Inorganic P sub(i) increases neuronal survival in the acute early phase following excitotoxic/oxidative insults

Inorganic phosphate (P sub(i)) plays a vital role in intracellular energy metabolism. Its many effects include stimulation of glucose use, enhancement of high-energy phosphate concentrations, and modulation of cytosolic free [Ca super(2+)]. Cultured fetal rat cortical neurons constitutively import P sub(i), and cytosolic levels positively correlate with [ATP], [NADPH], and energy charge. In the present study, we demonstrate that the concentration of intracellular P sub(i) is an important determinant of acute neuronal survival after an excitotoxic or oxidative insult to cultured fetal rat cortical neurons. Extracellular P sub(i) dose-dependently enhanced survival of cortical neurons after exposure to NMDA at early ( less than or equal to 6 h) time points after termination of the insult. P sub(i) similarly increased neuronal survival after exposure to kainic acid or H sub(2)O sub(2). P sub(i)-exposed neurons had higher basal intracellular [P sub(i)], [ATP], and [GSH], and slightly lower cytosolic free [Ca super(2+)], compared with P sub(i)-deprived neurons. P sub(i)-exposed neurons maintained increased [ATP] after exposure to NMDA and displayed reduced formation of reactive oxygen species after exposure to kainic acid or H sub(2)O sub(2), compared with P sub(i)-deprived neurons. These findings demonstrate that changes in extracellular and intracellular P sub(i) can affect neuronal survival after excitotoxic or oxidative insults.