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

Brain Res. 2015 Oct 22:1624:359-369. doi: 10.1016/j.brainres.2015.07.057. Epub 2015 Aug 10.

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.

Keywords: Calpain; Cdk5; Chronic cerebral hypoperfusion; S-nitrosoglutathione; p25, and tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / pathology
  • Calpain / metabolism
  • Chronic Disease
  • Cyclin-Dependent Kinase 5 / metabolism
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 / metabolism
  • Neuroprotective Agents / therapeutic use*
  • Phosphorylation / drug effects
  • Rats
  • S-Nitrosoglutathione / therapeutic use*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • tau Proteins / metabolism*

Substances

  • Neuroprotective Agents
  • tau Proteins
  • 3-nitrotyrosine
  • Tyrosine
  • S-Nitrosoglutathione
  • Cyclin-Dependent Kinase 5
  • Glycogen Synthase Kinase 3
  • Calpain