Interleukin-6 reduces NMDA-induced Ca2+ overload via prevention of Ca2+ release from intracellular store.

A mechanism for neuroprotection of interleukin-6 (IL-6) via reduction of intracellular Ca2+ overload induced by N-methyl-D-aspartate (NMDA) was explored. Cerebellar granule neurons (CGNs) from postnatal 8-day infant rats were chronically exposed to IL-6 for 8 days. Confocal laser scanning microscope was used to measure dynamic changes of intracellular Ca2+ fluorescence intensity. NMDA triggered an acute and sustaining enhancement of intracellular Ca2+ fluorescence intensity in the cultured CGNs, whereas NMDA stimulation of the neurons that had been exposed to IL-6 reduced the intracellular Ca2+ fluorescence intensity relative to that of non-IL-6-pretreated neurons. Ethylene glycol bis(aminoethylether) tetraacetate (EGTA), a chelator of extracellular Ca2+, decreased the intracellular Ca2+ overload triggered by NMDA. The component of intracellular Ca2+ overload after EGTA treatment was prevented by IL-6 chronic exposure. Cotreatment with dantrolene sodium (DAN) and 2-aminoethoxydiphenylborate (2-APB), blockers of ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (IP3R), respectively, also decreased the intracellular Ca2+ overload triggered by NMDA. However, the component of intracellular Ca2+ overload after DAN and 2-APB treatment was only slightly but not significantly diminished by IL-6. These results suggest that IL-6 has a neuroprotective effect against NMDA-induced intracellular Ca2+ overload, and that the effect is implemented primarily via a suppression of Ca2+ release from the intracellular Ca2+ store.