THE EFFECTS OF EXTRACELLULAR PH AND CALCIUM MANIPULATION ON PROTEIN-SYNTHESIS AND RESPONSE TO ANOXIA AGLYCEMIA IN THE RAT HIPPOCAMPAL SLICE/

Extracellular pH modulates the function of the N-methyl-D-aspartate (N MDA) receptor, which may influence pathophysiological responses to glu tamate. While damage due to oxygen and glucose deprivation or glutamat e exposure is attenuated by acidification of the incubating medium of cultured neurons, neuron damage is enhanced in vivo following ischemia in hyperglycemic animals. A persistent inhibition of protein synthesi s (to less than 5% of normoxic levels) is a reliable index of damage t o neurons both in vivo and in the rat hippocampal slice. We explored t he influence of extracellular pH and calcium manipulation on protein s ynthesis inhibition and energy failure due to anoxia/aglycemia or expo sure to N-methyl-D-aspartate in the rat hippocampal slice. Moderate ac idification of the medium during anoxia/aglycemia did not reduce the d amage to protein synthesis in hippocampal neurons (9% of normoxic leve ls) and did not alter basal ATP levels or the rate of ATP depletion du ring anoxia/aglycemia. However, when calcium levels were lowered durin g the acidification and following the anoxia/aglycemia, protein synthe sis was almost completely protected (84% of normoxic levels). Calcium reduction itself also attenuated the protein synthesis inhibition due to anoxia/aglycemia (to 55.6% of normoxic controls), but the protectio n was not as complete. In contrast, moderate acidification of the medi um significantly reduced the damage to protein synthesis due to a brie f exposure to NMDA (37% of control with NMDA, 78.9% of control with ac idification during NMDA), even in the presence of extracellular calciu m. Alkalinization of the medium exacerbated the protein synthesis inhi bition following anoxia/aglycemia, and significantly reduced basal ATP levels (to 52% of normoxic control levels). Thus, pH(0) changes influ ence neuronal metabolism and response to anoxia/aglycemia. In addition , while acidification can reduce the excitotoxic damage caused by dire ct exposure to NMDA, it cannot reduce damage due to anoxia/aglycemia u nless calcium is lowered concomitantly. Thus, both NMDA receptor activ ation and calcium are involved in the damage due to oxygen and glucose deprivation in the slice. (C) 1998 Elsevier Science B.V.