IntroductIonIn spite of availability of considerable number of antiepileptic drugs, many patients continue to have seizures that are refractory to treatment defying our understanding and approaches of epilepsy. [1] Many old drugs continue to be evaluated for newer indications. Before such experiments, it is prudent to understand the pathological basis of epilepsy considering many newer understandings. Many of the currently used antiepileptic drugs are shown to inhibit calcium channel activity. [2,3] Theoretical considerations and few animal model studies have suggested that calcium channel antagonists may play a role as anticonvulsants. [4] These drugs are postulated to inhibit the positive inward burst firing activating wide range of neurons leading to seizures. To support such theoretical considerations, few animal model studies and clinical studies have shown that nimodipine has anticonvulsant property. [5] Combination of calcium channel blockers was shown to have mixed effects. Diltiazem enhances the nimodipine's antiseizure effects. Flunarizine inhibits nimodipine's effects. [6] During the last decade of the 20 th century, there was a heightened interest in the evaluation of calcium channel blockers for epilepsy in animal model. However after the introduction of gabapentin, topiramate, tiagabine, levetiracetam, and zonisamide, the interest in the evaluation of monotherapy for epilepsy has waned. However, the evaluation has continued as add-on therapy in both animal model and in clinical trials.Objective: To evaluate the anticonvulsant and antioxidant actions of diltiazem, nimodipine, and flunarizine in the Wistar albino rats using the maximum electroshock-induced seizure (MES) model. Materials and Methods: Thirty inbred Wistar rats were divided into five groups of six rats in each group. Groups 3, 4, and 5 were pretreated with diltiazem (20 mg/kg), nimodipine (20 mg/kg), and flunarizine (10 mg/ kg), respectively. Group 2 served as a standard group and received phenytoin (25 mg/kg). All groups were subjected to MES. Twenty-four hours after the MES, hemisections of the rat brain were homogenized, and oxidative markers (glutathione [GSH], lipid peroxidation [LPO], and myeloperoxidase [MPO]) and neurotransmitters (dopamine, serotonin, gamma-aminobutyric acid, acetylcholine, and glutamate levels) were estimated. Histological changes were studied with hematoxylin and eosin-stained hemisection of rat brain. Apoptotic marker heat shock protein (HSP) was used for immunohistochemical changes. Results: Rats pretreated with diltiazem, nimodipine, and flunarizine showed a statistically significant reduction in duration of hind limb extension phase and clonic seizures. GSH, LPO, and MPO changes indicate better oxidative stress outcomes in rat brains pretreated with diltiazem and flunarizine. Neurotransmitters showed variable and significant changes. There were histoarchitectural changes such as cerebral edema, vacuole formation, and intracytoplasmic granules with all three calcium channel blockers in acute phase. HSP was ...