Neuroproteomic study of nitrated proteins in moderate traumatic brain injured rats treated with gamma glutamyl cysteine ethyl ester administration post injury: Insight into the role of glutathione elevation in nitrosative stress

Abstract

Purpose The aims of this study are to establish a time point to determine the most beneficial time to administer GCEE post incident to reduce oxidative damage and second, by using redox proteomics, to determine if GCEE can readily suppress 3-NT modification in TBI animals. Experimental design By using a moderate traumatic brain injury model with Wistar rats, it is hypothesized that the role of 3-nitrotyrosine (3-NT) formation as an intermediate will predict the involvement of protein nitration/nitrosation and oxidative damage in the brain. Results In this experiment, the levels of protein carbonyls, 4-hydroxynonenal, and 3-nitrotyrosine were significantly elevated in TBI injured, saline treated rats compared with those who sustained an injury and were treated with 150 mg/kg of the glutathione mimetic, GCEE. Conclusion and clinical relevance Determining the existence of elevated 3-NT levels provides insight into the relationship between the protein nitration/nitrosation and the oxidative damage, which can determine the pathogenesis and progression of specific neurological diseases.

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia

“…The intravenous injection of 100 μmol/kg (33.54 mg/kg) of GSHee elicited an array of responses in freely-moving adult male Sprague–Dawley rats and had dramatic effects on the responses elicited by subsequent injection of fentanyl (100 μmol/kg). It is likely that GSHee exerts its effects in naïve rats by increasing levels of GSH and metabolites (γ-glutamylcysteinyl and cysteine) in cells (e.g., neurons) in which GSH 53 – 74 and the metabolites 82 , 105 – 108 affect a number of biological processes. It is unlikely that GSHee directly inhibits OR function (loss of affinity or down-regulation of membrane accessible receptors) since GSHee augmented the analgesic effects of fentanyl, which are known to be OR-mediated 15 .…”

The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GGC), Can Ameliorate Oxidative Damage and Neuroinflammation Induced by Aβ40 Oligomers in Human Astrocytes

“…This suggests that GGC may increase GSH levels in the clinic with potential as adjunct therapy for the treatment of disorders associated with acute and/or chronic GSH depletion. Previous preclinical studies have demonstrated little or no toxicity following administration of GGC (Joshi et al, 2007; Espinosa-Diez et al, 2015; Zhang et al, 2015; Ding et al, 2016; Henderson et al, 2016; Salama et al, 2016). The present study set out for the first time to evaluate GGC as a GSH-elevating strategy in primary human astrocytes, starting from homeostatic levels, with promising data.…”

The cysteine-rich whey protein supplement, Immunocal®, preserves brain glutathione and improves cognitive, motor, and histopathological indices of traumatic brain injury in a mouse model of controlled cortical impact

“…In this context, a prior study using a novel closed skull injury model in mice demonstrated that transcranial administration of GSH ameliorated brain injury and neuroinflammation (Roth et al, 2014). Moreover, multiple studies have shown that administration of various GSH precursors, including N-acetylcysteine and gamma-glutamylcysteine ethyl ester, as well as the GSH analog, S-nitrosoglutathione, provide antioxidant and neuroprotective effects in mouse and rat models of TBI (Xiong et al, 1999; Hicdonmez et al, 2006; Reed et al, 2009; Lok et al, 2011; Khan et al, 2009, 2011; Henderson et al, 2016). Although these studies are quite supportive of a therapeutic role for GSH in TBI, most are somewhat limited in scope in that they only evaluated neuronal degeneration and various indices of oxidative or nitrosative stress while neglecting to assess cognitive or motor deficits induced by TBI.…”