Heterogeneous effects of distinct tocopherol analogues on NO release, cell volume, and cell death in microglial cells

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Tocopherols (vitamin E) are potent antioxidants as well as modulators of enzymes involved in signal transduction, like nitric oxide synthase (NOS). In primary murine microglial cells and in the microglial cell line BV-2, α-, γ-, and δ-tocopherol and α-tocopherol acid succinate, respectively, promote nitric oxide (NO) release. The NOS inhibitors aminoguanidine and NG-methyl-L-arginine (L-NMMA) suppressed α- and γ-tocopherol-induced NO release, but had no significant effect on δ-tocopherol- and α-tocopherol acid succinate–induced NO release. In BV-2 cells, but not in primary microglial cells, γ- and δ-tocopherol and α-tocopherol acid succinate, respectively, led to cell death, characterized by exposition of phosphatidylserine on the cell surface, chromatin condensation, changes in cell volume, and formation of blebs on the cell surface. Aminoguanidine, L-NMMA, and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) enhanced apoptosis in γ-tocopherol-exposed cells and suppressed apoptosis in δ-tocopherol-treated cells, but had no effect on cells supplemented with α-tocopherol acid succinate. The NO donors sodium nitroprusside and 2-(N,N-diethylamino)-diazenolate 2-oxide enhanced apoptosis in γ- or δ-tocopherol-treated cells, but rescued cells from α-tocopherol acid succinate–induced cell death.

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