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Nanomolar vitamin E α‐tocotrienol inhibits glutamate‐induced activation of phospholipase A 2 and causes neuroprotection
Author(s) -
Khanna Savita,
Parinandi Narasimham L.,
Kotha Sainath R.,
Roy Sashwati,
Rink Cameron,
Bibus Douglas,
Sen Chandan K.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06550.x
Subject(s) - glutamate receptor , neuroprotection , arachidonic acid , phospholipase a2 , biochemistry , docosahexaenoic acid , bapta , vitamin e , phospholipid , chemistry , phospholipase , glutamic acid , pharmacology , tocotrienol , biology , intracellular , fatty acid , polyunsaturated fatty acid , antioxidant , tocopherol , enzyme , amino acid , membrane , receptor
J. Neurochem. (2010) 112 , 1249–1260. Abstract Our previous works have elucidated that the 12‐lipoxygenase pathway is directly implicated in glutamate‐induced neural cell death, and that such that toxicity is prevented by nM concentrations of the natural vitamin E α‐tocotrienol (TCT). In the current study we tested the hypothesis that phospholipase A 2 (PLA 2 ) activity is sensitive to glutamate and mobilizes arachidonic acid (AA), a substrate for 12‐lipoxygenase. Furthermore, we examined whether TCT regulates glutamate‐inducible PLA 2 activity in neural cells. Glutamate challenge induced the release of [ 3 H]AA from HT4 neural cells. Such response was attenuated by calcium chelators (EGTA and BAPTA), cytosolic PLA 2 (cPLA 2 )‐specific inhibitor (AACOCF 3 ) as well as TCT at 250 nM. Glutamate also caused the elevation of free polyunsaturated fatty acid (AA and docosahexaenoic acid) levels and disappearance of phospholipid‐esterified AA in neural cells. Furthermore, glutamate induced a time‐dependent translocation and enhanced serine phosphorylation of cPLA 2 in the cells. These effects of glutamate on fatty acid levels and on cPLA 2 were significantly attenuated by nM TCT. The observations that AACOCF 3 , transient knock‐down of cPLA 2 as well as TCT significantly protected against the glutamate‐induced death of neural cells implicate cPLA 2 as a TCT‐sensitive mediator of glutamate induced neural cell death. This work presents first evidence recognizing glutamate‐induced changes in cPLA 2 as a novel mechanism responsible for neuroprotection observed in response to nanomolar concentrations of TCT.