S-Nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats

Abstract

BackgroundTraumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury in the neurovascular unit following TBI. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. Peroxynitrite has been implicated in blood brain barrier (BBB) leakage, altered metabolic function, and neurobehavioral impairment. S-nitrosoglutathione (GSNO), a nitrosylation-based signaling molecule, was reported not only to reduce brain levels of peroxynitrite and oxidative metabolites but also to improve neurological function in TBI, stroke, and spinal cord injury. Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury.MethodsTBI was induced by controlled cortical impact (CCI) in adult male rats. GSNO or 3-Morpholino-sydnonimine (SIN-1) (50 μg/kg body weight) was administered orally two hours following CCI. The same dose was repeated daily until endpoints. GSNO-treated (GSNO group) or SIN-1-treated (SIN-1 group) injured animals were compared with vehicle-treated injured animals (TBI group) and vehicle-treated sham-operated animals (Sham group) in terms of peroxynitrite, NO, glutathione (GSH), lipid peroxidation, blood brain barrier (BBB) leakage, edema, inflammation, tissue structure, axon/myelin integrity, and neurotrophic factors.ResultsSIN-1 treatment of TBI increased whereas GSNO treatment decreased peroxynitrite, lipid peroxides/aldehydes, BBB leakage, inflammation and edema in a short-term treatment (4-48 hours). GSNO also reduced brain infarctions and enhanced the levels of NO and GSH. In a long-term treatment (14 days), GSNO protected axonal integrity, maintained myelin levels, promoted synaptic plasticity, and enhanced the expression of neurotrophic factors.ConclusionOur findings indicate the participation of peroxynitrite in the pathobiology of TBI. GSNO treatment of TBI not only reduces peroxynitrite but also protects the integrity of the neurovascular unit, indicating that GSNO blunts the deleterious effects of peroxynitrite. A long-term treatment of TBI with the same low dose of GSNO promotes synaptic plasticity and enhances the expression of neurotrophic factors. These results support that GSNO reduces the levels of oxidative metabolites, protects the neurovascular unit, and promotes neurorepair mechanisms in TBI.

Protective Role of S-Nitrosoglutathione (GSNO) Against Cognitive Impairment in Rat Model of Chronic Cerebral Hypoperfusion

“…Although modest inflammation plays a role in neuroprotection in acute insults, chronic inflammation is detrimental to neurogenesis [41]. Previously, we reported that GSNO protects the brain against injuries from ischemia/reperfusion [17, 18], traumatic brain injury [42, 43], and experimental autoimmune encephalomyelitis [19, 44] by inhibiting neural and vascular inflammation. Based on these studies, we investigated whether the GSNO-mediated protective mechanisms involve anti-inflammatory effects in animals with BCCAO.…”

S-Nitrosoglutathione Induces Ciliary Neurotrophic Factor Expression in Astrocytes, Which Has Implications to Protect the Central Nervous System under Pathological Conditions

“…Importantly, PPAR-␥ activators are documented to enhance anti-inflammatory activities in astrocytes and other cell types (64,65). In light of these studies, we conclude that NO signaling in astrocytes is crucial to provide anti-inflammatory and neuroprotective activities in experimental autoimmune encephalomyelitis and traumatic brain injury models (25,26,30,31).…”

“…GSNO has recently been reported to regulate various cellular functions (23,38). In addition, earlier we documented that exogenously administered GSNO restores blood brain barrier integrity and attenuates disease severity in experimental autoimmune encephalomyelitis (25,26) and traumatic brain injury (30,31) models. These studies provide evidence that regardless of the excessive expression of inducible nitric-oxide synthase/NO production by activated CNS glial cells in response to inflammatory insult, the exogenously administered GSNO has a tendency to limit the generation of circulating reactive nitrogen species NO/ONOO in vivo (39).…”

Synthesis of S-nitrosoglutathione-alginate for prolonged delivery of nitric oxide in intestines

“…However, recently reported results indicate that these products can be in vivo recycled and transformed back into NO, which represents an important unconventional source of NO outside of the classical L-arginine-NO synthase pathway (Lundberg et al, 2008). Based on the study by Khan et al (2011), both nitrite and nitrate ions may be significant precursors of NO and can increase the NO concentration in brain. SNA F2 was comparatively more stable than GSNO and finally degraded to nitrite and nitrate ions after 10 h (Figure 2).…”