Effects of herbimycin A in the pilocarpine model of temporal lobe epilepsy.
Pilocarpine-induced status epilepticus (SE) causes widespread tyrosine phosphorylation in the brain. It has been postulated that this intracellular signal may mediate potentially epileptogenic changes in the morphology and physiology of particular brain regions, including the hippocampus. The present study evaluated the effects of herbimycin A, a protein tyrosine kinase (PTK) inhibitor, over the acute (during which intense biochemical and electrophysiological activation occurs) and the chronic phase (characterized by spontaneous and recurrent epileptic seizures and the presence of synaptic reorganization, e.g., mossy fiber sprouting) of the pilocarpine model of epilepsy. The administration of a single dose of 1.74 nmol of herbimycin A (i.c.v., 5 microL) 5 min after the onset of SE did not change the acute behavioral manifestation of seizures despite significantly decreasing c-Fos immunoreactivity in different areas of the hippocampus and of the limbic cortex. Herbimycin-treated animals developed spontaneous recurrent seizures, as did control animals, with a similar latency for the appearance of the first seizure and similar seizure frequency. Neo-Timm staining revealed that all animals experiencing SE, regardless of whether or not injected with herbimycin, showed aberrant mossy fiber sprouting in the supragranular region of the dentate gyrus. Herbimycin did not obviously affect neuronal cell death as evaluated in Nissl-stained sections. These results indicate that the PTK blockade achieved with the current dose of herbimycin reduced the acute c-Fos expression but failed to alter the spontaneous seizure frequency or to attenuate the morphological modifications triggered by the SE.
Queiroz
Claudio Marcos Teixeira de
CM
Department of Physiology, UNIFESP-EPM, Rua Botucatu, 862- 04023-062, São Paulo, SP, Brazil.
Mello
Luiz Eugênio
LE
D000704:Analysis of Variance; D000818:Animals; D016227:Benzoquinones; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D047029:Lactams, Macrocyclic; D008297:Male; D018721:Muscarinic Agonists / Q000633:toxicity*; D010862:Pilocarpine / Q000633:toxicity*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011809:Quinones / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D017828:Rifabutin / Q000031:analogs & derivatives
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D018721:Muscarinic Agonists; D016760:Proto-Oncogene Proteins c-fos; D011809:Quinones; D010862:Pilocarpine; D017828:Rifabutin; C020754:herbimycin