Intracellular calcium concentrations during "chemical hypoxia" and excitotoxic neuronal injury

Abstract

Because hypoxic/ischemic neurodegeneration appears to be in part linked to glutamate neurotoxicity, we measured intracellular calcium (Ca2+i) levels in cultured hippocampal neurons during exposure to toxic doses of glutamate (GLU) and to an anoxic environment simulated by sodium cyanide (NaCN). Changes in Ca2+i produced by cyanide greatly exceeded those induced by GLU. The NaCN response was mimicked when oxidative metabolism was also disrupted by sodium azide, oligomycin, or dinitrophenol. Noncompetitive NMDA receptor antagonists and enzymatic GLU degradation abolished the GLU-induced Ca2+i increases and attenuated those produced by NaCN. Only NaCN-induced increases were blocked when dantrolene and ruthenium red were applied to prevent release from intracellular pools. All responses were reduced proportionally in the absence of added external calcium. These results suggest that extracellular GLU accumulation and subsequent activation of GLU receptors were involved in the NaCN response. During such metabolic compromise, however, GLU-induced elevations of Ca2+i were enormously amplified. In parallel toxicity studies, NaCN was not neurotoxic despite the large elevations in Ca2+i, indicating that a general elevation in cytoplasmic calcium does not necessarily predict neurodegeneration.

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

“…In contrast, delayed excitotoxic neuronal death occurs hours to days after the initial insult (Choi, 1985;Rothman et al, 1987). Delayed excitotoxic neuronal death is fundamentally dependent on the influx of extracellular Ca 2+ ions (Choi, 1985(Choi, , 1987 through the activated NMDA receptor (Dubinsky & Rothman, 1991;Hartley et al, 1993;Tymianski et al, 1993;Sattler & Tymianski, 2000). Just as NMDA receptor antagonists reduce the volume of the ischemic infarct in the whole animal (Gill et al, 1992), NMDA receptor antagonism protects cultured neurons from glutamate excitotoxicity Moudy et al, 1994).…”

“…The dependence of these phenomena on NMDA receptor activation and extracellular Ca 2+ has led to the Ca 2+ hypothesis of glutamate excitotoxicity, wherein NMDA receptor-mediated Ca 2+ influx causes the disruption of Ca 2+ homeostatic mechanisms and Ca 2+ overload which initiate pathways leading to neuronal death (Choi, 1987;Rothman et al, 1987;Siesjo & Bengtsson, 1989;Dubinsky & Rothman, 1991;Randall & Thayer, 1992;Hartley et al, 1993;Tymianski et al, 1993;Sattler & Tymianski, 2000).…”

Na+ and Ca2+ homeostasis pathways, cell death and protection after oxygen–glucose-deprivation in organotypic hippocampal slice cultures

“…Intracellular Ca 2ϩ is abnormally increased in neurons exposed to ischemic conditions. This effect has been described for in vivo conditions (Nakamura et al, 1999;Silver and Erecinska, 1992), during in vitro ischemia in hippocampal slices (Lobner and Lipton, 1993;Zhang and Lipton, 1999) and in neuronal cell cultures exposed to mitochondrial and glycolytic inhibitors (Dubinsky and Rothman, 1991). In these studies, Ca 2ϩ rises during the first few minutes after ischemia and progressively returns close to the resting level after the end of the ischemic conditions.…”

MK-801 (Dizocilpine) Protects the Brain from Repeated Normothermic Global Ischemic Insults in the Rat

“…It has been recently hypothesized that partial energy failure may be conducive to excitotoxicity mediated by the NMDA receptor complex (Favaron et aI., 1988;Novelli et aI., 1988;Henneberry, 1989;Wie loch et aI., 1989). Glutamate-induced elevations of intracellular calcium are greatly amplified by meta bolic compromise (Dubinsky and Rothman, 1991).…”