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% 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.
Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.
C M
CM
Queiroz
L E
LE
Mello
D000704:Analysis of Variance; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology*; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008032:Limbic System / Q000166:cytology / Q000187:drug effects; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D017828:Rifabutin / Q000031:analogs & derivatives; D012640:Seizures / Q000503:physiopathology; D018709:Statistics, Nonparametric
D016227:Benzoquinones; D002227:Carbazoles; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D026121:Indole Alkaloids; D047029:Lactams, Macrocyclic; D009414:Nerve Growth Factors; D017828:Rifabutin; C020754:herbimycin; C049985:staurosporine aglycone; D011505:Protein-Tyrosine Kinases; D007608:Kainic Acid