Prevention of post-traumatic epilepsy by scavengers of reactive oxygen species which involved in the pathogenesis of post-traumatic epilepsy

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PATHOPHYSIOLOGY AND MECHANISMS OF POS'I'rRAUMATIC EPILEPTOGENESIS L. James Wlllmore Depadments of Neurology and Neurosurgery, University of Texas Medical School, Houston, Texas USA Epilepsy complicates severe head trauma in 20-45% of injured patients. Development of persistent seizures appears to correlate with seveflty of injury, but particularly with the occurrence of intracerebral hemorrhage. Head trauma Initiates a sequence of responses that include altered blood flow and vasoregulation, disruption of the blood-bmln barrier, increases in intracranial pressure, focal or diffuse ischemia, hemorrhage, inflammation, necrosis and disruption of fiber tracts. The presence of an intracranial hematomaappears to have a robust association with the d e v e ~ of posttmurnatlc epllepsy. Extmvasation of blood is followed by red blood cell hemolysis and deposition of heme containing compounds into the neuropil, initiating a sequence of univalent redox reactions and generate various free radical species, including superoxides, hydroxyl radicals, peroxkles, and pederryl ions. Free radicals initiate peroxidation reactions by hydrogen abstraction from methylene groups adjacent to double bonds of fatty acids and lipids within cellular membranes. Intrinsic enzymatic mechanisms for control of free radical reactions include activation of catalase, peroxidase, and superoxide dismutase. Steroids, proleins and tocopherol also terminate peroxidative reaclions. Tocopherol and selenium are effective in preventing tissue injury initiated by ferrous chloride, and heine compounds. Antio)ddants and chelators may be useful, given the speculation that peroxidative reactions may be an important component of brain injury responses. Molecular modulation accounting for specific liability to develop an enduring seizure focus may depend upon enzymatic competence in quenching free radical reactions. Further, altered or defective DNA base alteration repair responses may account for cellular changes leading to disinhibition within a neuronal region. Potential protective efficacy of GABA agonists, NMDA receptor antagonists, and barbiturates need further scientific assessment. Treatment strategies for prevention or prophylaxis of posttraumatic epilepsy must await absolute knowledge o! mechanisms of pathogen(sis.

$5-B1-1-07 P R E V E N T I O N O F P O S T - T R A U M A T I C EPILEPSY BY S C A V E N G E R S OF REACTIVE O X Y G E N E SPECIES In T H E PATHOGENESIS OF P O S T - T R A U M A T I C EPILEPSY. I.Yokoi,H. Kabuto,H. Habu, A. Mori Dept. of Neuroscience,Inst.of Molecular& CellularMedicine.,Okayama Univ. Med. Sch.,Okaymm 700,Japan

W H I C H INVOLVED

Post-traumatic epilepsy is characterized by recurrent epileptic seizures due to brain damage after head trauma. Neurosurgeons classify post-traumaiic ep~lelmy into two types, i.e., early seizures (or early epilepsy) and late epilepsy, which is post-traumatic epilepsy proper. Early seizures is defined as convulsive seizure(s) occurring within 1 week of bead traun~ Seizures occur more fzequently during the first week after the head traumL Patients with early seizures have a high risk of late epilepsy. In 1978, V~rdlmore et al. reported an animal model of post-traumatic epilepsy. They showed that a single injection of FeCl2 or FeCls solution into the rat cerelral cor1~.x resulted in epileptic seizures. Using t l ~ model, it has been clear step by step that oxidation by reactive oxygen species (ROS), especially hydroxyl rad/cals (.OH), is thought to be involved in the mechanisms responsible for post-traum~c epilepsy. After/ntracr~;,l hemorrlmge, red blood cells break down and release iron ions from hemoglobin, and then ROS are genera~e~l in brain 1~sue by iron- and/or hemoglobin-mediated reactions. These radicals may be responsible for the initiat/on of lipid pero:ddatic~ at carbon double bonds in unsatulated fatty ,~a~ in neural membranes. Injury to the membranes impairs Na + ,K +ATPase activ/ty, and then it results in decrease of convulsive threshold. Injury to the membrane also leads neurotrausmitter disorders. For example, the release of aspagic add increases, and the release of 7 -aminobut~.c acid decreased. On the other hand, .OH accelerate the production of methylipumidine, which is known as an endogenous convulsant, from creatinine. These disorders may result in early epilepsy, that is major risk factor of post-traumatic epilepsy. To unde~tand the the biochemical patho~enesis of post-traumatic epilepsy as above, it is quite reasonable that ROS scavengers has been developed as preven~ve Ior post--traunm~c epilepsy. According to this strategy, many drugs have been e~mt/ned. Vitamin E, (-)-epig~ocatechin and (-)-el~g~Iocatechin-3-O-gallate isolated from green b~a leaves, and L--ascorb/c acid 2 - [ 3 , 4 dihydro-2,5,7,8-tetnunethyl- 2(4,8,12-trimethyltr/decyl)-2H-l-benzopFmn-6-yl hydrogenphosphate] potassium salt synthesized with vitamin C and vilmmn E connected with the phosphate s c a ~ ROS, and prevented or slowed the occurrence of epilel~iC discImr&~s induced by FeCI3. Recently, we found that adenosine (Ade) and 2-chroloadenosine (CI-Ade), which have been thought to have auticonvulsant effects, scavenged OH radicals. Also, they suppressed or delayed occurrence of epileptic disclmrges induced by FeCI3. CI-Ade and Ade may suppress the occurrence of el~leptic discharges through their effect as a ~)H scavenger and as an anticonvulsant

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