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

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 percent 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.

Anti-seizure efficacy of nimodipine in pentylenetetrazole and kainic acid combined seizure models in mice.

The present study aimed at establishing two models of experimental seizures by combination treatment with subconvulsive doses of PTZ and kainic acid in adult male mice and evaluating the modulatory role of cerebroselective dihydropyridine calcium channel blocker, nimodipine. The CD50 +/- SEM value for PTZ was found to be 20.00 +/- 0.92 mg/kg, ip in kainic acid (administered at per se subconvulsive dose of 1.00 mg/kg, ip) pretreated mice while CD50 +/- SEM value for kainic acid was found to be 0.30 +/- 0.08 mg/kg, ip in PTZ (administered at per se subconvulsive dose of 30.00 mg/kg, ip) pretreated mice. Nimodipine (5.00 mg/kg, ip) significantly protected the mice from seizure in both of the combination in vivo seizure models. The results suggested synergistic interaction between PTZ and kainic acid at subconvulsive dose combination while the protective efficacy of nimodipine suggested the role of calcium ion as an important mediator for the genesis of seizures.

Kainic acid induced epileptogenesis in developing normal & undernourished rats--a computerised EEG analysis.

Experimental epilepsy was induced in developing normal, undernourished and subsequently rehabilitated rats by locally injecting graded doses of Kainic acid (KA) in the right frontal cortex. Frequency and power spectral analysis of EEG was carried out to assess the progressive changes in EEG during KA-epileptogenesis. Undernourished animals were highly susceptible to seizure discharge. They exhibited generalized tonic-clonic discharge and had episodes of clinical seizures even after temporary neuronal recovery. Increase in power of delta, theta and decrease in alpha power was observed in the compressed spectral array (CSA) of undernourished animals. Delayed neuronal recovery with reduced background EEG and marked electrosilence in response to intra-rectal sodium valproate was observed in undernourished animals. Rehabilitated animals exhibited partial recovery which was related to the body weight gain. Spike frequency, spike amplitude and neuronal recovery time were not significantly differet between normal and undernourished animals at lower doses of KA (7.5-60 ng) whereas at higher doses (120-500 ng) marked differences were observed in these parameters. In KA treated undernourished rats 3H-glycine incorporation was significantly higher than normal in the hippocampus and spinal cord and lower in the cerebellum.