Research ReportMg2+ ions reduce microglial and THP-1 cell neurotoxicity by inhibiting Ca2+ entry through purinergic channels

Mg2+ is a known antagonist of some Ca2+ ion channels. It may therefore be able to counteract the toxic consequences of excessive Ca2+ entry into immune-type cells. Here we examined the effects of Mg2+ on inflammation induced by Ca2+ influx into microglia and THP-1 cells following activation of purinergic receptors. Using tissue culture, an inflammatory response was induced by treatment with either the P2X7 purinergic receptor agonist 2′,3′-[benzoyl-4-benzoyl]-ATP (BzATP) or the P2Y2,4 receptor agonist uridine 5′-triphosphate (UTP). Both microglia and THP-1 cells expressed the mRNAs for these receptors. Treatment produced a rapid rise in intracellular Ca2+ which was significantly reduced by Mg2+ or the calcium chelator BAPTA-AM. Purinergic receptor stimulation activated the intracellular inflammatory pathway P38 MAP kinase and NFκB. This caused release of TNFα, IL-6, nitrite ions and other materials that are neurotoxic to SH-SY5Y cells. These effects were all ameliorated by Mg2+. They were also partly ameliorated by the P2X7R antagonists, oxATP and KN-62, the P2YR antagonist MRS2179, and the store operated Ca2+ channel blocker, SK96365. These results indicate that elevated Mg2+ is a broad spectrum inhibitor of Ca2+ entry into microglia or THP-1 cells. Mg2+ administration may be a strategy for reducing the damaging consequences Ca2+ induced neuroinflammation in degenerative neurological disorders such as Alzheimer disease and Parkinson disease.

Research Highlights►Magnesium inhibits Ca2+ influx through multiple ion channels. ►These channels activate microglia and stimulate inflammation. ►Magnesium counteracts the neurotoxic effects of such activation. ►Magnesium is a safe, broad spectrum inhibitor of pathological Ca2+ influx.