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

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.

Protein kinase inhibitor as a potential candidate for epilepsy treatment

“…It has been shown that increased activity of different kinases can contribute to the dysfunction of both ion (Bernard et al., 2004) and neurotransmitter receptor channels (Tehrani & Barnes, 1995; Rakhade et al., 2008) that are involved in several types of epilepsy. Inhibition of several kinases has also been reported to reduce seizure activity (Weisner et al., 1999; Inan & Büyükafsar, 2008; Queiroz & Mello, 2008) and to have antiepileptogenic properties in genetic epilepsy (Zeng et al., 2009).…”

Selective Upregulation of Brain-Derived Neurotrophic Factor (BDNF) Transcripts and BDNF Direct Induction of Activity Independent N-Methyl-D-Aspartate Currents in Temporal Lobe Epilepsy Patients with Hippocampal Sclerosis

“…15 -17 Inhibition of this receptor can significantly reduce aberrant mossy fibre sprouting and modify epileptic activity in a model of TLE. 18 Upregulated BDNF was confirmed in a number of chronic seizure models in animals and in human epileptic brains. 19 -22 N-Methyl-D-aspartic acid (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor, mimicking the action of glutamate, which normally binds to that receptor.…”

Involvement of the neuronal phosphotyrosine signal adaptor N-Shc in kainic acid-induced epileptiform activity

“…Treatments with either TrkB-Fc or K252a, an inhibitor of the TrkB receptor, have reduced KA-induced epileptiform activity and the development of kindling in rats 6 25 . Interestingly, the conditional deletion of the TrkB receptor prevents epileptogenesis in the mouse model of kindling 26 .…”