Kilanczyk Ewa, Saraswat Ohri Sujata, Whittemore Scott R, Hetman Michal
Kentucky Spinal Cord Injury Research Center, University of Louisville, KY, USA Department of Neurological Surgery, University of Louisville, KY, USA.
Kentucky Spinal Cord Injury Research Center, University of Louisville, KY, USA Department of Neurological Surgery, University of Louisville, KY, USA Department of Anatomical Sciences and Neurobiology, University of Louisville, KY, USA.
ASN Neuro. 2016 Jul 21;8(4). doi: 10.1177/1759091416660404. Print 2016 Aug.
The pentose phosphate pathway is the main source of NADPH, which by reducing oxidized glutathione, contributes to antioxidant defenses. Although oxidative stress plays a major role in white matter injury, significance of NADPH for oligodendrocyte survival has not been yet investigated. It is reported here that the NADPH antimetabolite 6-amino-NADP (6AN) was cytotoxic to cultured adult rat spinal cord oligodendrocyte precursor cells (OPCs) as well as OPC-derived oligodendrocytes. The 6AN-induced necrosis was preceded by increased production of superoxide, NADPH depletion, and lower supply of reduced glutathione. Moreover, survival of NADPH-depleted OPCs was improved by the antioxidant drug trolox. Such cells were also protected by physiological concentrations of the neurosteroid dehydroepiandrosterone (10(-8) M). The protection by dehydroepiandrosterone was associated with restoration of reduced glutathione, but not NADPH, and was sensitive to inhibition of glutathione synthesis. A similar protective mechanism was engaged by the cAMP activator forskolin or the G protein-coupled estrogen receptor (GPER/GPR30) ligand G1. Finally, treatment with the glutathione precursor N-acetyl cysteine reduced cytotoxicity of 6AN. Taken together, NADPH is critical for survival of OPCs by supporting their antioxidant defenses. Consequently, injury-associated inhibition of the pentose phosphate pathway may be detrimental for the myelination or remyelination potential of the white matter. Conversely, steroid hormones and cAMP activators may promote survival of NADPH-deprived OPCs by increasing a NADPH-independent supply of reduced glutathione. Therefore, maintenance of glutathione homeostasis appears as a critical effector mechanism for OPC protection against NADPH depletion and preservation of the regenerative potential of the injured white matter.
磷酸戊糖途径是NADPH的主要来源，NADPH通过还原氧化型谷胱甘肽，有助于抗氧化防御。虽然氧化应激在白质损伤中起主要作用，但NADPH对少突胶质细胞存活的意义尚未得到研究。本文报道，NADPH抗代谢物6-氨基-NADP（6AN）对培养的成年大鼠脊髓少突胶质细胞前体细胞（OPC）以及OPC衍生的少突胶质细胞具有细胞毒性。6AN诱导的坏死之前是超氧化物生成增加、NADPH耗竭和还原型谷胱甘肽供应减少。此外，抗氧化药物曲洛司坦可改善NADPH耗竭的OPC的存活。这种细胞也受到生理浓度的神经甾体脱氢表雄酮（10(-8) M）的保护。脱氢表雄酮所提供的保护与还原型谷胱甘肽的恢复有关，而与NADPH无关，并且对谷胱甘肽合成的抑制敏感。cAMP激活剂福斯高林或G蛋白偶联雌激素受体（GPER/GPR30）配体G1也参与了类似的保护机制。最后，用谷胱甘肽前体N-乙酰半胱氨酸处理可降低6AN的细胞毒性。综上所述，NADPH通过支持OPC的抗氧化防御对其存活至关重要。因此，损伤相关的磷酸戊糖途径抑制可能对白质的髓鞘形成或再髓鞘化潜能有害。相反，类固醇激素和cAMP激活剂可能通过增加还原型谷胱甘肽的NADPH非依赖性供应来促进NADPH缺乏的OPC的存活。因此，维持谷胱甘肽稳态似乎是OPC保护免受NADPH耗竭和保留损伤白质再生潜能的关键效应机制。
