF- α or thrombin exposure. 120
TISSUE FACTOR
The best known function of tissue factor is its role in blood coagulation. Blood coag -
ulation begins when a mammalian vessel is damaged and reacts by beginning a coagulation cascade in order to preserve the integrity of the circulation. The coagu -
lation cascade can also be generated by mediators of the inflammatory response, such as cytokines. The coagulation cascade leads to clot formation by the exposure of flowing blood to tissue factor, also called thromboplastin. Tissue factor is the cellular receptor and cofactor for factor VII and binds both 
factors VII and VIIa. 121 Tissue factor is the high-affinity receptor for factors VII and 
Vlla and is the cofactor necessary for the catalytic function of factor VIIa.122 As tis -
sue factor binds factor VIIa, it activates Factor IX and Factor X, a process that results in fibrin formation. 123 Fibrin is the building block of the hemostatic plug. Tissue factor is a key protein in the activation of coagulation and thrombus for -
mation and has been associated with acute coronary syndromes, myocardial infarc -
tion,121 and microvascular perfusion defects following focal cerebral ischemia.124
Electron microscopic evidence has shown the presence of fibrin in cerebral 
microvessels derived from degranulated platelets and poymorphonuclear leukocytes following middle cerebral artery (MCA) occlusion. 125 The use of antitissue factor 
agents as DMSO has been shown to be, may be, clinically useful to prevent the coagulation cascade that can lead to microvascular plugs following the ischemic process related to blunt brain trauma and stroke. It has been reported that DMSO has an effect on blocking Na
+ and Ca+ entry 
into cells.50,51 Since substantial Na+ and Ca+ entry into myocytes typically occurs 
after cardiac arrhythmias and myocardial infarction, DMSO administration may prevent this inward cellular ion flux while preserving K
+ outflux from cardiac tis -
sue. The mechanisms exerted by DMSO on Na+ and Ca+ channels need to be fur -
ther investigated in mammalian models of ischemic injury since the results of such studies could produce an extremely useful and relatively safe agent for a variety of cardiac and brain ischemic disorders affected by changes involving these cations (Figure  8 .3). Drugs that block abnormal Na
+ entry into damaged brain cells have 152 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
been shown to exhibit strong, neuroprotective activity in animal models of brain 
ischemia and hypoxia, and a number of clinical trials are now in progress to test these class of drugs when cerebral ischemia is present. 126–128 Curiously, DMSO is not 
presently being considered for such clinical testing. DMSO given at clinical doses has been reported to suppress in a relatively rapid 
(minutes) and 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 oxidative or metabolic stress
54 (Figure 8 .3). This 
excitotoxic  process by glutamate leads to electrophysiological responses and calcium 
influx into brain cells when activated is blocked by DMSO, resulting in the protec-tion of hippocampal neurons against deadly pathway. 54
Although the mechanism responsible for DMSO’s suppression of glutamate exci -
totoxicity is unclear, two possible explanations may be relevant. First, it is shown that 
Voltage-sensitive
Ca+ channel AMPA
receptor
Na+
Depo lariza tion
Nerve ending
Dimethyl sulf oxide mole cular ta rgetsNa+Na+ ATP
Cell deat hExcessive
K+Ca+ ATPaseCa+
Na+Ca+Vesicular
glutamate
releaseOH
ROS6
754123
NMDA
receptorCa+
Brain
ischemi a
Voltage-sensitive
Na+ channe l
K+Na+
Na +/K+ ATPase
FIGURE 8.3  (See color insert.) Scheme detailing some of the molecular mechanisms 
DMSO is reported to target at the subcellular level in nerve endings or neuronal cytoplasm following cerebral ischemia. DMSO is reported to suppress excessive calcium (Ca
2+) influx 
into cells (1) and block NMDA ( N-methyl- d-aspartate) and AMPA (alpha-amino-3-hydroxy-
5-methyl-4-isoxazolepropionate) receptor channels (2, 3) following ischemic events that can promote excitotoxic death of neurons. DMSO is reported to block sodium (Na
2+) channel 
activation (4), a reaction seen after CNS injury that may activate a biochemical cascade result -
ing in intracytoplasmic potassium efflux (5), cell energy hypometabolism ( ↓ATP), ROS and 
hydroxyl radical (OH) production (6), and cell death (7). DMSO has been shown to increase the levels of high-energy phosphates cAMP and creatine phosphate and inhibit tissue factor expression, thrombus formation, and vascular smooth muscle cell (VSMC) proliferation and migration (not shown), elements known to participate in cerebral ischemia and stroke. See text for details.153 DMSO in Basic Neuroprotection
DMSO can reduce Na+ and K+ currents in cardiac myocytes,129 and as we have seen, 
this can also occur in neurons to reduce their excitability and action potentials,51 
a process that could quell Na+ channel current into excitable glutamatergic neurons. A second possibility is the anti-inflammatory modulation that DMSO demonstrates 
against proinflammatory trauma-induced cytokines such as  TNF- α,  i nterleukin-6, 
and NF-kB, a transcription factor involved in inflammatory responses. Part of the 
modulation of toxic cytokines by DMSO is the scavenging of free radicals and anti -
oxidant activity, an effect that can help resolve the development of brain edema after trauma. 47,52,130,131
Stabilization of cellular membranes by DMSO is yet another property that helps 
tissue resist the effects of physical and physiological damage that can occur after blunt or ischemic injury to the brain. This cell membrane protection has been shown consistently by DMSO on cells exposed to freezing, radiation, and sonic stress. 59,132,133
Lim and Mullan59 showed that astrocytoma cells subjected to sonic stress from 
a sonicator in an in vitro  system was capable of tearing apart the cell membrane by 
violent collapse. They found that exposure of 10% DMSO to the astrocytoma cells afforded significant protection and survival rate of these cells when compared to no treatment controls or to glycerol, an agent used in brain edema to control brain swelling. 59
Another important property that may explain DMSO’s ability to reduce brain 
injury and edema is its effect on the Janus kinase/signal transducer and activator of transcription (JAK2/STAT) signaling pathway. JAK2/STAT signaling pathway appears to be one of the main pathways downstream of cytokine receptors and growth factor receptors that functions by transducing signals from cell surface to the nucleus. 55 This activity has been shown to have a protective role in brain trauma.55 
Recent studies have revealed that the JAK2/STAT signaling pathway plays a role in the regulation of gene expression during inflammation. 134,135 Immunohistochemical 
examination following contusive brain injury in rats showed that JAK2/STAT pathway was mildly activated in both neurons and astrocytes 3  h after injury. 55 
Conversely, the inhibition of the JAK2/STAT pathway was associated with the pro -
motion of brain edema, which can increase the severity of neurological deficits.55
When DMSO was given intraperitoneally 20 min prior to pericontusional trauma 
to rat cortex, increased levels of the JAK2/STAT pathway were observed together with improved neurological recovery and reduced neurological deficits when com -
pared to animals not given DMSO. 55 It is unclear how DMSO is able to accelerate or 
increase the activation of this neuroprotective pathway. CEREBRAL BLOOD FLOW
DMSO has been reported to increase cerebral blood flow in many preparations involving brain trauma, stroke, and SCI,
35,41,61,118,136,137 but the mechanisms DMSO 
may tap to increase cerebral perfusion have not been investigated. VSMCs in brain vessels are known to modulate vessel tone when they receive 
signals to vasodilate,35 but the only evidence that DMSO contacts VSMC is in pre -
venting their migration,119 a process known to be associated with vascular damage 
and atherogenesis.138154 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
One curious observation that should be mentioned is the fact that injected DMSO, 
even at extremely high doses, does not appear to increase cerebral blood flow appre -
ciably in normal dog brain.139 Normal dogs given mega intravenous doses of 2–8 g/kg 
of 100% DMSO showed an increase in cerebral blood flow in the cortex and caudate 
nucleus but only after 6 g/kg, a dose that produced hemolysis and increased intravas -
cular volume.139 Cerebellar tissue and brain stem blood flow remained unchanged.139
This study indicates that DMSO’s effect in increasing cerebral blood occurs when 
a neuropathological state is present, for example, brain trauma or stroke, where doses ranging from 0.5 to 1 g/kg of a 25%–40% DMSO solution are sufficient to signifi -
cantly increase cerebral perfusion. 41,61,137 This outcome implies that DMSO’s ability 
to increase cerebral blood flow from an ischemic state may occur by affecting associ -
ated factors: (1) reducing cerebrovascular resistance and blood viscosity, (2) reducing tissue edema and ICP, (3) modulating PG control of vessel tone and/or platelet aggre -
gability, (4) relief of inflammatory, and (5) a combination of these factors. The physiopathological responses to pressure-induced cerebral ischemia in 
canine brain were investigated using DMSO. Brain retraction pressure over the somatosensory cortex was achieved using a De Martel retractor fixed into place by a micromanipulator, and DMSO was administered at 250 mg/kg prior to retraction and every 12 h after retraction for 3 days. DMSO treatment was significantly better than untreated controls with respect to CPP, focal swelling, and tissue necrosis. 140
These gross findings were reinforced by neurobehavioral scoring following brain 
retraction, with DMSO treatment showing improved recovery when compared to mannitol, methyl prednisolone, furosemide, and barbiturate treatments. 140 This study 
received support by the same group of investigators who used the brain retraction model to induce focal ischemia in animals pretreated with ethanol to simulate a drunken vehicle driver sustaining a head injury. 140 In the untreated animals, ethanol 
intoxication led to a large source of hydroxyl-free radicals and neuronal tissue dam-age, an effect that was markedly attenuated by DMSO treatment.
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:

        Although intravenous urea still remains one of the most reliable drugs to combat 
acute brain swelling, another osmotic agent, mannitol, has shown fewer complications 135 DMSO in Basic Neuroprotection
in treating head injuries, but its action is half as short as that of urea (about 4 h), plus, 
it does not improve brain tissue pO2 in severe head trauma and its effect is not as 
dramatic when brain edema is severe. 16
A fundamental guide to emergency department management of head injuries at 
the present time is ensuring adequate CPP, adequate oxygenation, and preventing even brief or transient episodes of hypotension, hypoxia, seizures, hyperglycemia, and hypocapnia. 17 CPP is a function of ICP and systemic blood pressure, and it must 
be monitored and controlled at all times to prevent further structural and functional damager. 18
When severe brain tissue trauma occurs, brain cells respond in a typical manner. The anatomic changes in neurons following trauma have been well studied and con -
sist of cytoplasmic swelling secondary to sodium influx and a failure of membrane ionic regulation. 19 This is followed by characteristic cytoplasmic eosinophilia, severe 
loss of the endoplasmic reticulum and Golgi apparatus, chromatin clumping, nuclear shrinking with peripheral shifting, and disappearance of axonal microtubules, a phe -
nomenon that generates synaptic dystrophy and neurotransmission failure. 20
Depending on its location and severity, a focal traumatic insult to the brain will 
destabilize ischemic neurons by inducing hypoxia, glutamate excitotoxicity, a mas -
sive and disruptive intracellular rise of Ca2+, mitochondrial energy loss, formation 
of oxygen and nitric oxide free radicals, and impairment of adenosine triphosphate (ATP) synthesis that fuel all brain cells. 21 The biochemical cascade associated with 
anatomic changes in ischemic neurons and glial cells is the product of irreversible oxygen–glucose deprivation resulting from the severe ischemia that leads inevitably to ATP production failure and a neurometabolic energy crisis in adjacent hypoper -
fused neurons. 22
The reduced mortality and improved outcome for patients with severe traumatic 
brain injury in the past decade has been attributed to the partial but incomplete success of trying to squeeze oxygenated blood through a swollen brain. This plan requires quantification of cerebral perfusion by monitoring the ICP and by prompt treatment of cerebral hypoperfusion to lower the incidence of secondary injury. Although this plan can mean the difference between good survival and incapacitat -
ing, long-lasting neurological deficits or death, it is not generally possible to achieve due to the absence of an agent that can address cerebral hypoperfusion, brain edema, excitotoxic release of glutamate and cytokines, ionic cell shifts involving sodium and calcium channels, and free radical formation. Is there an agent that can address the pathologic cascade results from severe brain trauma and clinical success and improved outcome. SECONDARY INJURY AND ISCHEMIC PENUMBRAL NEURONS
Because traumatic brain injury results in irreversible damage at the site of impact and initiates cellular and molecular processes that lead to secondary neural injury 
in the surrounding tissue, understanding the pathophysiology of secondary injury is 
critical to the development of effective therapy. Adding to the cell and molecular damage that results at the site of trauma, sec -
ondary injury to the surrounding brain tissue also undergoes electrophysiological 136 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
changes without the anatomic necrotic changes to neurons described earlier. The  s econdary injury primarily involves reduced cerebral perfusion, inflammatory 
changes, lowered cerebral energy metabolism, release of excitatory neurotransmit -
ters, and oxidative stress. 23,24 These cell and molecular abnormalities not only add to 
the site of injury but can give rise to an area of the brain adjacent to the injury core 
where a ring of ischemic penumbral neurons can accumulate. In his classic paper describing the ischemic penumbra, Astrup and his colleagues25 
recognized two stages where penumbral neurons can experience functional impair -
ment and irreparable degenerative damage, usually with the former stage preceding the latter. However, irreparable damage to penumbral neurons is not always the case, and 
it is clear that at least in embolic stroke, these neurons are salvageable with the proper treatment, for example, using intra-arterial thrombolytics such as the tissue plasminogen activators (tPAs). These clot busters are able to accelerate the conver -
sion of plasminogen to plasmin, the major enzyme that catalyzes clot breakdown. However, one of the disadvantages of tPA therapy is that it must be administered as quickly as possible after an embolic stroke, usually within 4½ h after the onset of symptoms. 26
This brief window of opportunity means that only 3% of persons qualify for treat -
ment with tPAs since most patients wait beyond this time period to seek medical help after the onset of stroke symptoms. Another serious disadvantage of tPAs is the risk of hemorrhage in the brain, worsening the primary damage from stroke. Due to the bleeding risk, tPA has not been assessed in any traumatic brain injury 
trial that we are aware of, but other agents have been used to address the disturbances in platelet function, leading to hyperaggregability following a head injury. 27
Neurons in the ischemic penumbra are formed as a result of critically subnor -
mal brain perfusion following a stroke or local brain trauma. 28 These penumbral 
neurons retain their structural integrity but lose their ability to function normally. 29 
The penumbral region is therefore a functionally silent population of neurons. The physiological outcome of penumbral neurons is dependent on the degree and dura -
tion of ischemia. 30 It has been reported that an ischemic penumbra results when local 
cerebral blood flow dips between 12 and 18 mL/100 g tissue/min following brain trauma. 31 Below 12 mL/100 g tissue/min, the tissue becomes irreparably damaged 
and soon dies. 31
The penumbral neurons are more likely to die if normal cerebral perfusion is 
not quickly restored. However, the grace time before penumbral neurons die from a reduced blood flow supply is variable and dependent on the type of injury involved, severity, region of the brain affected, and many other constants. Penumbral neu -
rons have been reported to remain viable for hours, days, months, or even beyond a year. 32–34 During traumatic brain injury, astrocytes become reactive and increase 
proinflammatory cytokines to produce excitotoxicity through the excessive pro -
duction of extracellular glutamate. This results in brain edema and swelling, a 
 condition that promotes neuronal death from the activation of reactive oxygen 
 species (ROS). In addition, the activation of Janus kinase and signal transducer and activator of 
transcription signaling pathway is one of the most important transducing signals 137 DMSO in Basic Neuroprotection
from the cell surface to the nucleus in response to cytokines, particularly the 
 proinflammatory interleukin-6 cytokine family. 36 The Janus kinase and signal trans -
ducer and activator of transcription signaling pathway is the focus of much research 
at the present time due to studies that report its involvement in the pathophysiology of brain ischemia, brain trauma, and spinal cord injury (SCI). 37,38
It is clear that when primary traumatic brain injury cannot be prevented, secondary 
injuries must be restricted with appropriate neuroprotective strategies. Nevertheless, present drug treatments are not generally able to do that consistently or effectively. 39
The ability of pharmacotherapy to rescue salvageable neurons following brain 
trauma and arrest or reverse the quantitative damage that results from such injuries remains elusive and extremely limited. A recent Cochrane Database of Systematic Reviews and Cochrane Injury Group 
conducted an exhaustive literature search analyzing drug therapeutic studies dealing with severe head injury. The search concluded that the majority of these clinical tri -
als included only a modest number of patients largely due to the uncertainty of the trial drug effectiveness. 40 Not surprisingly, the quality of these clinical trials was 
regarded as more or less questionable. 40
For this reason, there is an expectation that the effects of dimethyl sulfoxide 
(DMSO) used to treat brain trauma, stroke, Alzheimer’s disease (AD), and SCI will receive the clinical attention it deserves. When brain trauma, stroke, AD, and SCI are combined, it represents a block of disorders that affect 8% of adult Americans and more than 15 million individuals in the United States alone. The findings reviewed here will reveal a very unusual molecule possessing a num-
ber of biological actions that may explain its positive therapeutic effects following traumatic brain injury and other CNS insults. DMSO IN EXPERIMENTAL BRAIN TRAUMA
The mechanism of action(s) exerted by DMSO in improving the outcome of trau -
matic brain injury remains unknown. However, DMSO is reported to display a range of properties, which may be useful in the management of the brain trauma patient or animal. For example, DMSO increases cerebral blood flow without altering blood pressure,
41,42 quickly reduces ICP without a rebound effect,43–46 is a potent diuretic 
that does not affect cardiac rate or output,41,42 reduces cerebral edema,47,49 blocks 
sodium channel activation,50,51 is a powerful free radical scavenger,52,53 prevents glu -
tamate excitotoxic neuron death,54 lowers the Janus kinase and signal transducer 
and activator of transcription signaling pathway whose activation can be induced by excitotoxic cytokines following brain ischemia,
55 and suppresses NMDA-
AMPA-induced (NMDA, N-methyl- d-aspartate; AMPA, alpha-amino-3-hydroxy-5-  
methylisoxazole-4-propionate) ion currents and excessive calcium influx known to damage and kill neurons. 54,56 Additionally, DMSO has a protective and stabilizing 
effect on cell membranes57–59 and inhibits inflammation, a reaction that is generally 
associated with moderate-to-severe brain trauma. 60–62
The biological actions listed earlier for DMSO are relevant to our review of the 
cellular–molecular events associated with CNS injuries, including traumatic brain injury, stroke, or neurodegenerative conditions since these events generally involve 138 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
sodium channel activation, free radical formation, and glutamate excitotoxic signal -
ing involving NMDA-AMPA-induced ion channels and calcium signaling in cell-
death pathways. 50,51,54,61 These cellular–molecular actions modified by DMSO will 
be discussed in detail in this section of this chapter and in Chapter 9. Chapter 9 will detail how the basic research of DMSO in cerebral injuries has been successfully applied to humans sustaining a variety of insults to the brain. It is important to point out that the cellular and subcellular biological actions of 
DMSO with the exception of lowering brain edema after trauma are not known to be associated with mannitol, a drug commonly used for the treatment of head injuries. This may be one of the reasons why DMSO treatment has been shown to be more efficacious and safer than mannitol when used in patients with severe, closed head injury. 44,45
The initial studies with DMSO were first carried out in the early 1970s in the 
Division of Neurosurgery at the University of Chicago by a team of investigators led by Jack de la Torre. How DMSO was chosen to be tested against an animal model of head injury among dozens of other potentially worthwhile compounds is worth men-tioning. At that time, about a dozen head injury centers existed in the United States funded by National Institutes of Health (NIH) and most of these centers were des -
perately seeking new agents to address the rising incidence of head trauma. These head injuries occurred from falls, especially in children and the elderly. Automobile accidents were also high on the list of head injury causes. Since seat belts were not in common use in the early 1970s, about 50,000 deaths 
per year were recorded from acceleration–deceleration brain damage sustained mainly from falls and car crashes. Most of these deaths occurred from complications that followed injury to the brain, generally within several days following hospital admissions. The frustration from personnel working in the emergency room after admitting a severe head-injured patient, whether the patient was a child or an adult, was the inconsistent nature of the treatments available at the time, which sometimes worked, but more often did not. At the research meeting held every other week in the Division of Neurosurgery 
at the University of Chicago in 1971, DMSO was proposed by a member of the fac -
ulty, Jack de la Torre, as a possible agent to test in experimental animals with severe head injury. When asked by Sean Mullan, the chief of neurosurgery, for the reasons behind this proposal, de la Torre pointed out DMSO’s unique properties as a power -
ful diuretic, anti-inflammatory, and cell membrane protector from freezing dam -
age, properties, he argued, that could potentially counteract cerebral edema buildup resulting from increased ICP. The research project was approved, and the first series of experiments involving traumatic brain injury in rhesus monkeys were scheduled soon after. A vivid account by Jack C. de la Torre described in a letter to a colleague what happened on the very first experiment following a single, acute intravenous dose of DMSO as the primary treatment for this devastating brain insult. I remember it was bitterly cold in Chicago that March morning of 1971. Tucked away 
on a corner of the second floor of Billings Hospital, my technician and I struggled with 
a myriad of cables, wires and electronic monitors set up to detect any changes in the brain-injured animal lying on the table. I was a newly appointed Assistant Professor 139 DMSO in Basic Neuroprotection
to the Division of Neurosurgery at the University of Chicago, the lowest professorial 
rank in academics. The academic trail for me would involve over 200 publications, six books and hundreds of international medical conferences where I would lecture about injuries to the brain and spinal cord. However, that March morning, only one thing was on my mind. Will the animal survive a severe brain trauma when given a new drug that had never been tested for that purpose. The odds were not good. We had already tested, as part of being one of seven Head Injury Centers in the U. S. , dozens of worthless treatments reputed to benefit this usually lethal injury. And, we would keep on searching when…on that morning, “looky, looky, look at that…. ” my technician’s eyes rolled off the animal as I finished my intravenous administration of the drug. She pointed excitedly to the monitoring charts. The charts were going crazy, instead of cardiac collapse, respiratory arrest, a flat EEG and sure death, the heart rhythm stabi -
lized, breathing returned, at first in gigantic gasps, then in steady, normal, breathing pattern. The electroencephalogram, monitoring brain cell activity, returned in full force and blood flow to the brain, which had ceased in the final stages of the injury, began flowing again and reviving the almost dead brain. It was, as if the hand of God had 
somehow touched the animal’s forehead. ‘I don’t believe it’, I   stammered. But it w as 
true. I felt a tingling in my spine because this reawakening of a virtually dead animal had all the markings of a medical breakthrough. The drug was dimethyl sulfoxide or DMSO for short, used years earlier as a pain lotion and anti-inflammatory agent. What we would discover and publish about dimethyl sulfoxide in the next 8 years at the University of Chicago laboratories, would be pharmacological actions of a simple molecule that should have sent shock waves through the field of medical therapeutics as one of the most important drug discoveries of the century in treating devastating brain and spinal cord trauma. Instead, the discovery, the potential for saving lives and the continued research that should have uncovered other uses for dimethyl sulfoxide and similar agents was quietly laid to rest in the coffers of forgotten medicine. It was a baffling paradox that defied a reasonable explanation and to this day still remains unclear to me. The model to simulate acute head injury in rhesus monkeys employed in some head injury centers’ research laboratories consisted of an intracranial balloon inserted extradurally via a cranial burr hole near the temporoparietal region to produce pro -
gressive brain compression and increased ICP. This injury simulated and provoked an expanding extradural hematoma, common in acceleration–deceleration injuries from motor vehicle accidents. This type of slowly evolving compression injury is also commonly seen in falls, aggression, and sports-related injuries. Once in place in the extradural space, the balloon was slowly expanded with 0. 2 mL water incre -
ments until respiratory arrest was reached. One hour after each treatment, the bal -
loon was decompressed. 63 We were later to discover that no other agent tested for 
head injury in our laboratories, including steroids and hypertonic agents, had the dramatic effects seen with DMSO. In the initial experiments by de la Torre,
63 40 monkeys were divided into three 
groups ( Table 8. 1). Group 1 received 1 g/kg urea; Group 2, 2 g/kg of a 50% solution 
of DMSO; and Group 3, physiological saline at the same volume as the experimental 
treatments. All drugs were given intravenously at the rate of 8 mL/min. The results 
using DMSO or urea on brain swelling secondary to an expanding extradural lesion in monkeys showed that 10 of 15 urea-treated monkeys survived (33% mortality) and 140 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
the examination of these animals after 24 h showed 4 survivors sustained right-side 
paresis, uneven pupil size (anisocoria), and general lethargy. 63
Of the DMSO-treated monkeys, 14 survived (7% mortality) and 1 survivor showed 
mild right-side paresis only. In the monkeys treated with physiological saline, 9 of 10 animals died (90% mortality) within an hour after injury, a lone survivor showed severe neurological deficits and died the following day. 63 Respiration, systemic arte -
rial pressure, carotid blood flow, ICP, and electroencephalography (EEG) were sig -
nificantly modified during the endpoint of brain compression but returned to baseline in the surviving monkeys that were free of deficits upon recovery. On the average, cortical blood flow as seen through a pial window installed in 
every animal prior to injury returned to normal 23 min after treatment with DMSO and 45 min after treatment with urea. Copious volumes of urine were excreted from all monkeys within an hour after the administration of DMSO and considerably less after urea treatment. 63,64
All neurological deficits seen in the monkeys treated with either urea or DMSO 
were temporary, and recovery was observed from 1 to 5 weeks after the experimen -
tal head injury. 63,64 This remarkable study in nonhuman primates indicated that a 
promising new agent, DMSO, was significantly more effective than urea, the clinical drug of choice at the time and used even presently for severe, closed head injury
63,64 
(Table 8.
To test the effects of DMSO on reducing platelet aggregation and vasodilation in response to brain trauma.
What is the primary focus of the studies conducted by the San Diego group?
To evaluate the efficacy of DMSO in reducing platelet aggregation and vasodilation in the context of brain trauma.
What is the primary goal of the studies conducted by the San Diego group?
The text does not specify the primary mechanism by which DMSO increases cerebral blood flow, but it is mentioned that DMSO increases cerebral blood flow without altering blood pressure.
What is the primary mechanism by which DMSO acts to increase cerebral blood flow?
The study aimed to investigate the effects of DMSO on the biosynthesis of prostaglandins and its potential therapeutic use in brain trauma.
What is the purpose of the study conducted by Ikeda and colleagues?
The primary goal of the studies was to investigate the efficacy of DMSO in reducing platelet aggregation and vasodilation in response to brain trauma, as well as its potential therapeutic use in brain trauma.
What is the primary goal of the studies conducted by the University of Chicago investigators?