Brain Tissue Concentrations of ATP, Phosphocreatine, Lactate, and Tissue pH in Relation to Reduced Cerebral Blood Flow following Experimental Acute Middle Cerebral Artery Occlusion

Abstract

Local CBF (LCBF) was compared with the corresponding local tissue concentration of ATP, phosphocreatine (PCr), and lactate in anaesthetized baboons subjected to focal ischaemia produced by middle cerebral artery occlusion (MCAO). LCBF hydrogen electrodes were implanted in cortical regions where MCAO had been previously shown to produce severe and penumbral ischaemia and in posterior regions where blood flow is not altered. Metabolites were assayed in small tissue samples collected either by cryoprobe biopsy in the regions where LCBFs were measured (series 1) or by sampling appropriate regions of the rapidly frozen brain (series 2). Subsequent topographical study of brain tissue pH with umbelliferone was performed in this latter series. The results from these two series are compared and discussed in terms of the more appropriate way to perform simultaneous electrode measurements and analysis of tissue samples for studying focal ischaemia in the primate brain. They confirm that the concentrations of ATP and PCr decrease, and that lactate level increases, with decreasing blood flow. These metabolites tended to change more rapidly below a blood flow threshold, rather than showing a steady decrease as the blood flow was reduced, although the variability of the data precluded us from establishing this with confidence. Topographical study of tissue pH often showed sharp boundaries between zones of very low pH and regions with normal pH.

Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a

“…Lactate and arachidonic acid, which are released by ischemia, might also enhance ASIC activity (13,42,43). An ASIC1-mediated increase in Ca 2ϩ influx could contribute to Ca 2ϩ overload, an important mechanism of cell damage and death in ischemia (37).…”

cAMP-dependent protein kinase phosphorylation of the acid-sensing ion channel-1 regulates its binding to the protein interacting with C-kinase-1

“…Disrupting the mouse ASIC1 gene markedly reduced H ϩ -gated currents in hippocampal neurons, impaired long-term potentiation of synaptic transmission, and produced learning and memory deficits (11). The observation that extracellular acidosis activates ASIC1 has suggested that it may also be activated in pathologic conditions, for example, when extracellular pH falls during cerebral ischemia (12,13). Because protein kinases regulate the function of many brain ion channels, we asked whether ASIC channels are phosphorylated.…”

Effects of 2-Deoxy-D-Glucose on Focal Cerebral Ischemia in Hyperglycemic Rats

“…In an in vitro study, 2DG suppression of synaptic transmission in the CA1 region of hippocampal slices was observed (Tekkok and Krnjevic, 1995). These data suggest that inhibiting energy-dependent processes can reduce hypermetabolic neuronal necrosis, which involves ATP depletion and lactate accumulation (Obrenovitch et al, 1988), glutamate excitotoxicity, and increased free radical formation. Here we test the hypothesis that by manipulating neuronal stores of glucose we can affect intracellular formation of lactate, thereby preventing the exacerbation of the brain lesion volume resulting from MCAO/R.…”