S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion

Abstract

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.

Combined treatment with GSNO and CAPE accelerates functional recovery via additive antioxidant activities in a mouse model of TBI

“…In such an environment, the levels of endogenous redox modulator GSNO are depleted, causing activation of calpains and caspases, leading to neuroinflammation, cell death and functional deficits (Annamalai et al 2015; Corti et al 2014; Khan et al 2016; Khan et al 2011). Supplementation of GSNO in a number of neurodegenerative diseases provides neuroprotection and functional recovery (Khan et al 2016; Khan et al 2012; Khan et al 2011; Khan et al 2005; Won et al 2015). These neuroprotective effects of GSNO may be associated with its reported inhibition of the activity of caspase-3 (Khan et al 2005; Mohr et al 1997) as well as calpains (Annamalai et al 2015; Khan et al 2016).…”

Loss of Endothelial Nitric Oxide Synthase Promotes p25 Generation and Tau Phosphorylation in a Murine Model of Alzheimer’s Disease

“…Furthermore, it is reported that S-nitrosylation can inhibit calpain activity, an enzyme responsible for cleavage of p35 to p25 19, 20 . Won et al (2015) reported that S-nitrosoglutathione (GSNO) treatment of purified calpain protein inhibited its activity 21 . Consistent with our findings, Annamalai et al (2015) demonstrated that treatment of APP/PS1 mice with GSNO led to decreased calpain-mediated cleavage of p35 and decreased Cdk5 activity 22 .…”

Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease

“…In chronically hypoperfused rat brains, GSNO treatment decreased iNOS expression and nitrotyrosine formation. GSNO showed a protective role in iNOS/nitrosative stress‐mediated calpain/tau pathologies (Won et al, ). GSNO reduced Aβ and ICAM‐1/VCAM‐1 levels in the rat brain following chronic cerebral hypoperfusion.…”