NMDA preconditioning and neuroprotection in vivo: delayed onset of kainic acid-induced neurodegeneration and c-Fos attenuation in CA3a neurons.
Intraventricular (i.c.v.) kainic acid (KA) causes an acute excitotoxic lesion to the CA3 region of rodent hippocampus. Recent evidence implicated c-fos gene in regulating neuron survival and death following an excitotoxic insult. In this study we attempted to prevent KA-induced damage in CA3 neurons with NMDA preconditioning, which produced a marked expression of c-fos in the hippocampus. NMDA (0.6-6 microg, i.c.v.) was injected to anesthetized rats alone or 1 h before KA (0.15 microg, i.c.v.). Following KA injection, vibratome sections were processed for immunohistochemistry/electron microscopy. c-Fos and Nissl staining were used to estimate the extent of neuronal excitation and damage, respectively. Quantitative evaluation of c-Fos-labeled cells showed significantly less c-Fos in CA3a than in neighboring CA3b and CA2 from 1 to 4 h after KA alone. Attenuation of expressed c-Fos in CA3a was accompanied by damage of neurons with more apoptotic than necrotic signs. NMDA preconditioning elevated CA3a c-Fos expression and at 1 and 2 h exceeded markedly that after KA alone. However, at 4 h after KA, NMDA-preconditioned c-Fos induction in CA3a diminished to the same level as that seen after KA alone. The onset of neuronal degeneration was delayed in similar way. While NMDA-induced c-Fos expression in CA3a could be blocked by MK-801 completely, MK-801 and CNQX were both without significant effect on KA-induced c-Fos expression and neuronal damage. In conclusion, inhibition of c-Fos expression and onset of neuronal damage in CA3a following icv KA injection might be transiently delayed by i.c.v. NMDA preconditioning.
Mohammadi
Shirin
S
Department of Physiology, Faculty of Medicine, Kuwait University, P.O.Box 24923, 131 10 Safat, Kuwait.
Pavlik
Alfred
A
Krajci
Dimitrolos
D
Al-Sarraf
Hameed
H
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000627:therapeutic use; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000627:therapeutic use*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016291:Dizocilpine Maleate; D007608:Kainic Acid; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate