Acidosis induces necrosis and apoptosis of cultured hippocampal neurons

Acidosis, hypoxia, and hypoglycemia rapidly and transiently appear after re duction of cerebral blood flow. Acidosis also accompanies head trauma and s ubarachnoid hemorrhage. These insults result in necrotic and apoptotic loss of neurons. We previously demonstrated that transient acidification of int racellular pH from 7.3 to 6.5 induces delayed neuronal loss in cultured hip pocampal slices (49). We now report that acidosis induced both necrotic and apoptotic loss of neurons. necrosis and apoptosis were distinguished tempo rally and pharmacologically. Necrosis appeared rapidly and was dose depende nt with the duration of the acidosis treatment. Apoptosis was delayed with maximal number of apoptotic cells seen with a 30-min acidosis treatment. Ap optotic neuronal loss was accompanied by DNA fragmentation and was blocked by inhibitors of protein and RNA synthesis, ectopic expression of the anti- apoptotic gene blc-2, or an inhibitor of caspases, proteases known to be ac tivated during apoptosis. Necrotic neuronal loss was unaffected by these tr eatments. Hypothermia, a treatment known to attenuate neuronal loss followi ng a variety of insults, blocked both acidosis-induced acidosis is neurotox ic in vitro and suggest that acidosis contributes to both necrotic and apop totic neuronal loss in vivo. (C) 2000 Academic Press.