PMID- 26271717 OWN - NLM STAT- MEDLINE DCOM- 20160810 LR - 20181113 IS - 1872-6240 (Electronic) IS - 0006-8993 (Print) IS - 0006-8993 (Linking) VI - 1624 DP - 2015 Oct 22 TI - S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion. PG - 359-369 LID - S0006-8993(15)00602-2 [pii] LID - 10.1016/j.brainres.2015.07.057 [doi] AB - 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-beta 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-3beta 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. CI - Published by Elsevier B.V. FAU - Won, Je-Seong AU - Won JS AD - Department of Pathology, Medical University of South Carolina, USA. FAU - Annamalai, Balasubramaniam AU - Annamalai B AD - Department of Pathology, Medical University of South Carolina, USA. FAU - Choi, Seungho AU - Choi S AD - Department of Pediatrics, Medical University of South Carolina, USA. FAU - Singh, Inderjit AU - Singh I AD - Department of Pediatrics, Medical University of South Carolina, USA. FAU - Singh, Avtar K AU - Singh AK AD - Department of Pathology, Medical University of South Carolina, USA; Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC, USA. Electronic address: avtar.singh@va.gov. LA - eng GR - I01 BX001072/BX/BLRD VA/United States GR - NS072511/NS/NINDS NIH HHS/United States GR - R01 NS072511/NS/NINDS NIH HHS/United States GR - NS 037766/NS/NINDS NIH HHS/United States GR - I01 BX001062/BX/BLRD VA/United States GR - R01 NS037766/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20150810 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Neuroprotective Agents) RN - 0 (tau Proteins) RN - 3604-79-3 (3-nitrotyrosine) RN - 42HK56048U (Tyrosine) RN - 57564-91-7 (S-Nitrosoglutathione) RN - EC 2.7.11.1 (Cyclin-Dependent Kinase 5) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - EC 3.4.22.- (Calpain) SB - IM MH - Analysis of Variance MH - Animals MH - Brain/drug effects/metabolism MH - Brain Ischemia/*drug therapy/pathology MH - Calpain/metabolism MH - Chronic Disease MH - Cyclin-Dependent Kinase 5/metabolism MH - Disease Models, Animal MH - Glycogen Synthase Kinase 3/metabolism MH - Neuroprotective Agents/*therapeutic use MH - Phosphorylation/drug effects MH - Rats MH - S-Nitrosoglutathione/*therapeutic use MH - Synaptosomes/drug effects/metabolism MH - Tyrosine/analogs & derivatives/metabolism MH - tau Proteins/*metabolism PMC - PMC4630117 MID - NIHMS715299 OTO - NOTNLM OT - Calpain OT - Cdk5 OT - Chronic cerebral hypoperfusion OT - S-nitrosoglutathione OT - p25, and tau EDAT- 2015/08/15 06:00 MHDA- 2016/08/11 06:00 PMCR- 2016/10/22 CRDT- 2015/08/15 06:00 PHST- 2014/12/08 00:00 [received] PHST- 2015/07/08 00:00 [revised] PHST- 2015/07/31 00:00 [accepted] PHST- 2015/08/15 06:00 [entrez] PHST- 2015/08/15 06:00 [pubmed] PHST- 2016/08/11 06:00 [medline] PHST- 2016/10/22 00:00 [pmc-release] AID - S0006-8993(15)00602-2 [pii] AID - 10.1016/j.brainres.2015.07.057 [doi] PST - ppublish SO - Brain Res. 2015 Oct 22;1624:359-369. doi: 10.1016/j.brainres.2015.07.057. Epub 2015 Aug 10.