Inorganic Pi Increases Neuronal Survival in the Acute Early Phase Following Excitotoxic/Oxidative Insults

Abstract: 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.