Tauskela Joseph S, Brunette Eric, Kiedrowski Lech, Lortie Karine, Hewitt Melissa, Morley Paul
National Research Council, Institute for Biological Sciences, Synaptic Pathophysiology Group, Ottawa, Ontario, Canada.
J Neurochem. 2006 Aug;98(4):1324-42. doi: 10.1111/j.1471-4159.2006.03973.x.
We evaluated whether both inert and catalytically active metalloporphyrin antioxidants, meso-substituted with either phenyl-based or N-alkylpyridinium-based groups, suppress Ca(2+)-dependent neurotoxicity in cell culture models of relevance to cerebral ischemia. Representatives from both metalloporphyrin classes, regardless of antioxidant strength, protected cultured cortical neurons or PC-12 cultures against the Ca(2+) ionophores ionomycin or A23187, by suppressing neurotoxic Ca(2+) influx. Some metalloporphyrins suppressed excitotoxic Ca(2+) influx indirectly induced by the Ca(2+) ionophores in cortical neurons. Metalloporphyrins did not quench intracellular fluorescence, suggesting localization to the plasma membrane interface and/or interference with Ca(2+) ionophores. Metalloporphyrins suppressed ionomycin-induced Mn(2+) influx, but did not protect cortical neurons against pyrithione, a Zn(2+) ionophore. In other Ca(2+)-dependent paradigms, Ca(2+) influx via plasma membrane depolarization, but not through reversal of plasmalemmal Na(+)/Ca(2+) exchangers, was modestly suppressed by Mn(III)meso-tetrakis(4-benzoic acid)porphyrin (Mn(III)TBAP) or by an inert analog, Zn(II)TBAP. Mn(III)TBAP and Zn(II)TBAP potently protected cortical neurons against long-duration oxygen-glucose deprivation (OGD), performed in the presence of antagonists of NMDA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and L-type voltage-gated Ca(2+) channels, raising the possibility of an unconventional mode of blockade of transient receptor protein melastatin 7 channels by a metalloTBAP family of metalloporphyrins. The present study extends the range of Ca(2+)-dependent insults for which metalloporphyrins demonstrate unconventional neuroprotection. MetalloTBAPs appear capable of targeting an OGD temporal continuum.
我们评估了中位被苯基或N - 烷基吡啶鎓基取代的惰性和催化活性金属卟啉抗氧化剂，是否能在与脑缺血相关的细胞培养模型中抑制钙（Ca(2+)）依赖性神经毒性。这两类金属卟啉的代表物，无论抗氧化强度如何，都通过抑制神经毒性的Ca(2+)内流，保护培养的皮质神经元或PC - 12细胞培养物免受Ca(2+)离子载体离子霉素或A23187的损伤。一些金属卟啉间接抑制了皮质神经元中由Ca(2+)离子载体诱导的兴奋性毒性Ca(2+)内流。金属卟啉不会淬灭细胞内荧光，这表明它们定位于质膜界面和/或干扰Ca(2+)离子载体。金属卟啉抑制离子霉素诱导的锰（Mn(2+)）内流，但不能保护皮质神经元免受锌（Zn(2+)）离子载体吡啶硫酮的损伤。在其他钙（Ca(2+)）依赖性模式中，通过质膜去极化而非通过质膜钠（Na(+)/Ca(2+)）交换体的反向转运的Ca(2+)内流，被中位四（4 - 苯甲酸）卟啉锰（Mn(III)TBAP）或惰性类似物锌（Zn(II)TBAP）适度抑制。Mn(III)TBAP和Zn(II)TBAP在存在N - 甲基 - D - 天冬氨酸、α - 氨基 - 3 - 羟基 - 5 - 甲基异恶唑 - 4 - 丙酸和L型电压门控钙（Ca(2+)）通道拮抗剂的情况下，有效保护皮质神经元免受长时间氧糖剥夺（OGD）的损伤，这增加了金属卟啉家族通过非传统方式阻断瞬时受体电位香草酸亚型7通道的可能性。本研究扩展了金属卟啉表现出非传统神经保护作用的钙（Ca(2+)）依赖性损伤范围。金属卟啉似乎能够针对OGD的时间连续性发挥作用。
