Protein tyrosine kinase inhibitors modify kainic acid-induced epileptiform activity and mossy fiber sprouting but do not protect against limbic cell death

C.M Queiroz,L.E Mello

doi:10.1590/s0100-879x2008000500009

Abstract

Intrahippocampal administration of kainic acid (KA) induces synaptic release of neurotrophins, mainly brain-derived neurotrophic factor, which contributes to the acute neuronal excitation produced by the toxin. Two protein tyrosine kinase inhibitors, herbimycin A and K252a, were administered intracerebroventricularly, in a single dose, to attenuate neurotrophin signaling during the acute effects of KA, and their role in epileptogenesis was evaluated in adult, male Wistar rats weighing 250-300 g. The latency for the first Racine stage V seizure was 90 +/- 8 min in saline controls (N = 4) which increased to 369 +/- 71 and 322 +/- 63 min in animals receiving herbimycin A (1.74 nmol, N = 4) and K252a (10 pmol, N = 4), respectively. Behavioral alterations were accompanied by diminished duration of EEG paroxysms in herbimycin A- and K252a-treated animals. Notwithstanding the reduction in seizure severity, cell death (60-90% of cell loss in KA-treated animals) in limbic regions was unchanged by herbimycin A and K252a. However, aberrant mossy fiber sprouting was significantly reduced in the ipsilateral dorsal hippocampus of K252a-treated animals. In this model of temporal lobe epilepsy, both protein kinase inhibitors diminished the acute epileptic activity triggered by KA and the ensuing morphological alterations in the dentate gyrus without diminishing cell loss. Our current data indicating that K252a, but not herbimycin, has an influence over KA-induced mossy fiber sprouting further suggest that protein tyrosine kinase receptors are not the only factors which control this plasticity. Further experiments are necessary to elucidate the exact signaling systems associated with this K252a effect.

Highlights

Kainate binding sites have been described in the hippocampus as being restricted to the molecular layer of granule cells and to the stratum lucidum of the CA3 region, where the mossy fibers terminate [1]
We investigated the effects of two different protein tyrosine kinase inhibitors, K252a and herbimycin A, on the acute epileptiform activity, cell death and mossy fiber sprouting (MFS) induced by the intrahippocampal injection of kainic acid (KA) in rats
While animals from the SAL-DMSO group walked, groomed and slept after surgery, animals injected with KA presented tremors, clonic movements, wild-running, Racine stage V seizure [14], and status epilepticus (KA-DMSO: 3 of 4 animals; KA and herbimycin A (KA-HERB): 3 of 4 animals; KA-K252a: 2 of 4 animals)

Summary

Introduction

Kainate binding sites have been described in the hippocampus as being restricted to the molecular layer of granule cells and to the stratum lucidum of the CA3 region, where the mossy fibers (granule cell axons) terminate [1]. Intracerebral injection of kainic acid (KA) leads to selective destruction of pyramidal CA3 neurons [2] and are associated with epileptiform discharges [3]. KA administration mimics some features of human temporal lobe epilepsy [4], i.e., hippocampal neuronal loss, reactive gliosis, mossy fiber sprouting (MFS), and spontaneous recurrent seizures [5]. Intrahippocampal injection of KA increases brain-derived neurotrophic factor (BDNF) immunoreactivity in the mossy fiber terminal zone [6] and it is postulated that www.bjournal.com.br.

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