Post-Treatment with Voltage-Gated Na super(+) Channel Blocker Attenuates Kainic Acid-Induced Apoptosis in Rat Primary Hippocampal Neurons

• Published in: Neurochemical research Vol. 35; no. 12; pp. 2175 - 2183
• Main Authors: Das, Arabinda, McDowell, Misty, O'Dell, Casey M, Busch, Megan E, Smith, Joshua A, Ray, Swapan K, Banik, Naren L
• Format: Journal Article
• Language: English
• Published: 01-12-2010
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-010-0321-1

Injection of rats with kainic acid (KA), a non-N-methyl-d-aspartate (NMDA) type glutamate receptor agonist, induces recurrent (delayed) convulsive seizures and subsequently hippocampal neurodegeneration, which is reminiscent of human epilepsy. The protective effect of anti-epileptic drugs on seizure-induced neuronal injury is well known; however, molecular basis of this protective effect has not yet been elucidated. In this study, we investigated the effect and signaling mediators of voltage-gated Na super(+) channel blockers (Lamotrigine, Rufinamide, Oxcarbazepine, Valproic Acid, and Zonisamide) on KA-induced apoptosis in rat primary hippocampal neurons. Exposure of hippocampal neurons to 10 mu M KA for 24h caused significant increases in morphological and biochemical features of apoptosis, as determined by Wright staining and ApopTag assay, respectively. Analyses showed increases in expression and activity of cysteine proteases, production of reactive oxygen species (ROS), intracellular free [Ca super(2+)], and Bax:Bcl-2 ratio during apoptosis. Cells exposed to KA for 15min were then treated with Lamotrigine, Rufinamide, Oxcarbazepine, Valproic Acid, or Zonisamide. Post-treatment with one of these anti-epileptic drugs (500nM) attenuated production of ROS and prevented apoptosis in hippocampal neurons. Lamotrigine, Rufinamide, and Oxcarbazepine appeared to be less protective when compared with Valproic Acid or Zonisamide. This difference may be due to blockade of T-type Ca super(2+) channels also by Valproic Acid and Zonisamide. Our findings thus suggest that the anti-epileptic drugs that block both Na super(+) channels and Ca super(2+) channels are significantly more effective than agents that block only Na super(+) channels for attenuating seizure-induced hippocampal neurodegeneration.