PubMed · 10507653
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R J Gazmuri, I Ayoub. 1999. How do you spell basic life support?. https://doi.org/10.1097/00003246-199909000-00069
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Acidosis is a rapid and inevitable event accompanying cerebral ischemia or trauma. We used hippocampal slice cultures to examine an immediate effect of acidosis, synaptic depression; and a delayed effect, neuronal loss. Exposure to low bicarbonate artificial cerebral spinal fluid (aCSF), pH 6.70 for 30 min at 32 degrees C, acidified intracellular pH from 7.31+/-0.12 to 6.53+/-0.08. Accompanying intracellular acidosis was a depression of synaptic responses. Both effects rapidly reversed after treatment with normal aCSF pH 7.35. Death analysis after acidosis treatment revealed no delayed neuronal loss. Increasing the duration of the acidosis to 60 min, however, induced irreversible synaptic depression and delayed neuronal loss. Increasing acidosis temperature to 37 degrees C acidified intracellular pH and depressed synaptic responses. Delayed neuronal loss was also observed. Acidosis using lactate aCSF, pH 6. 70 for 30 min at 32 degrees C acidified intracellular pH from 7. 19+/-0.13 to 6.43+/-0.07 and depressed synaptic responses. After reperfusion with lactate containing aCSF pH 7.35, intracellular pH recovered yet synaptic responses remained depressed and delayed neuronal loss was observed. This suggested that, for a 30-min treatment at 32 degrees C, lactate acidosis was neurotoxic while low bicarbonate acidosis was not. Increasing the duration or temperature of low bicarbonate acidosis induced neuronal loss. These data provide additional evidence that acidosis contributes to the neurotoxicity during stroke and trauma.
Thiamine deficiency (TD) in both humans and experimental animals results in severe compromise of mitochondrial function and leads to selective neuronal cell death in diencephalic and cerebellar structures. To examine further the influence of TD on neuronal survival in relation to metabolic changes, primary cultures of rat cerebellar granule cells were exposed to thiamine-deficient medium for up to 7 days in the absence or presence of the central thiamine antagonist pyrithiamine (Py). Exposure of cells for 7 days to thiamine-deficient medium alone resulted in no detectable cell death. On the other hand, 50 microM Py treatment led to reductions of thiamine phosphate esters, decreased activities of the thiamine-dependent enzymes alpha-ketoglutarate dehydrogenase and transketolase, a twofold increase in lactate release (P < 0.001), a lowering of pH, and significant (58%, P < 0.001) cell death. DNA fragmentation studies did not reveal evidence of apoptotic cell death. Addition of 50 microM alpha-tocopherol (vitamin E) or 100 microM of butylated hydroxyanisole (BHA) to Py-treated cells resulted in significant neuroprotection. On the other hand, addition of 10 microM MK-801, an NMDA receptor antagonist, was not neuroprotective. These results suggest that reactive oxygen species (ROS) play a major role in thiamine deficiency-induced neuronal cell death. Insofar as this experimental model recapitulates the metabolic and mitochondrial changes characteristic of thiamine deficiency in the intact animal, it might be useful in the elucidation of mechanisms involved in the neuronal cell death cascade resulting from thiamine deficiency.
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