It is now well recog -
nized that low cerebral blood flow and CPP are potentially harmful in patients with 
brain trauma and are associated with poor outcome.231,232
What is less clear is whether altering cerebral blood flow or CPP will lead to clini -
cal improvement. The study by Brown et al.230 suggests that the traumatized brain 3.0
2.0
1.0
11 03 0
Minutes* p<0.05Untreate d
DMSO
Hours12 46mL/100 g ms/min
FIGURE 8.9  Cerebral metabolic rate of oxygen consumption decreased in all animals after 
injury and rose progressively after DMSO (triangles) as compared to untreated animals (dark 
circles). (Adapted from Brown, F.D. et al., Ann. NY Acad. Sci ., 411, 245, 1983.) 100
50mm Hg
0
11 03 0
Minutes**
*
* p<0.05
Hours12 46Untreate d
DMSO
FIGURE 8.10  CPP fell to nearly half of the baseline values within 10 min of injury and was 
reversed by DMSO (triangles). Two hours after DMSO treatment, CPP values had returned to baseline unlike untreated animals (dark circles). (Adapted from Brown, F.D. et al., Ann. NY 
Acad. Sci ., 411, 245, 1983. )176 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
requires a normal CPP before adequate cerebral blood flow and satisfactory oxygen 
metabolism can be attained. This thinking is now supported by the work of investi -
gators from the Brain Trauma Foundation. With respect to DMSO’s ability to stabilize mean arterial pressure after a missile 
injury, several studies have documented that brain trauma worsens in patients who experience episodes of hypotension in the first few hours after injury. 233,234
DMSO COMPARED TO MANNITOL IN MISSILE INJURY
Based on the positive results obtained with DMSO versus no treatment following missile injury to the brain, another study was designed by Brown and colleagues. This study
230 compared DMSO to the standard treatment for cerebral trauma, man -
nitol, following a missile injury to the brain. While mannitol was observed to be better than no treatment in each parameter measured, CPP, mean arterial pressure, cerebral blood flow, and oxygen metabolism indicated DMSO as vastly more supe -
rior to mannitol treatment. 230 The authors’ conclusion from these findings was that 
this difference indicated that DMSO is a more effective agent than mannitol in their model injury and may have been due to many incalculable factors, including the abil -
ity of DMSO to maintain good cardiac output following cardiac ischemia, a problem often seen complicating brain trauma. 137,230,235
DMSO IN AGING RESEARCH
The average human life expectancy in the United States has increased from 50 to 78 years in males and 80 years in females in the last 100 years. According to U.S. Census Bureau projections, by 2050, one in five Americans will be 65 or older, and at least 400,000 will be 100 or older. 236 Some futurists think even more radical 
changes are coming, including medical treatments that could slow, stop, or reverse the aging process and allow humans to remain healthy and productive to the age of 120 or more. Aging research is now the focus of thousands of laboratories that include stud -
ies on telomerase to stem cells to energy and oxyradical formation. Moreover, the manipulation of the cellular and molecular mechanisms that extend lifespan such as prevention of DNA damage and genetic engineering as well as lifestyle objectives, involving a healthy diet, exercise, and risk assessment to disease, is an important mechanism in healthy life extension. Aging is a complex process driven by diverse molecular pathways and biochemi -
cal events, and it is not too surprising that lifespan is the outcome of a variety of inte -
grated processes. It is this diversity of processes that make it difficult to understand aging exclusively in terms of molecular or genetic mechanisms. While one research approach to study longevity can concentrate on identifying specific biochemical and biophysical processes of aging, another approach should promote the understanding 
of aging phenotypes and their variability. Much of the research into life extension is presently done using a roundworm 
called Caenorhabditis elegans . This nematode is a noninfectious, nonpathogenic, 177 DMSO in Basic Neuroprotection
and nonparasitic organism. C. elegans  is a transparent nematode about 1  mm in 
length that has become a model organism for aging research. C. elegans  is a very 
primitive organism that nonetheless shares many of the essential biological activi -
ties that are central to human biology. As simple as this organism is, it has a ner -
vous system that contains only 302 neurons and about 7000 synapses, compared to 
human brain that has about 100 billion neurons and probably one thousand times more synapses. Its simple nervous system seems to allow it to express behavior and even rudi -
mentary learning. Another useful feature of C. elegans  is its transparency, a detail that allows the 
study of cell differentiation and cell development, characteristics that are important in the study of aging. The Nobel Prize in Physiology or Medicine was awarded in 2002 to Sydney 
Brenner, Robert Horvitz, and John Sulston, for their discoveries concerning the genetic regulation of organ development and programmed cell death (apoptosis) and the significant contribution of experimental organisms such as C. elegans . This work 
has contributed much to our understanding of human physiology and pathophysiology. C. elegans  can be used for testing compounds that may have an effect on aging 
and longevity. The use of C. elegans  is a useful approach to study longevity because 
the worm has a fast, conventional lifespan of about 14–20 days, is small in size, is easy to maintain in the laboratory, and has a powerful genetic toolkit where manipu -
lation of the genome by adding, removing, or altering specific genes already known to lengthen lifespan can be made by relatively routine procedures. The worm can be frozen at −80°C and stored for 10 years with good survival. DMSO has been used in several studies as a solvent for compounds reported to 
extend the lifespan of C. elegans , but it was not determined in those studies whether 
DMSO was inert or played a role in extending lifespan. 237,238
Assuming that DMSO was inert, the authors failed to notice any positive function 
of DMSO on the lifespan of C. elegans . However, it has been recently reported that DMSO itself extends the lifespan 
of C. elegans . A study by Wang et al.239 revealed that DMSO extended the lifes -
pan of  C.  elegans  in a dose-dependent manner. The mean lifespan of C. elegans  
increased with DMSO treatment 15% and 23% at doses ranging from 0.01% to 2% and reached a maximum at 0.5%. At concentrations of 5% DMSO, it decreased the mean lifespan of C. elegans , indicating that DMSO is toxic at that concentration. 239
This study also attempted to clarify the underlying mechanism of DMSO to 
increase lifespan extension in this model nematode. Several assays suggested that DMSO increased the lifespan of C. elegans  by modulating gene expression. These 
assays pointed to DMSO modulating gene expression in the insulin/IGF-1 signaling pathway (Wang). Genetic analysis suggested that DMSO did not function through dietary restriction or thermal resistance since there was no life extension by DMSO during thermal stress of this organism. 239
The discovery of antiaging properties of DMSO from Wang et al.’s239 study pro -
vides a good basis to try DMSO in other aging models to detail more precisely its role in life extension.178 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
DMSO IN EXPERIMENTAL DEMENTIA
Dementia is the term used for a group of symptoms caused by disorders that affect 
brain function and, as such, is not a specific disease. Dementia is characterized by progressive deterioration of intellectual functions and inability to carry out daily activities. Memory loss is an early and common symptom of dementia. AD and VaD are the two most common forms of dementia among older people. Although traditionally considered separate pathologies, strong evidence indicates that AD and VaD share common pathogenic mechanisms including vascular risk factors, histopathology, clinical signs, diagnostic criteria, and treatment approach. 240
AD is an insidious disorder that progressively ravages the brain, resulting in syn -
aptic and neuronal loss, ultimately destroying memory, intellect, and human dignity in the process. AD begins slowly involving parts of the brain that control thought, planning, 
language, and memory. People with AD may have trouble remembering things that happened recently or names of people they know. Over time, AD symptoms get worse. People may not recognize family members 
or have trouble speaking, reading, or writing. They may forget how to brush their teeth or comb their hair. Later on, they may become anxious or aggressive. AD usually begins after age 60. The risk goes up as you get older. No treatment 
can stop the disease. It is estimated that AD affects 5½ million people in the United States and will increase to 14 million by 2050. Although it is not presently known what causes AD, it has been speculated for 
sometime that abnormal deposits of proteins called Abeta form amyloid plaques and produce neurofibrillary tangles throughout the brain. This accumulation of plaques and tangles is believed to cause massive neurodegeneration and stop communication between neurons, thus leading to loss of cognitive function and eventually dementia. However, a conceptual shift in our understanding of dementia came in 1993, when 
de la Torre and Mussivand
241 proposed that sporadic AD was a vascular disorder with 
neurodegenerative consequences rather than vice versa. This proposal was supported by strong epidemiological, pathological, pharmacotherapeutic, and neuroimaging data, which collectively explained how the metabolic, inflammatory, hemodynamic, and physiopathological events seen to develop preclinically in AD are associated with a cerebral energy crisis secondary to chronic brain hypoperfusion. Reduced blood flow to the brain appears to result from the presence of one or more of two dozen described vascular risk factors. 242 These risk factors include atherosclerosis, dyslipidemia, car -
diovascular disease, diabetes type 2, and stroke, all which commonly affect elderly individuals who are more vulnerable to damage from these conditions during advanced aging. 243
It is not surprising that many animal models have been created to study this dev -
astating dementia. The animal models used mainly serve to test and screen potential pharmacotherapy aimed at arresting, slowing, or reversing the pathological process 
that begins at the onset of AD. Models of AD include transgenic mice that produce 
abnormally high levels of Abeta peptides,
244,245 animals whose cholinergic system 
can be manipulated,246 animals with induced amnesia,247 knockout mice for tau,248 
animals with lesions of  me mory-related sites,249 and even the nematode C. elegans .250179 DMSO in Basic Neuroprotection
A rat dementia model was developed251 and used to study the ability of DMSO 
combined with the glycolytic intermediate FDP.252,253
This model was unique in the sense that most other models previously used 
induced brain ischemia by lesioning the brain with cytotoxic chemicals, cold freez -
ing, or focal electrolytic lesions. Temporary or transient bilateral common carotid 
artery occlusion (2-vessel occlusion [2-VO]) did not injure the brain directly, allow -
ing instead a process where chronic brain hypoperfusion and its effect in producing memory impairment take place. This pathologic and progressive process mimics severe human carotid artery stenosis or occlusion, which over a protracted period of time results in mild cognitive impairment, the preclinical precursor of AD. 254,255
Older rats 14  months old were subjected to either permanent bilateral carotid 
artery occlusion (2-VO) ( Figure 8 .11) or sham occlusion where surgery but no occlu -
sion was done. Following surgical recovery, rats were tested for visuospatial memory function every 2 weeks for a total of six sessions. 252 On week 14 postsurgery, four 
rats from the 2-VO group who in previous trials had shown persistent and severe visuospatial memory impairment were selected to receive DMSO + FDP pharmaco -
therapy. These four rats were given once a day, a combined 28% solution composed of DMSO–FDP (250:130 mg/kg) intraperitoneally for seven consecutive days. Nontreated 2-VO rats that only showed moderate visuospatial memory deficits 
and sham controls that had no memory impairment were given an equivalent volume of the vehicle, dextrose 5% intraperitoneally for 7 days. On week 15, after 7 days of daily treatments, all rats were retested in a water maze for memory function. Following this testing session, all treatments were discontinued for an additional 
Carotid ar teryCarotid ar tery
2-Vessel occlusion
Mild co gnitive impairment model
FIGURE 8.11  (See color insert.) Permanent occlusion of both common carotid arteries 
(2-VO) in 14-month old rats. After 1 to 14 weeks, mild cognitive impairment characterized by progressive visuospatial memory impairment is observed that can be quantified and reversed with DMSO treatment. (From de la Torre, J.C. et al., Brain Res ., 779, 285, 1998. )180 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
3 weeks and rats were tested again in the water maze on weeks 16 and 18.252 The 
results showed that after 14 weeks of 2-VO, rats given DMSO + FDP had a 54% 
improvement in their visuospatial memory task, which nearly reached controls who had no carotid artery occlusion ( Figure 8 .12). Moreover, when treatment of DMSO + 
FDP was discontinued, the marked memory improvement seen on weeks 15 and 16 regressed to almost pretreatment level
252 (Figure 8 .12). Postmortem microscopic and densitometric analysis of brain sections stained for 
neurons and axonal fibers showed only mild loss of hippocampal neurons in rats with 2-VO regardless of treatment, and an increase in glial density was observed only in untreated 2-VO animals. 252
The results of this study imply that DMSO + FDP is an effective treatment for 
improving severe ischemic-induced visuospatial memory impairment in aging rats. The effect of DMSO + FDP on visuospatial memory improvement and its partial loss after discontinuation of therapy on week 16 is suggestive of a drug cause and effect. It also suggests that in order to maintain memory improvement during induced brain ischemia, this drug combination must be maintained. Studies have suggested that 
from 2 to 3 years before clinical dementia symptoms begin at a stage called mild 
cognitive impairment, there are already changes occurring in patients’ slowdown of visuospatial skills involving speeded tasks that require coordination of eye and visual representation needed for normal short-term memory function. 25660
5040Platfo rm loca tion latency (s)302010
13 14* p<0.01DMSO-FDP
Untreate d
No oc clusion
15 16 17
Weeks of tria lDMSO–FDP in ischemic memory loss
Treatmen tT reatment discontinu ed18 190* 
FIGURE 8.12  Old rats subjected to permanent bilateral carotid artery occlusion (2-VO) 
for 14 weeks. Rats with severest rate of visuospatial memory impairment selected by high -
est platform location latency (PLL) were given DMSO-FDP (triangles) for 7 days on weeks 
14 and 15. Significant (54%) improvement is seen in PLL after DMSO-FDP as compared to untreated 2-VO in reference to non occlusion rats. Following discontinuation of DMSO-FDP on weeks 16–18, gained memory improvement is partially lost. Untreated rats with 2-VO (circles) show unchanging moderate rate of visuospatial memory impairment, while rats with no 2-VO (squares) show no memory deficits throughout the 18 weeks of trials. Bars are ± 
SEM. See text for details. (Adapted from de la Torre, J.C. et al., Brain Res ., 779, 285, 1998. )181 DMSO in Basic Neuroprotection
Since visuospatial memory deficit is one of the earliest signs of impending AD 
during the mild cognitive impairment stage,257 DMSO + FDP may have interven -
tional value in preventing irreversible memory impairment in patients at high risk of 
developing AD. Confirmation of DMSO-FDP study was reported using the brain hypoperfusion 
model of bilateral carotid artery occlusion (2-VO) to test DMSO without FDP in rats.256 
DMSO at doses of 0.25 mL administered intraperitoneally for 5 consecutive days 11 weeks following 2-VO was seen to improve spatial memory learning as compared to nontreated 2-VO animals whose memory capacity was markedly worse. 258 In addition, 
microscopic examination of rat brains showed that 2-VO without postoperative treat -
ment induced hippocampal and cortical neuronal loss in nontreated animals, but it was observed that in DMSO-treated rats, this loss of neurons was significantly reduced. 258
An interesting study using Lurcher mice was recently reported by Markvartova 
and her colleagues.259 Lurcher mutant mice represent one of the frequently used 
mouse models of olivocerebellar degeneration. It is caused by a mutation in the δ2 
glutamate receptor subunit encoding gene.260
Lurcher mice suffer from almost complete degeneration of cerebellar Purkinje 
cells after birth and develop decreased density of granule, stellate, inferior olivary neurons, and basket cells but mild changes in deep cerebellar nuclei. 261
With almost total disruption of cerebellocortical signal processing, loss of 
Purkinje cells makes walking progressively more difficult for heterozygous Lurchers and clearly abnormal by 30 days postnatally. Homozygous Lurchers die at birth. Another characteristic of Lurcher mice is the link between cerebellar pathology 
and a physical activity that can influence the long-term potentiation (LTP) in the hippocampal region. LTP is widely considered one of the major cellular mechanisms that underlie 
learning and memory. 262
In this setting, DMSO was found to attenuate the age-related deterioration of some 
cognitive functions, including spatial learning abilities in 21-day-old treated Lurcher mice. 259
Animals were tested in a water maze designed to measure their learning and 
short-term memory ability. Before each memory trial, mice received either saline (no treatment) or DMSO administered intraperitoneally 30 min before the experiment at a dose of 4 μL/g of the body weight. Lurcher mice showed spatial navigation and 
spatial memory deficits compared to normal wild mice. In DMSO-treated Lurcher mice, a substantial improvement was observed in the learning and memory ability as compared to Lurcher mice given saline. 259
The possible mechanism for this improvement was not discussed by the authors. It is possible that DMSO may have imparted some usefulness to Lurcher mice by its ability to protect loss of function mutations like that which occurs in olivocerebel -
lar neurodegeneration. The damaging mechanism could involve an attack of nor -
mal protein folding and lead to their degradation, a process that has been shown 
to be inhibited by DMSO with help from the neuron’s own defense counterattack 
mechanisms. 176
Additionally, DMSO is also capable of minimizing the formation of hydroxyl-
induced sugar/base assault that is known to form near the vicinity of DNA damage 182 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
during double-strand DNA breaks.263,264 These mechanisms have not been studied 
in detail, and no final conclusions can be made with certainty. Finally, DMSO may 
be acting as a chemical chaperone, that is, as a low-molecular-weight compound whose function is to help correct conformational diseases characterized by protein misfolding, including neurodegenerative disorders. 265,266 This therapeutic approach 
would work by allowing the mutant proteins to escape the quality control systems of their genotype so that their function can be rescued by so-called folding agonists. These small molecules or folding agonists like DMSO, glycerol, and deuter -
ated water are osmotically active, a property thought to nonselectively stabilize the mutant proteins to facilitate their proper folding. 267
DMSO IN EXPERIMENTAL SPINAL CORD INJURY
SCI refers to any physical damage that results in impaired function to movement or feeling below the level of trauma. Injury to the spinal cord is either complete, where sensory-motor function is lost below the injury site on both sides of the body, or incomplete, where some function remains and complete recovery is possible. The level of injury is important because it determines what parts of the body will 
be affected. For example, a complete injury to the fourth cervical level of the cord (C-4) will result in quadriplegia with little function below the neck and will require a ventilator for breathing, whereas an injury to C-7 will retain the ability to breathe well and extend the arms but there may be trouble working the fingers with dexter -
ity. Paraplegias can be complete or incomplete injuries that result from damage to the first thoracic level of the cord (T-1) and below and where the use of the arms is retained but not the legs or parts of the trunk. The main causes of spinal cord injuries are from motor vehicle accidents, vio -
lence, falls, and sports, and CDC estimates about 11,000 spinal cord injuries occur annually who join a population of about 260,000 persons who already have an injury to the spinal cord. There have been a number of advances made in the last 50 years in the study of 
injured spinal cord, including basic and clinical tools to examine the spinal cord objectively and as critical adjuncts of neurologic examinations. Evoked potential is an important tool that can provide a quantitative measure of 
function in the respective sensory and motor tracts. Evoked potentials can also reveal the presence of unsuspected demyelinating disorders and their processes as well as monitor sensory-motor changes over time to assess neurologic progress and long-term prognosis. 268 Evoked potentials can be supplemented with newer techniques of 
evaluating spinal cord trauma such as transcranial magnetic motor-evoked potentials and dermatomal somatosensory-evoked potentials, which provide additional quanti -
fiable information about the status of the cord. 269
Aside from the use of neurophysiologic monitoring systems and methods that 
detail the morphology and contents of cord tissue, much of the experimentation 
conducted within the last 25 years has provided a better understanding and clini -
cal therapeutic approach to the injured spinal cord than at any time before. Such 
work has exposed significant aspects in the biochemistry and vascular mechanics 183 DMSO in Basic Neuroprotection
associated with trauma to the cord.270 A growing and intriguing area of spinal injury 
research lies in probing the factors related to neuronal plasticity and regeneration of 
the cord tissue. Despite hundreds of experimental treatments reported in the last half century 
on dozens of SCI animal models, no drug therapy thus far has shown effectiveness in reversing or arresting the pathologic damage, leading to paralysis when tested in randomized human clinical trials. The failure of testing DMSO to treat severe spinal cord trauma in humans, as will be seen, is a curious phenomenon given the positive evidence that will be presented here. Instead, clinically, intravenous steroid infusions, which were available 40 years 
ago and have been compared experimentally to DMSO in rigorous animal experi -
ments (see the following), are presently used in patients by many hospitals after a traumatic SCI in order to reduce the acute swelling that generally results after a severe contusion injury. This approach is baffling to many who treat spinal inju -
ries. The reason is that strong evidence indicates that methylprednisolone, the ste -
roid of choice, lacks evidence of effectiveness at the doses recommended following an SCI in humans and may in fact be harmful to the patient. 271 Interestingly, it was 
found that neurosurgeons in North America had been prescribing methylpredniso -
lone for acute spinal cord trauma not out of conviction that the drug was effective but out of fear of being sued for malpractice. 272
A recommendation by several Canadian studies was based on a wide search of 
citations that specifically addressed spinal cord injuries and the use of methylpred -
nisolone in humans and that, after analyses, did not support the use of this drug as a standard treatment for spinal cord trauma. 271–273 The call into question surrounding 
methylprednisolone as a standard therapy for spinal cord injuries pointed to the dubi -
ous study design and inappropriate statistical analysis used in the original study.274 
As a result of this controversy, the FDA has decided not to approve methylpredniso -
lone for SCI. Surgery and decompression may be needed when the injury has caused the bones 
to be unstable or when there is pressure on the spinal cord or spinal nerves by broken or displaced vertebral bones, a blood clot, or a displaced disk. These bones can move and cause further injury if not stabilized. The use of DMSO in SCI was introduced by de la Torre and his group
63,275–277 in 
1973, as a result of experiments showing dramatic benefit of this drug in rhesus and squirrel monkeys following severe brain trauma and disabling brain ischemia. 63
DMSO has been used in experimental SCI, but it has not been studied in a large 
human population.278 The results of animal experiments indicate that if a severe 
spinal cord trauma is treated with intravenous DMSO within 2 h, paralysis may be prevented. 63,275,276,279 Most studies performed thus far are consistent with this action 
by DMSO. When DMSO was examined for its action in experimental SCI and compared with 
other standard therapy such as steroids, HBO, mannitol, or urea, the findings indicated 
that DMSO fared far superior with respect to faster sensory-motor  r ecovery, reduced 
neural damage to the cord, lower swelling of tissue after trauma, increased muscle tone return, and earlier return of somatosensory-evoked potentials. 63,280–282184 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
The membrane-protecting and membrane-repair qualities after DMSO admin -
istration have been described for axons and their myelin sheaths after spinal cord 
trauma.280 An underlying mechanism in neuronal degeneration following trauma to 
the spinal cord is the inability of the tissue to repair itself in the face of membrane damage from edema, hemorrhage, and toxic molecules generated by the injury. DMSO was found to render significant improvement in resealing guinea pig axo -
lemma following transection of the cord. 283
This was physiologically demonstrated by monitoring membrane potential recov -
ery and by the lack of extrusion of the marker horseradish peroxidase (HRP) given 60 min after injury. 283 It is difficult to explain how DMSO may achieve the protec -
tion or repair ability of tissue membranes, but a likely mechanism may rely on how DMSO can limit spinal cord tissue inflammation and tissue cavitation while increas -
ing spinal cord blood flow. 281,282
One of the original studies on the use of DMSO in SCI involved permanent paral -
ysis induced in dogs from experimental trauma to the spinal cord.63 Drug treatments 
consisting of mannitol(1 g/kg), dexamethasone 0.5 mg/kg), isotonic saline (5 mL), or DMSO (2.5 g/kg, 40% solution) were given intravenously 1 h after trauma and for the next 3 days after injury. 63 Dogs were evaluated daily for 90 days with respect to 
sensory-motor function and bladder control, and strict posttrauma veterinary care was provided for bladder, pain, and discomfort during recovery. The results of this study are summarized in Figure 8 .13. Essentially, a ben -
eficial response to DMSO treatment was seen in 3 of 8 dogs 4 days after SCI, 
5
4Neurolog ic scale3210
4DMSO
MannitolDexameth asone
No treatmen t
60
Days of obse rvationDMSO in SC I
90
FIGURE 8.13  Neurological status using a 0–5 scale after SCI in dogs (N = 8/group) was 
recorded and graded daily for 90 days by an observer unaware of treatment. Each symbol 
represents a dog. Full recovery 90 days after SCI is seen in five dogs treated with DMSO (triangles), and two dogs treated with dexamethasone (dark circles) (p < 0.01). One other dog treated with DMSO also reached good recovery (grade 4), and one dog remained at grade 2, 
while another dog in this series died. Five dexamethasone-treated dogs did not reach a grade 
above 2 at the end of the 90-day observation period, one dog died in this series. Mannitol (circled cross) and no treatment (squares) showed no benefit and remained at grade 0–1 for 90 days after SCI. Scale: 0 = flaccid paraplegia, 1 = some muscle tone, 2 = reflex standing, 3 = spastic walking, 4 = walking, running with deficit, 5 = normal, full recovery. 63185 DMSO in Basic Neuroprotection
and a gradual improvement was noted in these animals so that 5 dogs in this 
series recovered completely and 1 dog showed walking and running ability with deficit. By contrast, dexamethasone-treated dogs showed improvement late in the first 
and second month with 2 dogs showing full recovery at 90 days and 5 dogs remain -
ing incapacitated ( Figure 8 .13). Dogs treated with mannitol or isotonic saline showed 
little to no improvement during the 90-day observation period. When somatosensory-evoked potentials were taken 4 h after trauma, only DMSO-treated dogs showed a partial response, which was later seen to be a positive correlation with the prognosis of eventual full recovery. 63
This study by de la Torre and his team63 indicated two key points. First, it estab -
lished that DMSO, if given within an hour after an SCI, can protect cord tissue using this model from neurodegeneration, an effect that was evident 4 days following trauma; and second, DMSO appeared superior to steroid therapy, which is presently considered standard treatment at many U.S. centers that treat spinal trauma. These findings were never extended to explore how late in time the protective action by DMSO can be maintained after an SCI. The findings also imply that if DMSO were approved for the treatment of SCI and was seen to lose its neuroprotective activ -
ity after 1 h following trauma, it would be expedient for ambulance technicians to assess the patient at the place of injury and, if indicated, administer a bolus of DMSO intravenously. Because DMSO has been found superior to methylprednisolone and similar 
steroid in cats, dogs, monkeys, and rodents sustaining a severe spinal cord trauma with respect to better motor performance, improved somatosensory-evoked poten -
tials, and less cord tissue damage, it has been argued that substituting DMSO for methylprednisolone in the treatment of human SCI could not only prove to be neu -
rologically superior to methylprednisolone but that DMSO would likely cause less postoperative medical complications that are seen with steroid therapy. 278,279 This 
argument is compelling for the following reasons. DMSO has been shown in several studies to consistently improve somatosensory-
evoked potentials following spinal cord trauma.63,280–282 This action has not been 
reported following steroid treatment in spinal trauma. For example, it was found that DMSO given intraperitoneally 1 h after injury produced better motor control of rats’ lower legs than methylprednisolone or naloxone 14 days after injury, a finding that was clinically supported by the improvement of the somatosensory-evoked poten -
tials when all treatments were compared. 280
Spinal trauma–induced dogs were given 0.63 g/kg of DMSO intravenously in a 
40% solution 1 h after injury and once daily for the first two postoperative days.281 
In the same study, DMSO was compared to dexamethasone (2.2 mg/kg) at the same time schedules as DMSO. It was reported that DMSO-treated animals had a mark -
edly significant higher group score than dexamethasone or no treatment in catego -
ries such as recovery of walking, running ability, cortical-evoked potentials, and 
histologically, with less cavitation, meningeal hyperplasia, and necrosis of the cord. The authors concluded that even though steroids are used clinically to treat SCI, DMSO may be a better treatment option as suggested by their findings and those of others. 281186 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
DMSO was examined by Gelderd and his colleagues282 after complete spinal cord 
trauma, where recovery of function below the lesion site is unlikely. Rats under -
went complete transection of the cord at T5 and after surgery; the animals were 
treated with either HBO, DMSO, or both. These investigators found that in animals receiving HBO for 54 consecutive days, 3 of 10 rats showed coordinated hind-limb movement and weight-bearing ability, whereas 6 of 10 animals given HBO + DMSO showed similar improvements and some sensory return. There were additionally less scarring and collagen formation with more undamaged nerve fibers in HBO + DMSO than other treatments. 282
DMSO was observed to lower the neuropathic pain threshold in rats following 
chronic pressure on the sciatic nerve.239 When 2% DMSO was injected intrathecally 
twice daily for 5 days, raised cytochrome oxidase-2 levels in the ipsilateral to injury dorsal horn resulted and significant analgesic effects were seen when compared to untreated animals. 239
The neuroprotective effect of DMSO administration after spinal cord trauma is 
also observed by the ability of this drug to maintain better structural integrity than other potential neuroprotective agents, including steroids, when examined by elec -
tron microscopy. DMSO appears able to detoxify oxidative stress and peroxynitrite damage by lowering lipid peroxidase and nitrite–nitrate activity in the presence of cord ischemia. 284
Oxidative stress is involved in a host of disorders, including brain trauma, stroke, 
AD, atherosclerosis, and cardiac disease,285 while peroxynitrite is known to impair 
cell signal transduction, cause DNA strand breaks, and change protein structure.286
As reviewed in this chapter and in Chapters 1, 2, and 4, DMSO has been shown to 
play a positive role in brain trauma, ischemic stroke, experimental dementia, cardiac deficits, atherosclerosis, DNA strand breaks, and protein folding. It is safe to say that these properties are highly unusual for any drug that has received the intense scrutiny and experimental testing that DMSO has undergone in the past 50 years and which continues to this day. The specific bioactivities shown by DMSO in the face of central nervous system pathology together with its relative safety record should be a gold standard in pharmacotherapeutic research. These activities have been reviewed in this chapter and include its anti-inflammatory, anti-ischemic, antiedema, anticyto -
toxic, membrane protective, and ionic channel–stabilizing properties. The results summarized in this chapter also suggest that DMSO in combination 
with an agent or agents that provide a positive biologic activity that is lacking in DMSO may result in unanticipated benefit to medical conditions refractory to other treatments. This is observed when DMSO and FDP are combined into one solution to treat brain ischemia in animals
70 or humans.210 When brain ischemia or hypoperfu -
sion occurs, there is a reduction of acute or chronic energy metabolism that gener -
ally affects Na+, K+-ATPase, a biochemical pump that is dependent on the generation 
of ATP derived from anaerobic glycolysis and oxidative phosphorylation.287 Na+, 
K+-ATPase is critical for maintaining ionic concentration gradients, neuronal action 
potentials, neurotransmitter synthesis, and slow/fast axonal transport. In addition, low glucose turnover in brain resulting from continuing ischemia will downregulate anaerobic glycolysis by inhibiting the key regulatory enzyme controlling glycolysis, phosphofructokinase. 288187 DMSO in Basic Neuroprotection
DMSO has no known activity in improving anaerobic glycolysis or restoring 
the activity of the Embden–Meyerhof pathway to activate oxidative phosphory -
lation when administered during prolonged ischemic states. On the other hand, 
FDP can because it is a glycolytic intermediate in the Embden–Meyerhof cycle that can stimulate anaerobic glycolysis and increase the production of the energy fuel ATP. However, FDP is not known to increase cerebral blood flow or scav -
enge free radicals during ischemia as DMSO can. So, it is reasonable to pair off these two substances to augment the quality and potential of the treatment in conditions such as stroke, coronary artery disease, and vascular-dependent dementias. This appears to work in a rat model of dementia
70 as reported here, 
and it is only speculative, but intriguing, to theorize that this drug combination could be useful if administered as a neuroprotector in preventing or delaying the onset of AD or vascular dementia. It is only hypothetical that DMSO may be synergistic with many other standard drugs in increasing their effectiveness and reducing their dose and side effects. DMSO AS A SOLVENT
One note of caution concerns the use of DMSO as a solvent for testing other poten -
tially therapeutic drugs. Since DMSO is an excellent solvent, it is a common practice to dissolve an experimental drug in DMSO and then test the compound on a given disorder. However, even small doses of DMSO can be active or synergistic when mixed with other agents. A case in point is a study by Levine et al. 289 who used 
the matrix-metalloproteinase inhibitor GM6001 dissolved in DMSO to treat dogs that had sustained an SCI. 289 The dogs were evaluated for long-term motor-sensory 
recovery using a modified Frankel scale and were shown to have significant improve -
ment when GM6001 + DMSO were used but not when GM6001 was used alone. These investigators attributed the improved neurological outcome to DMSO and not to GM6001. 289
A similar situation arose when an epidermal growth factor inhibitor was dissolved 
in DMSO and tested in a rodent SCI model. When the inhibitor was compared to the DMSO vehicle, recovery of motor and bladder function was significantly greater in rats treated with DMSO relative to the inhibitor. 290
In the realm where the politics of science exists, it seems an ethical dilemma that 
a simple, inexpensive, relatively safe, and highly effective agent like DMSO, which appears to be superior to standard therapy for brain trauma, brain ischemia, spinal injury, and many other traumatic conditions, has not been the object of more meticu-lous and comprehensive clinical studies that can determine the merits of this drug. Since many good therapies throughout the times have languished in obscurity and 
apathy until a chance rediscovery has allowed them a second chance at helping con -
trol damage from disease and physical injury, it is hoped that DMSO is one of those drugs that will escape this indifference and be the object of some well-designed, 
randomized clinical trials that can determine its place in the history of medicine. The simple molecular structure of DMSO also invites further research into the 
possibility of finding other chemically similar molecules that may be even more 
powerful and effective than DMSO in treating brain and spinal trauma.188 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
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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:

        It is now well recog -
nized that low cerebral blood flow and CPP are potentially harmful in patients with 
brain trauma and are associated with poor outcome. 231,232
What is less clear is whether altering cerebral blood flow or CPP will lead to clini -
cal improvement. The study by Brown et al. 230 suggests that the traumatized brain 3. 0
2. 0
1. 0
11 03 0
Minutes* p<0. 05Untreate d
DMSO
Hours12 46mL/100 g ms/min
FIGURE 8. 9  Cerebral metabolic rate of oxygen consumption decreased in all animals after 
injury and rose progressively after DMSO (triangles) as compared to untreated animals (dark 
circles). (Adapted from Brown, F. D. et al. , Ann. NY Acad. Sci. , 411, 245, 1983. ) 100
50mm Hg
0
11 03 0
Minutes**
*
* p<0. 05
Hours12 46Untreate d
DMSO
FIGURE 8. 10  CPP fell to nearly half of the baseline values within 10 min of injury and was 
reversed by DMSO (triangles). Two hours after DMSO treatment, CPP values had returned to baseline unlike untreated animals (dark circles).
The study by Wang et al. revealed that DMSO extended the lifespan of C. elegans in a dose-dependent manner.
What is the purpose of the study by Wang et al.?
The study did not discuss the mechanism by which DMSO may achieve its protective effects.
What is the primary mechanism by which DMSO may achieve its protective effects in the brain?
The study by Gelder et al. did not report the purpose of their study.
What is the purpose of the study by Gelder et al.?
The text does not discuss the primary mechanism by which DMSO may achieve its protective effects in the spinal cord.
What is the primary mechanism by which DMSO may achieve its protective effects in the spinal cord?
The study by Wang et al. found that DMSO extended the lifespan of C. elegans in a dose-dependent manner.
What is the purpose of the study by Wang et al.?