Decrease of glutathione content in the prefrontal cortical mitochondria of rats with acute hepatic encephalopathy: prevention by histidine

Abstract

Mitochondrial glutathione (mGSH) is a critical factor in the cell defense against oxidative and nitrosative stress (ONS), and ONS is a key pathogenic event in hepatic encephalopathy (HE). Acute HE in the thioacetamide (TAA) model caused a 54 % decrease of mGSH content in the rat prefrontal cortex (pfc), but not in the striatum (str), nor did it affect the GSH content in the pfc or str homogenate. In the pfc, treatment with L- histidine (His), which is known to alleviate ONS-related symptoms in HE animals, attenuated the decrease of mGSH, and increased the GSH content in pfc and str homogenates and pfc microdialysates of control animals. His increased the expression of mRNA coding for the GSH synthesizing enzyme, glutamate cysteine ligase (GCL) and decreased that of the GSH-degrading enzyme γ-glutamyltranspeptidase (γGT). The results suggest that the decrease of mGSH may be an important contributing factor to mitochondrial dysfunction in HE, and delineate a new mechanistic aspect of the therapeutic potential of His in HE.

Astroglial NMDA receptors inhibit expression of Kir4.1 channels in glutamate-overexposed astrocytes in vitro and in the brain of rats with acute liver failure

“…Our results, however, negated this hypothesis. In the TAA-induced HE, His, administered at a dose that inhibited ONS in the cerebral cortex by counteracting mitochondrial damage (Rama Rao et al, 2010) and decreased the loss of whole-brain and mitochondrial GSH (Ruszkiewicz et al, 2013), did not rescue Glu-induced inhibition of Kir4.1 mRNA expression (Fig. 5B).…”

“…A number of recent studies have highlighted the contribution of ONS to the astrocytic dysfunction associated with HE in vivo (Rama Rao et al, 2010;Ruszkiewicz et al, 2013). Similarly emphasized is the ability of ammonia and other pathogenic factors operating in HE to induce ONS in cultured astrocytes, with activation of astrocytic NMDA receptors being considered as a possible intermediate step (Kruczek et al, 2011;Lachmann et al, 2013;Reinehr et al, 2007;Schliess et al, 2002;Zieliń ska et al, 2003) (for recent review, see Häussinger and Görg, 2010).…”

“…In contrast, i.p. administration of histidine (His) (100 mg/ml, 3 administrations at 24 h intervals), which attenuates the oxidative stressrelated symptoms of HE associated with glutamine accumulation (Rama Rao et al, 2010) and with a loss of intramitochondrial glutathione (GSH) (Ruszkiewicz et al, 2013), was ineffective in ameliorating the HE-induced decrease of Kir4.1 transcription (71.2 ± 12.1%, n = 11, *P < 0.01, Fig. 5B).…”

The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: Modulation by histidine

“…His was suggested to exert these effects by inhibiting mitochondrial Gln transport. Alternatively, the protective properties of His could be due to its antioxidative potential of this amino acid as noted both in the central nervous system (CNS) and in non CNS tissues in different conditions (Wade and Tucker, 1998), and recently confirmed in the TAA model of HE (Ruszkiewicz and Albrecht, 2014;Ruszkiewicz et al, 2013). The decrease of ADMA concentration evoked by His in TAA rat model of ALF could be most likely due to one, or the combination, of the following events: (i) changes in DDAH activity and/or expression, (ii) inter-cellular or blood-brain barrier ADMA transport.…”

“…His is capable of reducing oxidative stress (OS) in both the CNS and peripheral tissue (Wade and Tucker, 1998). In the CNS, His has been reported to ameliorate OS evoked by TAA-induced HE by multiple, mutually not exclusive mechanisms including inhibition of mitochondrial permeability transition (mPT) related by controlling excessive mitochondrial Gln uptake (Rama Rao et al, 2010), or preventing a decrease of glutathione content in mitochondria (Ruszkiewicz et al, 2013). We speculated that the OS-attenuating activity of His may result in correcting the ADMA/DDAH system imbalance and therefore NO synthesis.…”