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Pharmacology of dmso
Department of Surgery • Oregon Health Science University • Portland, Oregon 97201
A wide range of primary pharmacological actions of dimethyl sulfoxide (DMSO) hasbeen documented in laboratory studies: membrane transport, effects on connectivetissue, anti-inflammation, nerve blockade (analgesia), bacteriostasis, diuresis,enhancements or reduction of the effectiveness of other drugs, cholinesteraseinhibition, nonspecific enhancement of resistance to infection, vasodilation, musclerelaxation, antagonism to platelet aggregation, and influence on serum cholesterolin emperimental hypercholesterolemia. This substance induces differntiation andfunction of leukemic and other malignant cells. DMSO also has prophylacticradioprotective properties and cryoprotective actions. It protects against ischemicinjury. (1986 Academic Press, Inc.)
The pharmacologic actions of dimethyl sulfoxide (DMSO) have stimulated muchresearch. The purpose of this report is to summarize current concepts in this area.
When the theorectical basis of DMSO action is described, we can list literallydozens of primary pharmacologic actions. This relatively brief summary will touchon only a few:
(A) membrane penetration(B) membrane transport(C) effects on connective tissue(D) anti-inflamation(E) nerve blockade (analgesia)(F) bacteriostasis(G) diuresis(H) enhancement or reduction of effectiveness of other drugs(I) cholinsterase inhibition(J) nonspecific enhancement of resistance of infection(K) vasodilation(L) muscle relaxation(M) enhancement of cell differentiation and function(N) antagonism to platelet aggregation(O) influence on serum cholesterol in experimental hypercholesterolemia(P) radio-protective and cryoprotective actions(Q) protection against ischemic injury
Primary Pharmocological Actions
DMSO readily crosses most tissue membranes of lower animals and man.
Employing [35S] DMSO, Kolb et al,59 evaluated the absorption and distribution ofDMSO in lower animals and man. Ten minutes after the cutaneous application inthe rat, radioactivity was measured in the blood. In man radioactivity appeared inthe blood 5 minutes after cutaneous application. One hour after application of
DMSO to the skin, radioactivity could be detected in the bones.
Denko22 and his associates applied 35S-labeled DMSO to the skin of rats. Within 2hour a wide range of radioactivity was distributed in all organs studied. The highestvalues occurred in decreasing order in the following soft tissues; spleen, stomach,lung, vitreous humor, thymus, brain, kidney, sclera, colon, heart, skeletal muscle,skin, liver, aorta, adrenal, lens of eye, and cartilage.
Rammler and Zaffaroni80 have reviewed the chemical properties of DMSO andsuggested that the rapid movement of this molecule through the skin, a proteinbarrier, depends on a reversible configurational change of the protein occurringwhen DMSO substitutes for water.
Nonionized molecules of low molecular wight are transported through the skin withDMSO. Substance of high molecular weight such as insulin do not pass throughthe skin to any significant extent. Studies in our laboratory have revealed that a 90%concentration of DMSO is optimal for the passage of morphine sulfate dissoved inDMSO.77 It would have been expected that 100% would provide better transportthan 90%, and the reason for an optimal effect at 90% DMSO remains unexplained.
It is of course well known that 70% alcohol has a higher phenol:water partitioncoefficient than 100% alcohol.
Elfbaum and Laden27 conducted an in vitro skin penetration study employingguinea pig skin as the membrane. They concluded that the passage of picrate ionthrough this membrane in the presence of DMSO was a passive diffusion processwhich adhered to Fick's first law of diffusion. It is demonstrated by diffusion andisotope studies that the absolute rate constant for the penetration of DMSO wasapproximately 100 times greater than that for the picrate ion. Thus, the twosubstances were transferred through the skin independently of each other. Theexact mechanisms involved in the membrane penetrant action of DMSO have yet tobe elucidated.
Studies on membrane penetration and carrier effect have been carrier effect havebeen carried out in agriculture, basic biology, animals, and man. In field tests withseverely diseased fruit, Keil55 demonstrated that oxytetracycline satisfactorilycontrolled bacterial spot in peaches. Control was significantly enhanced by addingDMSO to the antibiotic spray. DMSO was applied to 0.25 and 0.5% with 66 ppm ofoxytetracycline. This application gave control of the disease similar to that producedalone by 132 ppm of oxytetracycline and suggested the possibility of diluting thehigh-priced antibiotic with relatively inexpensive DMSO. There is no good evidencein animals that 0.5% DMSO has significant carrier effects. It could well be that Keil'sresults were attributable to a carrier effect, but the possibility should always beconsidered that when DMSO is combined with another substance a new compoundresults which can then exert a greater or lesser influence on a given process.
Leonard63 studied different concentrations of several water-soluable iron sourcesapplied as foliage sprays to orange and grapefruit trees whose leaves showedvisible signs of iron deficiency. The application of iron in DMSO as a spray wasfollowed by a rapid and extensive greening of the leaves, with a higherconcentration of chlorophyll.
Amstey and Parkman2 evaluated the influence of DMSO on the infectivity of viralnucleic acid, an indication of its transmembrane transport. It was found that DMSOenhanced polio RNA infectivity in kidney cells from monkeys. Enhancementoccurred with all DMSO concentrations from 5 to 80% and was optimal at 40%DMSO, with a 20-minute absorption period at room temperature. A significantpercentage of nucleic acid infection was absorbed within the first 2 minutes.
Cochran and his associates14 concluded that concentrations of DMSO below 20%did no influence the infectivity of tobacco mosaic virus (TMV) or the viral RNA. Withconcentrations between 20 and 60% the infectivity of TMV and TMV RNA variedinversely with the DMSO concentration.
Nadel and co-workers72 suggested that DMSO enhanced the penetration of theinfectious agent in experimental leukemia of gunea pigs. Previously Schreck etal.97 had demonstrated that DMSO was more toxic in vitro to lymphocytic leukemiathan to lymphocytes from normal patients.
Djan and Gunberg24 studied the percutaneous absorption of 17-estradiol dissolvedin DMSO in the immature female rat. These steroids were given in aqueoussolutions subcutaneously or were applied topically in DMSO. Vaginal and uterineweight increases resulting from estrogen in DMSO administered topically werecomparable to results obtained in animals in which the drugs were administered inpure form subcutaneously.
Smith102 reported that a mixture of DMSO and diptheria toxoid applied frequentlyto the backs of rabbits causes a reduction of the inflammation produced by theShick test, indicating that a partial immunity of diphtheria has been produced.
Finney and his associates29 studied the influence of DMSO and DMSO-hydrogenperoxide on the pig myocardium after acute coronary ligation with subsequentmyocardial infaction. The addition of DMSO to a hydrogen peroxide perfusionsystem fascilitated the difffusion of oxygen into the ischemic myocardium.
Maddock et al.66 designed experiments to determine the usefulness of DMSO as acarrier for antitumor agents. The agents were dissoved in 85-100% concentrationsof DMSO. One of the tumors studied was the L1210 leukemia. Survival time withouttreatment was appoximately 8 days. The standard method of employing Cytoxanintraperitoneally produced a survival time of 15.5 days. When Cytoxan was appliedtopically in water, the survival time was 12.6 days, and topical Cytoxan dissolved inDMSO resulted in survival time of 15.3 days.
Spruance recently studied DMSO as a vehicle for topical antiviral agents,concluding that the penetration of acyclovir (ACV) through guinea pigs skin in vitrowas markedly greater with DMSO than when ployethylene glycol (PEG) was thevehicle. When 5% ACV in DMSO was compared with 5% ACV in PEG in thetreatmental herpes infection in the guinea pig, ACV DMSO was more effective.103
The possibility of altering the blood-brain diffusion barrrier with DMSO needsadditional exploration. Brink and Stein10 employed [14C]pemoline dissolved inDMSO and injected intraperitoneally into rats. It was found in larger amounts in thebrain than was a similar dose given in 0.3% tragacanth suspension. The authors
postulated that DMSO resulted in a partial breakdown of the blood-brain diffusionbarrier in vitro.
There is conflicting evidence as to whether dimethyl sulfoxide can reversibly openthe blood-brain barrier and augment brain uptake of water-soluable compounds,including anticancer agents. To investigate this, 125[-Human serum albumin, horse-radish peroxidase, or the anticancer drug melphalan was administered iv to rats ormice, either alone or in combination with DMSO. DMSO administration did notsignificantly increase the brain uptake of any of the compounds as compared tocontrol uptakes. These results do not support prior reports that DMSO increasesthe permeability of water-soluable agents across the blood-brain barrier.43
Maibach and Feldmann67 studied the percutaneous penetration of hydrocortisoneand testosterone in DMSO. The authors concluded that there was a threefoldincrease in dermal penetration by these steroids when they were dissolved inDMSO.
Sulzberger and his co-workers107 evaluated the penetration of DMSO into humanskin employing methylene blue, iodine, and iron dyes as visual tracers. Biopsiesshowed that the stratum corneum was completely stained with each tracer appliedto the skin surface in DMSO. There was little or no staining below this layer. Theauthors concluded that DMSO carried substances rapidly and deeply into the hornylayer and suggested the usefulness of DMSO as a vehicle for therapeutic agents ininflammatory dermatoses and superficial skin infections such as pyodermas.
Perliman and Wolfe76 demonstrated that allergens of low molecular weight such aspenicillin G potassium, mixed in 90% DMSO, were readily carried through intacthuman skin. Allergens having molecular weights of 3000 or more dissolved inDMSO did not penetrate human skin in these studies. On the other hand, Smithand Hegre101 had previously recorded that antibodies to bovine serum albumindeveloped when a mixture of DMSO and bovine serum albumin was applied to theskin of rabbits.
Turco and Canada112 have studied the influence of DMSO on lowering electricalskin resistance in man, In combination with 9% sodium chloride in distilled water,40% DMSO decreased resistance by 100%. It was postulated that DMSO incombination with electrolytes reduced the electrical resistance of the skin byfacilitating the absorption of these electrolytes while it was itself being absorbed.
DMSO in some instances will carry substances such as hydrocortisone orhexachlorophene into the deeper layers of the stratum corneum, producing areservoir.104 This reservoir remains for 16 days and resists depletion by washing ofthe skin surface with soap, water, or alcohol.105
Mayer and associates69 compared the effects of DMSO, DMSO with cortisoneacetate, cortisone acetate alone, and saline solutions on the incidence of adhesionsfollowing vigorous serosal abrasions of the terminal ileum of Wistar rats. Theirtechnique had developed adhesions in 100% of control animals in 35 days. Thetreatments were administered daily as postoperative intraperitoneal injections for 35days. The incidence of adhesions in different groups was DMSO alone: 20%,
DMSO-cortisone: 80%, cortisone alone: 100%, saline solution: 100%.
It has been observed in serial biopsy specimens taken from the skin of patients withscleroderma that there is a dissolution of collagen, the elastic fibers remainingintact.93 Gries et al.44 studied rabbit skin before and after 24 hour in vitro exposureto 100% DMSO. After immersion in DMSO the collagen fraction extractable withneutral salt solution was significantly decreased. The authors recorded that topicalDMSO in man exerted a significant effect on the pathological deposition of collagenin human postirradiation subcutaneous fibrosis but did not appear to change theequilibrium of collagen metabolism in normal tissue. Urinary hydroxyproline levelsare increased in scleroderma patients treated with topical DMSO.93 Keloidsbiopsied in man before and after DMSO therapy show histological improvementtoward normalcy.28
Berliner and Ruhmann7 found that DMSO inhibited fibroblastic proliferation in vitro.
Ashley et al.3 reported that DMSO was ineffective in edema following thermal burnsof the limbs of rabbits. Formanek and Kovak31 showed that topically applied DMSOinhibited traumatic edema induced by intrapedal injection of autologous blood in theleg of a rat.
DMSO showed no anti-inflammatory effect when studied in experimental effectwhen studied in experimental inflammation induced in the rabbit eye by mustard oilin the rat ear by croton oil.79
Gorog and Kovacs40 demonstrated that DMSO exerted minimal anti-inflammationeffects on edema induced by carrageenan. These authors also studied theanti-inflammatory potential of DMSO in adjuvant-induced polyarthritis of rats.
Topical DMSO showed potent anti-inflammatory properties in this model. Gorog andKovacs41 have also studied the anti-inflammatory activity of topical DMSO, incontact dermatitis, allergic eczema, and calcification of the skin of thr rat, using 70%DMSO to treat the experimental inflammation. All these reactions were significantlyinhibited.
The study of Weissmann et al.114 deserves mention in discussing theanti-inflammatory effects of DMSO. Lysosomes can be stabilized against a variety ofinjurious agents by cortisone, and the concentration of the agent necessary tostabilize lysosomes is reduced 10- to 1000-fold by DMSO. The possibility wassuggested that DMSO might render steroids more available to their targets withintissues (membranes of cells or their organelles).
Suckert106 has demonstrated anti-inflammatory effects with intra-articular DMSO inrabbits following the creation of experimental [croton oil] arthritis.
Immersion of the sciatic nerve in 6% DMSO decreases the conduction velocity by40%. This effect is totally reversed by washing the nerve in a buffer for 1 hour.89Shealy99 studied peripheral small fiber after-discharge in the cat. Concentrations of5-10% DMSO eliminated the activity of C fibers with 1 minute: activity of the fibersreturned after the DMSO was washed away.
DMSO injected subcutaneously in 10% concentration into cats produced a total lossof the central pain response. Two milliliters of 50% DMSO injected into thecerebrospinal fluid led to total anesthesia of the animal for 30 minutes. Completerecovery of the animal occurred without apparent ill effect.100
Haigler concluded that DMSO is a drug that produced analgesia by acting bothlocally and systemically. The analgesia appeared to be unrelated to that producedby morphine although the two appear to be a comparable magnitude. DMSO had alonger duration of action than morphine, 6 hr vs 2 hr, respectively.45
DMSO exerts a marked inhibitory effect on a wide range of bacteria and fungiincluding at least one parasite, at concentrations (30-50%) likely to be encounteredin antimicrobial testing programs in industry.6
DMSO at 80% concentration inactivated viruses tested by Chan and Gadenbusch.
These viruses included four RNA viruses, influenza A virus, influenza A-2 virus,Newcastle disease virus, Semliki Forest virus, and DNA viruses.12
Seibert and co-worker98 studied the highly pleomorphic bacteria regularly isolatedfrom human tumors and leukemic blood. DMSO in 12.5-25% concentration causedcomplete inhibition of growth in vitro of 27 such organisms without affecting theintact blood cells.
Among the intriguing possibilities for the use of DMSO is its ability to alter bacterialresistance. Pottz and associates78 presented evidence that the tubercle bacillus,resistant to 2000Ýg of treptomycin or isoniazide, became sensitive to 10Ýg of eitherdrug after pretreatment with 0.5-5% DMSO.
Kamiya et al.54 found that 5% DMSO restored and increased the sensitivity ofantibiotic-resistant strains of bacteria. In particular, the sensitivity of all four strainsof Pseudomonas to colistin was restored when the medium contained 5% DMSO.
The authors recorded that antibiotics not effective against certain bacteria, such aspenicillin to E. coli, showed growth inhibitory effects when the medium containedDMSO.
Ghajar and Harmon35 studied the influence of DMSO on the permeability ofStaphylococcus aureau, demonstrating that DMSO increased the oxygen uptakebut reduced the rate of glycine transport. They could not define the exactmechanism by which DMSO produced its bacteriostatic effect.
Gillchriest and Nelson37 have suggested that bacteriostasis from DMSO occursdue to a loss of RNA conformational structure required for protein synthesis.
Formanek and Suckert32 studied the diuretic effects of DMSO administeredtopically to rats five times daily in a dosage of 0.5 ml of 90% DMSO per animal. Theurine volume was increased 10-fold, and with the increase in urine volume, therewas an increase in sodium and potassium excretion.
H. Enhancement or Reduction of Concomitant Drug Action
Rosen and associates84 employed aqueous DMSO to alter the LD50 in rats andmice when oral quaternary ammonium salts were used as test compounds. In rats,the toxicity of pentolinium tartrate and hexamethonium bitartrate was increased byDMSO, while the toxicity of hexamethonium iodide was decreased.
Male68 has shown that DMSO concentrations of upward to 10% lead to a decidedincrease in the effectiveness of griseofulvin.
Melville and co-workers70 have studied the potentiating action of DMSO oncardioactive glycosides in cats, including the fact that DMSO potentiates the actionof digitoxin. This effect, however, does not appear to involve any change in the rateof uptake (influx) or the rate of loss (efflux) of glycosides in the heart.
Sams et al.90 studied the effects of DMSO on skeletal, smooth, and cardiacmuscle, employing concentrations of 0.6-6%. DMSO strikingly depressed theresponse of the diaphragm to both direct (muscle) and indirect (nerve) electricalstimulation, and caused spontaneous skeletal muscle fasciculations. DMSOincreased the response of the smooth muscle of the stomach to both muscle andnerve stimulations. The vagal threshold was lowered 50% by 6% DMSO.
Cholinesterase inhibition could reasonably explain fasciculations of skeletal muscle,increased tone of smooth muscle, and the lower vagal threshold observed in theseexperiments. In vitro assays show that 0.8-8% DMSO inhibits bovine erythrocytecholinesterase 16-18%.
In a study of antigen-antibody reactions, Reattig81 showed that DMSO did notdisturb the immune response. In fact, the oral administration of DMSO to mice for10 days prior to an oral infection with murine typhus produced a leukocytosis andenhanced resistance to the bacterial infection.
Adamson and his co-workers1 applied DMSO to a 3-1 pedicle flap raised on theback of rats. The anticipated slough was decreased by 70%. The authorssuggested that the primary action of DMSO on pedicle flap circulation was toprovoke a histamine-like reponse. Roth87 has also evaluated the effects of DMSOon pedicle flap blood flow and survival, concluding that DMSO does indeedincrease pedicle flap survival, but postulating that this increase takes place by somemechanism other than augmentation of perfusion. Kligman56, 57 had previouslydemonstrated that DMSO possesses potent histamine-liberating properties.
Leon62 has studied the influence of DMSO on experimental myocardial necrosis.
DMSO therapy effected a distinct modification with less myocardial fiber necrosisand reduced residual myocardial fibrosis. The author reported that neithermyocardial rupture nor aneurysm occured in the group treated with DMSO.
DMSO applied topically to the skin of patients produces electromyographicevidence of muscle relaxation 1 hour after application.8
Deutsch23 has presented experimental data showing that 5% DMSO lessons theadhesiveness of blood platelets in vitro. Gorog39 has shown that DMSO is a goodantagonist to platelet aggregation as well as thrombus formation in vivo. Gorogevaluated this in the hamster cheek pouch model.
N. Enhancement of Cell Differentiation and Function
It has been shown that dimethyl sulfoxide induces differentiation and function ofleukemic cells of mouse 11, 33, 46, 65, 92, 115, rat,58 and human.9, 15, 16, 34,109 DMSO was also found to stimulate albumin production in malignantlytransformed hepatocytes of mouse and rat49 and to affect the membrane-associated antigen, enzymes, and glycoproteins in human rectal adenocarcinomacells.111 Hydrocortisone-induced keratinization of chick embryo cells74 andadriamcycin-induced necrosis of rat skin108 were inhibited by DMSO.
Furthermore, modification by DMSO of the function of normal cells has beenreported. DMSO stimulates cyclic AMP accumulation and lipolysis and decreasesinsulin-stimulated glucose oxidation in free white fat cells of [the] rat. It alsoenhances heme synthesis in quail embryo yolk sac cells.110
Leukemic blasts can be induced by external chemical agents to mature toneutrophils, monocytes, or RBCs. The phenotype of leukemic cells thus resultsfrom both internal genetic aberrations and the response of leukemic cells to theirexternal environment. When human myeloid leukemia cells are exposed in vitro to avariety of agents (e.g.vitamin A or dimenthyl sulfoxide) the blasts lose theirproliferative potential, the expression of oncogene products is sharply decreased,and after 5 days the leukemic cells become morphologically mature and functionalneutrophils. Some patients with myeloid leukemias have responded to therapydesigned to induce maturation in vivo. The induced maturation of leukemic cells is anew therapeutic tactic-alternative to cytotoxic drug therapy-wherein leukemic cellsare destroyed by transforming them into neutrophils.86
O. Influence on Serum Cholesterol in Experimental Hypercholesterolemia
Rabbits given a high cholesterol diet with 1% DMSO showed one-half as muchhypercholesterolemia as control animals.48
P. Radioprotective and Cryoprotective Actions
M.J. Ashwood-Smith has written a comprehensive review of these actions.4
De la Torre has advanced a scheme based on both investigated and theoreticalactions of DMSO on the biochemical events generated after an ischemic injury. Hepreviously proposed this hypothetical model to help conceptualize how DMSO, orsimilar drugs, mights affect the pathochemical balance that results in lack of tissue
The biochemical and vascular responses to injury appear to have a cause andeffect relationship that can be integrated in terms of substances that either increaseor decrease blood flow. The substance's effect can be physical, i.e. reduce orincrease the vessel lumen obstruction, or chemical, i.e. reduce or increase thevessel lumen diameter (vasoconstriction/vasodilation).
Platelets, for example, can induce both conditions. Obstruction of the vessel lumencan result from platelet adhesion (platelet buildup in damaged vessel lining) orplatelet aggregation. Platelet damage moreover can cause vasoconstriction orvasospasm by liberating vasoactive substances locally with the blood vessel orperivascularly, if penetrating damage to the vessel has occurred. There are twostorage sites within platelets that contain most of these vasoactive substances. Thealpha granules contain fibrinogen, while the dense bodies store ATP, ADP,serotonin, and calcium, which can be secreted by the platelet into the circulation bya canalicular system.5 Thromboxane A2 has also been shown to be manufacturedin the microsomal fraction of animal and human platelets.73 All these vasoactivesubstances (with the exception of ATP) can cause significant reduction of bloodflow by physical or chemical reactivity on the vasculature.
DMSO can antagonize a number of these vasoactive substances released by theplatelets, which could consequently induce vasoconstriction, vasospasm, orobstruction of vessel lumen. For example, a study has shown that DMSO can inhibitADP and thrombin-induced platelet aggregation in vitro.95 It may presumable dothis by increasing the evels of cAMP (a strong platelet deaggregator) throughinhibition of its degradative enzyme, phosphodiesterase.26, 51 DMSO is reported todeaggregate platelets in vivo following experimental cerebral ischemia.26, 51 Thiseffect may be fundamental in view of the finding that cerebral ischemia producestransient platelet abnormalities that may promote microvascular aggregationformation and extend the area of ischemic injury.25
The biochemical picture is further complicated by the possible activity of DMSO onother vasoactive substances secreted by the platelets during injury or ischemia. Forexample, the release of calcium from cells from cells or platelets and its effect onarteriolar-wall muscle spasm may be antagonized by circulating DMSO.13, 88Collagen-induced platelet release may also be blocked by DMSO.44, 94
The following effects of DMSO are likely to be involved in its ability to protectagainst ischemic injury.
DMSO and PGTX System
Little is known about the actions of DMSO on the prostanoids (PG/TX). Studieshave reported that DMSO can increase the synthesis of PGE1, a moderatevasodilator.61. PGE1 can reduce platelet aggregation by increasing cAMP levelsand also inhibit the calcium-induced release of noradrenalin in nerve terminals, anaffect that may antagonize vasoconstriction and reduction of cerebral blood flow.53
DMSO, it will be recalled, also has a direct effect on cAMP. It increases cAMPpresumably by inhibiting phosphodiesterase,113 although an indirect action onPGI2-induced elevation of platelet cAMP by DMSO should not be ruled out. Any
process that increases platelet cAMP will exert strong platelet deaggregation.
It has also been reported that DMSO can block PFG2 receptors and reduce PFE2synthesis.82 Both these compounds can cause moderate platelet aggregation andPFG2 is known to induce vasoconstriction.60 The effects of DMSO on thromboxanesynthesis are unknown. It could, however, inhibit TXA2, biosynthesis in much thesame way as hydralazine or dipyridamole42 since it shares a number of similarproperties with these agents: specifically, their increase of cAMP levels.
DMSO and Cell Membrane Protection
The ability of DMSO to protect cell membrane integrity in various injury models iswell documented.38, 64, 91, 114
Cell membrane preservation by DMSO might help explain its ability to improvecerebral and spinal cord blood flow after injury.18 DMSO could be preventingimpairment of cerebrovascular endothelial surfaces where PGI2 is elaborated andwhere platelets can accumulate following injury. The effects of DMSO may betwo-fold: reduction of platelet adhesion by collagen,44 and reduction of plateletadhesion by protecting the vascular endothelium and ensuring PGI2 release.
DMSO, Hydroxyl Radicals, and Calcium
Although many hormones, chemical transmitters, peptides, and numerous enzymescan be found in mammalian circulation at any given time, it is the hydrozyl radicalsthat have drawn attention by playing an important role in the pathogenesis ofischemia.21, 30 Free radicals can be elaborated by peroxidation of cellularmembrane-bound lipids where oxygen delivery is not totally abolished, as inischemia and hypoxia, or when oxygen is resupplied after an ischemic episode.83
One of the significant sites where hydroxyl radicals can form following ischemia is inmitochondria. DMSO is known to be an effective hydroxyl radical scavenger.4, 20,75 Since it has been shown that DMSO can improve mitochondrial oxidativephosphorylation, it has been suggested that DMSO may act to neutralize thecytotoxic effects of hydroxyl radicals in mitochondria themselves.96 Oxidativephosphorylation is one of the primary biochemical activities to be negatively affectedfollowing ischemic injury. DMSO has also been reported to reduce ATPase activityin submitochondrial particles,17, 36 an effect that can lower oxygen utilizationduring cellular ischemia.
It has been proposed that DMSO may reduce the utilization of oxygen by aninhibiting effect on mitochondrial function. In one experiment the energy loss due toinhibition of oxidative activity after brain tissue was perfused with DMSO wascompensated for by an increase in glycolysis.36
It seems probable that the neutralizing action of DMSO on hydroxyl radical damagefollowing injury could diminish the negative outcome of ischemia. However theformation of hydroxyl radicals is dependent on time and oxygen availability, but thedevelopment of ischemia is immediate and its reversal may depend on moreprevalent subsystems such as the PG/TX and platelet interactions. Maintaining thebalance of these subsystems appears more critical in predisposing the outcome ofcerebral ischemia.
Another interesting effect of DMSO is on calcium. When isolated rat hearts areperfused with calcium-free solution followed by reperfusion with a calcium-containing solution, a massive release of creatine kinase (indicating cardiac injury)is observed. This creatine kinase level increase is accompanied byelectrocardiographic (EKG) changes and ultrastructural cell damage.50 DMSO hasbeen reported to significantly reduce the release of creatine kinase and preventEKG and ultrastructural changes if it is present during reperfusion of the isolatedrat heart with a calcium-containing solution.88 Moreover, examination of the hearttissue by electron microscopy showed that DMSO-treated preparations lacked themitochondrial swelling and contraction band formation otherwise induced by thereentry of calcium.88 These findings are supported by another investigationshowing that DMSO can block calcium-induced degeneration of isolated myocardialcells.13 This protective effect by DMSO on myocardial tissue may be critical duringischemic myocardial infarction when evolutionary EKG changes, serum createskinase levels are elevated, and myocardial necrosis can develop rapidly.
DMSO2 is not an effective cryoprotective agent; however, Herschler47 has recordedthat DMSO (dimethyl sulfone) is a natural source of biotransformable sulfur inplants and lower animals. Jacob and Herschler have reported a number of uniqueproperties possessed by DMSO.52 Since DMSO is oxidized to DMSO2 in vivo,scientists should include DMSO as a control in basic biologic studies on DMSO inplants and animals.
(a) Although the abbreviation "Me2SO" has been recommended for chemists by theIUPAC, the abbreviation for dimethyl sulfoxide most familiar to those concerned withits medicinal uses is "DMSO." Consequently, this generic pharmacological name fordimethyl sulfoxide will be employed throughout this paper.
(b) Supported in part by a grant from The Ronald J. Purer Foundation. Presented atthe Symposium Biological Effects of Cryoprotective Agents at the CryobiologyMeeting, June 1985, Madison, Wis.
(c) Stanley W. Jacob, MD, Gerlinger Associate Professor of Surgery and SurgicalResearch.
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Source: Received September 9, 1985. Accepted September 16, 1985 by theAcademic Press, Inc. Printed 1985 (pp. 14-27). DMSO Organization wishes to thankthe Academic Press, Inc., for allowing us to place this article on our World WideWeb site. Academic Press retains all copyright. To copy any portion of this article,please obtain permission from the publisher.
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Test deployment of the “turbulence mooring” By Ilker Fer, Geophysical Institute, University of Bergen The ocean surface is a complex boundary where air-sea fluxes of mass, momentum and energy take place. The processes in this dynamic interface are of crucial importance for ocean circulation and ecosystems in general. The coupling between surface gravity waves, winds and currents in the