In vivo treatment with the K+ channel blocker 4-aminopyridine protects against kainate-induced neuronal cell death through activation of NMDA receptors in murine hippocampus.
Activation of NMDA receptors has been shown to induce either neuronal cell death or neuroprotection against excitotoxicity in cultured neurons in vitro. To elucidate in vivo neuroprotective role of NMDA receptors, we investigated the effects of activation of NMDA receptors by endogenous glutamate on kainate-induced neuronal damage to the mouse hippocampus in vivo. The systemic administration of the K+ channel blocker 4-aminopyridine (4-AP, 5 mg/kg, i.p.) induced expression of c-Fos in the hippocampal neuronal cell layer, which expression was completely abolished by the noncompetitive NMDA receptor antagonist MK-801, thus indicating that the administration of 4-AP would activate NMDA receptors in the hippocampal neurons. The prior administration of 4-AP at 1 h to 1 day before significantly prevented kainate-induced pyramidal cell death in the hippocampus and expression of pyramidal cells immunoreactive with an antibody against single-stranded DNA. Further immunohistochemical study on deoxyribonuclease II revealed that the pretreatment with 4-AP led to complete abolition of deoxyribonuclease II expression induced by kainate in the CA1 and CA3 pyramidal cells. The neuroprotection mediated by 4-AP was blocked by MK-801 and by the adenosine A1 antagonist 8-cyclopenthyltheophylline. Taken together, in vivo activation of NMDA receptors is capable of protecting against kainate-induced neuronal damage through blockade of DNA fragmentation induced by deoxyribonuclease II in the murine hippocampus.
Ogita
Kiyokazu
K
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. ogita@pharm.setsunan.ac.jp
Okuda
Hiroaki
H
Watanabe
Mami
M
Nagashima
Reiko
R
Sugiyama
Chie
C
Yoneda
Yukio
Y
D015761:4-Aminopyridine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004706:Endodeoxyribonucleases / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000473:pathology; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors
D004277:DNA, Single-Stranded; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D026902:Potassium Channel Blockers; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015761:4-Aminopyridine; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II; D007608:Kainic Acid