The inhibitory effect of S‐nitrosoglutathione on blood–brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke

Khan, Mushfiquddin; Dhammu, Tajinder S; Sakakima, Harutoshi; Shunmugavel, Anadakumar; Gilg, Anne G.; Singh, Avtar; Singh, Inderjit

doi:10.1111/j.1471-4159.2012.07947.x

Cited by 63 publications

(67 citation statements)

References 61 publications

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“…GSNO treatment also reduced the Aβ load and ICAM- 1/VCAM-1 expression in the brains of pBCCAO rats and increased Aβ uptake by microglia and endothelial cells and decreased neuronal Aβ synthesis by inhibiting activity of BACE1 in in vitro cell culture models [6]. Taken together with previously reported role of GSNO in antiinflammation [6,7], anti-oxidation [8,9], and cerebrovascular and BBB protections [10,11], our study documented the potential neuro-cognitive protective efficacy of GSNO in AD.…”

Section: Introductionsupporting

confidence: 68%

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Annamalai

Won

Choi

et al. 2015

Biochemical and Biophysical Research Communications

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Hyperphosphorylation and polymerization of microtubule-associated protein tau into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer’s disease (AD). Here we report that neuronal tau hyperphosphorylation under AD conditions is regulated by Snitrosoglutathione (GSNO), an endogenous nitric oxide carrier molecule. In cultured rat cortical primary neurons, we observed that GSNO treatment decreased the β-amyloid (Aβ25–35)-induced pathological tau hyperphosphorylation (Ser396, Ser404, and Ser202/Thr205). The decreased tau hyperphosphorylation correlated with decreased activity of calpain and decreased p35 proteolysis into p25 and Cdk5 activation. GSNO treatment also attenuated the Aβ25–35-induced activation of GSK-3β which is known to play critical role in tau hyperphosphorylation in addition to Cdk5. Consistent with above studies using cultured neurons, we also observed that systemic GSNO treatment of transgenic mouse model of AD (APPSw/PS1dE9) attenuated calpain-mediated p35 proteolysis and Cdk5/GSK-3β activities as well as tau hyperphosphorylation. In addition, GSNO treatment provided neuro- and cognitive protection in APPSw/PS1dE9 mice. This study describing the GSNO-mediated regulation of tau hyperphosphorylation and cognitive function, for the first time, suggests for therapeutic potential of GSNO as neuro- and cognitive-protective agent for AD.

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Section: Introductionsupporting

confidence: 68%

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Annamalai

Won

Choi

et al. 2015

Biochemical and Biophysical Research Communications

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“…Therefore, breakdown of any of the individual components may contribute to BBB dysfunction [10,42]. During ischemic stroke and subsequent reperfusion, loss of the BBB integrity is a critical early event that contributes to the initiation of the inflammatory cascade, edema formation and, ultimately, poor outcomes [43]. Based on previous observations from our laboratory, the current study explored the multidimensional roles of early exercise in ischemic stroke, anti-inflammation, angiogenesis, mitochondrial biogenesis and neuron apoptosis [20–25].…”

Section: Resultsmentioning

confidence: 99%

Early Exercise Protects the Blood-Brain Barrier from Ischemic Brain Injury via the Regulation of MMP-9 and Occludin in Rats

Zhang

Shen

et al. 2013

IJMS

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Early exercise within 24 h after stroke can reduce neurological deficits after ischemic brain injury. However, the mechanisms underlying this neuroprotection remain poorly understood. Ischemic brain injury disrupts the blood-brain barrier (BBB) and then triggers a cascade of events, leading to secondary brain injury and poor long-term outcomes. This study verified the hypothesis that early exercise protected the BBB after ischemia. Adult rats were randomly assigned to sham, early exercise (EE) or non-exercise (NE) groups. The EE and NE groups were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). The EE group ran on a treadmill beginning 24 h after ischemia, 30 min per day for three days. After three-days’ exercise, EB extravasation and electron microscopy were used to evaluate the integrity of the BBB. Neurological deficits, cerebral infarct volume and the expression of MMP-9, the tissue inhibitors of metalloproteinase-1 (TIMP-1), and occludin were determined. The data indicated that early exercise significantly inhibited the ischemia-induced reduction of occludin, and an increase in MMP-9 promoted TIMP-1 expression (p < 0.01), attenuated the BBB disruption (p < 0.05) and neurological deficits (p < 0.01) and diminished the infarct volume (p < 0.01). Our results suggest that the neuroprotection conferred by early exercise was likely achieved by improving the function of the BBB via the regulation of MMP-9 and occludin.

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“…GSNO invokes anti-inflammatory, anti-oxidant, anti-neurodegeneration, and vascular protection effects, likely via S-nitrosylation (Chiueh and Rauhala, 1999; Hess and Stamler, 2012; Khan et al, 2012; Kim et al, 2013; Prasad et al, 2007). Reduced levels of NO (Malinski et al, 1993), GSH (Khan et al, 2006) or both, combined with increased degradation of GSNO by the inflammation-induced enzyme activity of GSNO reductase (Que et al, 2005) may contribute to the reduced levels of GSNO following TBI.…”

Section: Introductionmentioning

confidence: 99%

Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI

et al. 2016

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Traumatic brain injury (TBI) derails nitric oxide (NO)-based anti-inflammatory and anti-excitotoxicity mechanisms. NO is consumed by superoxide to form peroxynitrite, leading to decreased NO bioavailability for S-nitrosoglutathione (GSNO) synthesis and regulation of neuroprotective pathways. Neuronal peroxynitrite is implicated in neuronal loss and functional deficits following TBI. Using a contusion mouse model of TBI, we investigated mechanisms for the opposed roles of GSNO versus peroxynitrite for neuroprotection and functional recovery. TBI was induced by controlled cortical impact (CCI) in adult male mice. GSNO treatment at 2 h after CCI decreased the expression levels of phospho neuronal nitric oxide synthase (pnNOS), alpha II spectrin degraded products, and 3-NT, while also decreasing the activities of nNOS and calpains. Treatment of TBI with FeTPPS, a peroxynitrite scavenger, had effects similar to GSNO treatment. GSNO treatment of TBI also reduced neuronal degeneration and improved neurobehavioral function in a two-week TBI study. In a cell free system, SIN-1 (a peroxynitrite donor and 3-nitrotyrosinating agent) increased whereas GSNO (an S-nitrosylating agent) decreased calpain activity, and these activities were reversed by, respectively, FeTPPS and mercuric chloride, a cysteine-NO bond cleaving agent. These data indicate that peroxynitrite-mediated activation and GSNO-mediated inhibition of the deleterious nNOS/calpain system play critical roles in the pathobiology of neuronal protection and functional recovery in TBI disease. Given GSNO’s safety record in other diseases, its neuroprotective efficacy and promotion of functional recovery in this TBI study make low-dose GSNO a potential candidate for preclinical evaluation.

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The inhibitory effect of S‐nitrosoglutathione on blood–brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke

Cited by 63 publications

References 61 publications

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Early Exercise Protects the Blood-Brain Barrier from Ischemic Brain Injury via the Regulation of MMP-9 and Occludin in Rats

Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI

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