S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion.
S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion.
复制标题
S-亚硝基谷胱甘肽可减少 tau 过度磷酸化，并在慢性脑灌注不足的大鼠模型中提供神经保护。
DOI：
10.1016/j.brainres.2015.07.057
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发表时间：
2015
期刊：
影响因子：
2.9
通讯作者：
Singh,AvtarK
中科院分区：
文献类型：
--
作者：
Won,Je-Seong;Annamalai,Balasubramaniam;Choi,Seungho;Singh,Inderjit;Singh,AvtarK
我们以前曾报道，用内源性一氧化氮载体S-亚硝基谷胱甘肽（GSNO）治疗永久性双侧颈总动脉闭塞（pBCCAO）大鼠（慢性脑灌注不足（CCH）模型），可改善认知功能，减少大脑中淀粉样蛋白-β的积累。由于CCH与tau蛋白过度磷酸化诱导的神经退行性变有关，我们在大鼠pBCCAO模型中研究了GSNO在调节tau蛋白过度磷酸化中的作用。进行pBCCAO的大鼠tau过度磷酸化显著增加，海马/皮质区神经元损失增加。GSNO治疗不仅减弱了tau蛋白的过度磷酸化，而且还减弱了pBCCAO大鼠脑中的神经变性。pBCCAO大鼠脑还显示GSK-3β和Cdk 5（主要tau激酶）的活性增加，并且GSNO处理显著减弱其活性。GSNO减弱了钙蛋白酶活性的增加和钙蛋白酶介导的p35裂解，导致p25的产生和异常Cdk 5活化。在使用纯化的钙蛋白酶蛋白的体外研究中，GSNO处理抑制钙蛋白酶活性，而3-morpholinosydnonimine（过氧亚硝酸盐的供体）处理增加其活性，表明GSNO与过氧亚硝酸盐在钙蛋白酶活性调节中的相反作用。在pBCCAO大鼠脑中，GSNO处理减弱了诱导型一氧化氮合酶（iNOS）表达的表达，并且还降低了硝基酪氨酸形成的脑水平，从而表明GSNO在CCH条件下在iNOS/亚硝化应激介导的钙蛋白酶/tau病理中的保护作用。与我们以前的报告一起，这些数据支持GSNO的治疗潜力，生物NO载体，作为CCH条件下的神经和认知保护剂。
We have previously reported that treatment of rats subjected to permanent bilateral common carotid artery occlusion (pBCCAO), a model of chronic cerebral hypoperfusion (CCH), with S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, improved cognitive functions and decreased amyloid-β accumulation in the brains. Since CCH has been implicated in tau hyperphosphorylation induced neurodegeneration, we investigated the role of GSNO in regulation of tau hyperphosphorylation in rat pBCCAO model. The rats subjected to pBCCAO had a significant increase in tau hyperphosphorylation with increased neuronal loss in hippocampal/cortical areas. GSNO treatment attenuated not only the tau hyperphosphorylation, but also the neurodegeneration in pBCCAO rat brains. The pBCCAO rat brains also showed increased activities of GSK-3β and Cdk5 (major tau kinases) and GSNO treatment significantly attenuated their activities. GSNO attenuated the increased calpain activities and calpain-mediated cleavage of p35 leading to production of p25 and aberrant Cdk5 activation. In in vitro studies using purified calpain protein, GSNO treatment inhibited calpain activities while 3-morpholinosydnonimine (a donor of peroxynitrite) treatment increased its activities, suggesting the opposing role of GSNO vs. peroxynitrite in regulation of calpain activities. In pBCCAO rat brains, GSNO treatment attenuated the expression of inducible nitric oxide synthase (iNOS) expression and also reduced the brain levels of nitro-tyrosine formation, thereby indicating the protective role of GSNO in iNOS/nitrosative-stress mediated calpain/tau pathologies under CCH conditions. Taken together with our previous report, these data support the therapeutic potential of GSNO, a biological NO carrier, as a neuro- and cognitive-protective agent under conditions of CCH.