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

Inorganic phosphate (P(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 [Ca²⁺]. Cultured fetal rat cortical neurons constitutively import P(i), and cytosolic levels positively correlate with [ATP], [NADPH], and energy charge. In the present study, we demonstrate that the concentration of intracellular P(i) is an important determinant of acute neuronal survival after an excitotoxic or oxidative insult to cultured fetal rat cortical neurons. Extracellular P(i) dose-dependently enhanced survival of cortical neurons after exposure to NMDA at early (≤6 h) time points after termination of the insult. P(i) similarly increased neuronal survival after exposure to kainic acid or H₂O₂. P(i)-exposed neurons had higher basal intracellular [P(i)], [ATP], and [GSH], and slightly lower cytosolic free [Ca²⁺], compared with P(i)-deprived neurons. P(i)-exposed neurons maintained increased [ATP] after exposure to NMDA and displayed reduced formation of reactive oxygen species after exposure to kainic acid or H₂O₂, compared with P(i)-deprived neurons. These findings demonstrate that changes in extracellular and intracellular P(i) can affect neuronal survival after excitotoxic or oxidative insults.