HSP70 expression protects against hippocampal neurodegeneration induced by endogenous glutamate in vivo.
The K+ channel blocker 4-aminopyridine (4-AP) stimulates the release of glutamate from nerve endings and induces seizures and neurodegeneration when perfused by microdialysis in rat hippocampus. In addition, there is a temporal correlation between the progress of neurodegeneration in the perfused hippocampus and the expression of the inducible cellular stress marker heat shock protein 70 (HSP70) in the non-damaged contralateral hippocampus. All these effects of 4-AP are prevented by the NMDA receptor antagonists 3-phosphonopropyl-piperazine-2-carboxilic acid (CPP) and (+)5-methyl-10,11-dyhydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), indicating that they are due to NMDA receptor overactivation by excessive extracellular synaptic glutamate. We hypothesized that the induction of HSP70 in the non-damaged contralateral hippocampus should have a protective action against this excitotoxic effect. Here we demonstrate that 4-AP perfusion in one hippocampus prevented the neurotoxic effect of 4-AP when perfused by microdialysis in the contralateral hippocampus 24h later. However, both the stimulation of glutamate release and the EEG epileptiform discharges, which occur immediately after 4-AP perfusion, were similar after the first and the second perfusions. When CPP was coperfused with 4-AP during the first microdialysis, HSP70 induction in the contralateral hippocampus was prevented and the protection against the second 4-AP perfusion was abolished in 50% of the rats. These results suggest that HSP70 induction is an important cellular mechanism to protect vulnerable neurons from excitotoxic overactivation of glutamate receptors by endogenous glutamate, and may be relevant to pathological conditions in which extracellular endogenous glutamate is augmented, such as ischemia.
Ayala
Gabriela X
GX
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510-México DF, Mexico.
Tapia
Ricardo
R
D015761:4-Aminopyridine; D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004569:Electroencephalography; D007839:Functional Laterality / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D010879:Piperazines; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D015761:4-Aminopyridine