Na(+) and Ca(2+) homeostasis pathways, cell death and protection after oxygen-glucose-deprivation in organotypic hippocampal slice cultures.
Intracellular ATP supply and ion homeostasis determine neuronal survival and degeneration after ischemic stroke. The present study provides a systematic investigation in organotypic hippocampal slice cultures of the influence of experimental ischemia, induced by oxygen-glucose-deprivation (OGD). The pathways controlling intracellular Na(+) and Ca(2+) concentration ([Na(+)](i) and [Ca(2+)](i)) and their inhibition were correlated with delayed cell death or protection. OGD induced a marked decrease in the ATP level and a transient elevation of [Ca(2+)](i) and [Na(+)](i) in cell soma of pyramidal neurons. ATP level, [Na(+)](i) and [Ca(2+)](i) rapidly recovered after reintroduction of oxygen and glucose. Pharmacological analysis showed that the OGD-induced [Ca(2+)](i) elevation in neuronal cell soma resulted from activation of both N-methyl-d-aspartate (NMDA)-glutamate receptors and Na(+)/Ca(2+) exchangers, while the abnormal [Na(+)](i) elevation during OGD was due to Na(+) influx through voltage-dependent Na(+) channels. In hippocampal slices, cellular degeneration occurring 24 h after OGD, selectively affected the pyramidal cell population through apoptotic and non-apoptotic cell death. OGD-induced cell loss was mediated by activation of ionotropic glutamate receptors, voltage-dependent Na(+) channels, and both plasma membrane and mitochondrial Na(+)/Ca(2+) exchangers. Thus, we show that neuroprotection induced by blockade of NMDA receptors and plasma membrane Na(+)/Ca(2+) exchangers is mediated by reduction of Ca(2+) entry into neuronal soma, whereas neuroprotection induced by blockade of AMPA/kainate receptors and mitochondrial Na(+)/Ca(2+) exchangers might result from reduced Na(+) entry at dendrites level.
Project Group Neuropharmacology, Leibniz Institute for Neurobiology, Brenneckestrasse 6, D-39118 Magdeburg, Germany.
M
M
Martínez-Sánchez
F
F
Striggow
U H
UH
Schröder
S
S
Kahlert
K G
KG
Reymann
G
G
Reiser
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000502:physiology*; D002998:Clonazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D003620:Dantrolene / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016257:Fura-2 / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D000860:Hypoxia; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D007474:Ion Exchange; D008012:Lidocaine / Q000494:pharmacology; D020748:Mibefradil / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D009924:Organ Culture Techniques; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D001896:Boron Compounds; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D011810:Quinoxalines; D026941:Sodium Channel Blockers; D013841:Thiazepines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D020748:Mibefradil; D009553:Nimodipine; D002998:Clonazepam; D016291:Dizocilpine Maleate; C079032:CGP 37157; D000255:Adenosine Triphosphate; D008012:Lidocaine; D012964:Sodium; C109986:2-aminoethoxydiphenyl borate; D003620:Dantrolene; D013890:Thiourea; D005947:Glucose; D002118:Calcium; D016257:Fura-2; C000543:cyclopiazonic acid