Acute Brain Damage Induced by Acetaminophen in Mice: Effect of Diphenyl Diselenide on Oxidative Stress and Mitochondrial Dysfunction

Abstract

Organoselenium compounds exhibit antioxidant activity, as well as a variety of biological activities, with potential pharmacological and therapeutic applications. The aim of this study was to investigate the effect of diphenyl diselenide (PhSe)(2) in reversing oxidative brain damage and mitochondrial dysfunction caused by administration of acetaminophen (APAP) in mice. Mice received a toxic dose of APAP, followed by a dose of (PhSe)(2) 1 h later. Four hours after the administration of APAP, plasma was withdrawn from the mice and used for biochemical assays of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatotoxicity. Brain homogenate was examined to determine oxidative stress. Isolated brain mitochondria were examined to quantify mitochondrial transmembrane's electrical potential and mitochondrial swelling and to estimate reactive oxygen species (ROS) production. APAP administration caused an increase in plasma ALT and AST activities. APAP administration also caused a significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and dichlorofluorescein oxidation in brain homogenate. Similarly, mitochondrial swelling and ROS production increased after APAP administration. APAP treatment also caused a decrease in Na(+), K(+)- ATPase activity and in mitochondrial membrane potential. These alterations observed in the brain of APAP-treated mice were restored by (PhSe)(2). Glutathione levels were decreased by APAP, but (PhSe)(2) did not reverse this change. Treatment with (PhSe)(2) after APAP administration can reverse the neurotoxicity caused by a single toxic dose of APAP. The neuroprotective effect of (PhSe)(2) is likely associated with its antioxidant properties.

Homeostatic effect of p-chloro-diphenyl diselenide on glucose metabolism and mitochondrial function alterations induced by monosodium glutamate administration to rats

“…Samples of liver mitochondria were incubated in 1 mL of medium containing 10 mM Tris-HCl (pH 7.4), 320 mM mannitol, 8 mM K 2 HPO 4 , 4 mM MgCl 2 , 0.08 mM EDTA, 1 mM EGTA and 0.2 mg/mL BSA (Da Silva et al 2011). Respiration of mitochondria (1 mg of protein/mL was initiated with a cocktail of FAD + -linked substrates at 5 mM (rotenone and succinate) and phosphorylating (state III) respiration was initiated by the addition of 200 nmol of ADP.…”

Inhibitory effects of pain relief drugs on neurological enzymes: Implications on their potential neurotoxicity to aquatic animals

“…A previous study (da Silva et al, 2012) reported that brain Na + -K + -ATPase activity in mice is inhibited after acetaminophen treatment, but this inhibitory effect is eliminated by co-treatment with an antioxidant. Thus, inhibition in Na + -K + -ATPase activity is caused by pain relievers indirectly via oxidase stress, lipid peroxidation, and/or free radicals.…”

“…Current knowledge about the toxicity of overdosing pharmaceuticals suggests that acetaminophen exerts its neurotoxicity indirectly by decreasing the GSH level and generating reactive oxygen species (ROS), leading to oxidative stress and influencing the antioxidant capacity of the whole organism, including the brain (Bessems and Vermeulen, 2001;da Silva et al, 2012). Thus, brain damage induced by acetaminophen treatment in mice could be reversed by further treatment of anti-oxidative diphenyl diselenide (PhSe 2 ) (da Silva et al, 2012).…”

“…Thus, brain damage induced by acetaminophen treatment in mice could be reversed by further treatment of anti-oxidative diphenyl diselenide (PhSe 2 ) (da Silva et al, 2012). However, information about the direct effect and the mechanism(s) of pain relievers, including acetaminophen, on MAO activity of aquatic animals is limited.…”

“…The adverse effects of acetaminophen on neural systems and behavior of rodents have recently been demonstrated through in vivo and in vitro studies (da Silva et al, 2012;Posadas et al, 2010;Viberg et al, 2014). The potential for neurotoxicity from other pain relievers is also suspected (Sheppard et al, 2014), although some of them were once considered to have neuro-protective effects (Grilli et al, 1996).…”