Effect of phenytoin and corticosteroids on seizures and lipid peroxidation in experimental posttraumatic epilepsy

Abstract

Head trauma, intracerebral hematoma formation, and hemorrhagic cerebral infarction cause extravasation of the intravascular contents, red blood cell (RBC) hemolysis, hemosiderin deposition within the neuropil, and an increased incidence of epilepsy. Reports conflict regarding the efficacy of the administration of prophylactic anticonvulsant drugs to head-injured patients to prevent the development of posttraumatic epilepsy. In this study, rats received a 10-microliter injection of 100 mM FeCl2 at a depth of 1.8 mm into the isocortex, or an equal volume of saline. Rats were then treated with 30 mg/kg methylprednisolone (MPS), 90 mg/kg MPS, 100 mg/kg phenytoin, or with an equal volume of propylene glycol. Behavioral or electroencephalographic (EEG) seizures occurred in all control-treated iron-injected rats within 93 +/- 6 minutes of injection. Brain injury responses as measured by the occurrence of fluorescent product formation from iron-induced lipid peroxidation showed 6.6 +/- 0.8 units/gm in the saline-injected animals, and 16.7 +/- 2.5 units/gm in the control-treated iron-injected rats. Of the 90-mg/kg MPS-treated rats, 8% had seizures; fluorescence in those animals was 5.7 +/- 0.5 units/gm. Phenytoin treatment prevented the occurrence of convulsive and EEG seizures; however, lipid peroxidation was unaffected (16.5 +/- 4.1 units/gm). If posttraumatic epilepsy develops because of RBC extravasation, hemolysis, parenchymal deposition of heme compounds, and initiation of lipid peroxidation, then treatments designed to prevent peroxidation may be more effective for epilepsy prophylaxis than administration of anticonvulsant drugs that mask convulsive seizures while biochemical brain injury continues.

Zonisamide Reduces the Increase in 8‐Hydroxy‐2′‐Deoxyguanosine Levels Formed During Iron‐Induced Epileptogenesis in the Brains of Rats

“…These observations suggest that ZNS does have an antioxidant effect within the brain. We believe the effect of ZNS on the formation of 8-OHdG may be a specific feature of the drug since phenytoin, another antiepileptic drug known to act through an effect on sodium channels, fails to inhibit ferrous-induced lipid peroxidation in rat brains (19). Damage to DNA by the effects of reactive oxygen species appear to be associated with increased levels of 8-OHdG.…”

The relationship between excitotoxicity and oxidative stress in the central nervous system

“…63 It should also be recognized that in some seizures a prolonged hypertension may occur, which may contribute ROS generation as a result of accelerated arachidonate metabolism via prostaglandin H synthase. 3 • 4 A reciprocal relation between seizures and ROS appears to exist, since free radicals induced in the brain by hyperbaric oxygen can precede, and may provoke, convulsions.…”

“…22 · 99 Such events have been proposed to account for posttraumatic epileptogenesis. 100 Free radical generation during cerebral ischemia may underlie delayed neuronal death. 101 · 102 Ischemic injury and edema within the CNS have frequently been found to involve excessive oxidative activity as judged by lipid peroxidation, induction of superoxide dismutase, and the protection afforded by antioxidant chemicals, such as alpha-tocopherol, iron chelators, or 2 l-aminosteroids.…”

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

“…The concentration of TBARS was increased and total AO status was decreased in epilepsy, supporting a role for OS [19]. Treatments designed to prevent lipid peroxidation may be more effective for epilepsy prophylaxis than administration of antiepileptic drugs that mask convulsive seizures while brain injury continues [20]. Melatonin exhibits AO, antiexcitotoxic and radical scavenging abilities [21].…”