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

作者：Das Arabinda; McDowell Misty; O'Dell Casey M; Busch Megan E; Smith Joshua A; Ray Swapan K; Banik Naren L^*

来源：Neurochemical Research, 2010, 35(12): 2175-2183.

DOI：10.1007/s11064-010-0321-1

• Primary hippocampal neurons
• Kainic acid
• Voltage-gated Na+ channel blocker

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+ 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 24 h 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 [Ca2+], and Bax:Bcl-2 ratio during apoptosis. Cells exposed to KA for 15 min were then treated with Lamotrigine, Rufinamide, Oxcarbazepine, Valproic Acid, or Zonisamide. Post-treatment with one of these anti-epileptic drugs (500 nM) 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 Ca2+ channels also by Valproic Acid and Zonisamide. Our findings thus suggest that the anti-epileptic drugs that block both Na+ channels and Ca2+ channels are significantly more effective than agents that block only Na+ channels for attenuating seizure-induced hippocampal neurodegeneration.

• 出版日期2010-12