Mechanistic distinctions between excitotoxic and acidotic hippocampal damage in an in vitro model of ischemia.
Excitotoxicity is believed to underlie the selective loss of vulnerable neurons after transient ischemia, while lactic acidosis seems to be the principal feature and probable cause of tissue infarcts. Primary hippocampal cultures containing both neurons and astrocytes derived from fetal rats were used to examine the relative contributions of and interactions between excitotoxic and acidotic cell injury. Hypoxia-induced damage was energy dependent and involved the N-methyl-D-aspartate (NMDA) receptor. Glucose above 1 mM could completely protect against hypoxia-induced injury in a pH range of 7.4-6.5, while the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (500 microM) during the posthypoxic period provided only partial protection in the absence of glucose. Astrocyte cultures were undamaged by ischemic-like treatment in this pH range, suggesting that hypoxia-induced cell death in mixed cultures was restricted to neurons. Lowering the extracellular pH to 7.0 and 6.5 caused no neuronal damage in normoxic controls, but in each case provided significant protection against hypoxic neuronal injury. In contrast, a second type of neurotoxicity was observed after a 6-h exposure to pH 6.0, while exposure to pH 5.5 was required to kill astrocytes. This acidotic damage appeared to be energy independent and did not involve the NMDA receptor. These results suggest that excitotoxic neuron death has an energetic component and that acidosis may produce both protective and damaging effects in the hippocampus during ischemic insults.
Tombaugh
G C
GC
Department of Biological Sciences, Stanford University, CA 94305.
Sapolsky
R M
RM
D015763:2-Amino-5-phosphonovalerate / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002470:Cell Survival; D006624:Hippocampus / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D015763:2-Amino-5-phosphonovalerate; D007770:L-Lactate Dehydrogenase