Mg2+ ions reduce microglial and THP-1 cell neurotoxicity by inhibiting Ca2+ entry through purinergic channels.
Mg(2+) is a known antagonist of some Ca(2+) ion channels. It may therefore be able to counteract the toxic consequences of excessive Ca(2+) entry into immune-type cells. Here we examined the effects of Mg(2+) on inflammation induced by Ca(2+) 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 Ca(2+) which was significantly reduced by Mg(2+) 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 Mg(2+). They were also partly ameliorated by the P2X7R antagonists, oxATP and KN-62, the P2YR antagonist MRS2179, and the store operated Ca(2+) channel blocker, SK96365. These results indicate that elevated Mg(2+) is a broad spectrum inhibitor of Ca(2+) entry into microglia or THP-1 cells. Mg(2+) administration may be a strategy for reducing the damaging consequences Ca(2+) induced neuroinflammation in degenerative neurological disorders such as Alzheimer disease and Parkinson disease.
Kinsmen Laboratory of Neurological Research, 2255 Wesbrook Mall, University of British Columbia, Vancouver, BC, Canada.
Moonhee
M
Lee
Nattinee
N
Jantaratnotai
Edith
E
McGeer
James G
JG
McLarnon
Patrick L
PL
McGeer
D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000096:biosynthesis; D007477:Ions / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058913:Purinergic Agonists / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D015850:Interleukin-6; D007477:Ions; D058913:Purinergic Agonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D058473:Receptors, Purinergic P2Y2; D014409:Tumor Necrosis Factor-alpha; C104749:purinoceptor P2Y4; D008274:Magnesium; D002118:Calcium