Decreased epileptic susceptibility correlates with neuropeptide Y overexpression in a model of tolerance to excitotoxicity

Prior epileptic episodes have been shown to decrease markedly the neuronal damage induced by a second epileptic episode, similar to the tolerance foll owing an episode of mild ischemia. Endogenous neuroprotective effects media ted by various mechanisms have been put forward. This study investigated wh ether neuroprotection against the excitotoxic damage induced by re-exposure to an epileptic challenge can reflect a change in epileptic susceptibility . Tolerance was elicited in rats by a preconditioning session using intrahi ppocampal kainic acid (KA) administration followed at 1, 7 and 15-day inter vals by a subsequent intraventricular KA injection. The degree of pyramidal cell loss in the vulnerable CA3 subfield contralateral to the KA-injected hippocampus was extensively reduced in animals experiencing KA ventricular administration. This neuroprotection was highly significant 1 and 7 days af ter injection, but not 15 days after injection. In preconditioned animals, the after-discharge threshold was assessed as an index of epileptic suscept ibility. It increased significantly from 1 to 15 days after intrahippocampa l KA administration. Finally, an enhancement of neuropeptide Y expression i n both non-principal cells and messy fibers was detected, occurring at the same time as the decrease in epileptic susceptibility. These results provid e further evidence of an 'epileptic tolerance' as shown by the substantial neuroprotective effect of a prior episode of epileptic activity upon subseq uent epileptic insult and suggest that the prevention of excitotoxic damage after preconditioning results from an endogenous neuroprotective mechanism against hyperexcitability and seizures. (C) 2001 Elsevier Science B.V. All rights reserved.