Late N-methyl-D-aspartate receptor blockade rescues hippocampal neurons from excitotoxic stress and death after 4-aminopyridine-induced epilepsy.
The intrahippocampal perfusion of 4-aminopyridine (4-AP) in the rat produces immediate seizures and delayed neuronal death, due to the overactivation of N-methyl-D-aspartate (NMDA) receptors by endogenous glutamate released from nerve endings. With the same time course, 4-AP also induces the expression of the cell stress marker heat shock protein 70 (HSP70) in the contralateral non-damaged hippocampus. We have used this experimental model to study the mechanisms of the delayed neuronal stress and death. The NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), administered intraperitoneally 30 or 60 but not 120 min after 4-AP perfusion, when animals show intense electroencephalography epileptiform activity, prevented the delayed neurodegeneration whereas the seizures continued for about 3 h as in the control animals. With an identical time window, MK-801 treatment also modified the pattern of HSP70 expression; the protein was expressed in the protected perfused hippocampus but no longer in the undamaged contralateral hippocampus. The possible role of Ca2+ in the delayed cell death and HSP70 expression was also studied by coperfusing the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester) with 4-AP. This treatment resulted in protective and HSP70 effects very similar to those of MK-801. These results suggest that the seizures are not linked to neurodegeneration and that NMDA receptors need to be continuously overactivated by endogenous glutamate for at least 60 min in order to induce delayed neuronal stress and death, which are dependent on Ca2+ entry through the NMDA receptor channel.
Ayala
Gabriela X
GX
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510-México, DF, México.
Tapia
Ricardo
R
D015761:4-Aminopyridine; D000818:Animals; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D007839:Functional Laterality; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009410:Nerve Degeneration / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D013312:Stress, Physiological / Q000209:etiology / Q000473:pathology*; D013997:Time Factors
D002614:Chelating Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D018698:Glutamic Acid; D004533:Egtazic Acid; D016291:Dizocilpine Maleate; D015761:4-Aminopyridine