Expression of heat shock protein 70 induced by 4-aminopyridine through glutamate-mediated excitotoxic stress in rat hippocampus in vivo.
The intrahippocampal administration of 4-aminopyridine (4-AP) induces epileptic seizures and neurodegeneration, due probably to stimulation of glutamate release from synaptic terminals. We have studied the time course of the neurodegenerative changes produced by 4-AP, perfused through microdialysis cannulas in rat hippocampus, and correlated them with the expression of the inducible heat shock protein 70 (HSP70), detected immunocytochemically. Electroencephalographic seizure activity appeared immediately after the beginning of 4-AP perfusion. The first signs of histological neuronal damage were observed in CA1 and CA3 subfields of the perfused hippocampus 3 h after treatment and progressed until reaching a maximal neuronal loss at 24 h. In 4-AP-treated rats HSP70 was expressed mainly in neurons of the contralateral hippocampus, with a time course and cellular distribution very similar to the neurodegeneration observed in the perfused hippocampus, but no neuronal damage was observed. The N-methyl-D-aspartate (NMDA) receptor antagonists MK-801 and (3-phosphonopropyl)-piperazine-2-carboxylic acid prevented the seizures, the neurodegeneration and the expression of HSP70. These data demonstrate that the 4-AP-induced release of endogenous glutamate overactivates NMDA receptors in the perfused hippocampus and that the resulting neuronal hyperexcitability propagates to the contralateral hippocampus, generating a glutamate-mediated neuronal stress sufficient to induce the expression of HSP70 but not to produce neurodegeneration. These findings provide a useful model for investigating the relationships between neuronal hyperexcitation, neurodegeneration and the role of HSP expression.
Ayala
Gabriela X
GX
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, C.P. 04510 México D.F., Mexico.
Tapia
Ricardo
R
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004569:Electroencephalography; D004827:Epilepsy / Q000503:physiopathology; D005110:Extracellular Space / Q000378:metabolism; D007839:Functional Laterality; D015870:Gene Expression / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D017551:Microdialysis; D009410:Nerve Degeneration; D018696:Neuroprotective Agents / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013003:Somatosensory Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D013312:Stress, Physiological / Q000139:chemically induced / Q000378:metabolism*; D013997:Time Factors
D000927:Anticonvulsants; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D010879:Piperazines; D026902:Potassium Channel Blockers; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D015761:4-Aminopyridine