C60 Fullerene Reduces 3-Nitropropionic Acid-Induced Oxidative Stress Disorders and Mitochondrial Dysfunction in Rats by Modulation of p53, Bcl-2 and Nrf2 Targeted Proteins.

Olga O Gonchar,Andriy V Maznychenko,Inna Sokolowska,Iryna M Mankovska,Olena M Klyuchko,Agnieszka Borowik,Jacek Piosik,Kamila Butowska

doi:10.3390/ijms22115444

Abstract

C60 fullerene as a potent free radical scavenger and antioxidant could be a beneficial means for neurodegenerative disease prevention or cure. The aim of the study was to define the effects of C60 administration on mitochondrial dysfunction and oxidative stress disorders in a 3-nitropropionic acid (3-NPA)-induced rat model of Huntington’s disease. Animals received 3-NPA (30 mg/kg i.p.) once a day for 3 consecutive days. C60 was applied at a dose of 0.5 mg/kg of body weight, i.p. daily over 5 days before (C60 pre-treatment) and after 3-NPA exposure (C60 post-treatment). Oxidative stress biomarkers, the activity of respiratory chain enzymes, the level of antioxidant defense, and pro- and antiapoptotic markers were analyzed in the brain and skeletal muscle mitochondria. The nuclear and cytosol Nrf2 protein expression, protein level of MnSOD, γ-glutamate-cysteine ligase (γ-GCLC), and glutathione-S-transferase (GSTP) as Nrf2 targets were evaluated. Our results indicated that C60 can prevent 3-NPA-induced mitochondrial dysfunction through the restoring of mitochondrial complexes’ enzyme activity, ROS scavenging, modulating of pro/antioxidant balance and GSH/GSSG ratio, as well as inhibition of mitochondria-dependent apoptosis through the limitation of p53 mitochondrial translocation and increase in Bcl-2 protein expression. C60 improved mitochondrial protection by strengthening the endogenous glutathione system via glutathione biosynthesis by up-regulating Nrf2 nuclear accumulation as well as GCLC and GSTP protein level.

Highlights

IntroductionHuntington’s disease (HD) is a progressive and fatal neurodegenerative disorder, characterized by the clinical triad: Movement disorder, dementia, and psychiatric disturbance due to striatal-specific neuronal degeneration [2,3]
Mitochondria are key regulators of cell functions and cell survival, any changes in mitochondrial energy metabolism, impaired calcium buffering, and increased generation of reactive oxygen species (ROS) can cause mitochondrial dysfunction and be a trigger for a variety of neurological pathologies [1].Huntington’s disease (HD) is a progressive and fatal neurodegenerative disorder, characterized by the clinical triad: Movement disorder, dementia, and psychiatric disturbance due to striatal-specific neuronal degeneration [2,3]
It was found that abnormal aggregation of mutant huntingtin proteins could cause toxic effects in neurons, followed by a cascade of pathogenic mechanisms associated with bioenergetic defects and subsequent excitotoxicity, mitochondrial dysfunction, oxidative stress, transcriptional alterations, and apoptosis [3,4]. mHtt causes lesions in specific brain areas, and in peripheral tissues like skeletal muscles, kidney, heart, and liver, where mHtt abundance is the same as in the brain [5,6]

Summary

Introduction

Huntington’s disease (HD) is a progressive and fatal neurodegenerative disorder, characterized by the clinical triad: Movement disorder, dementia, and psychiatric disturbance due to striatal-specific neuronal degeneration [2,3]. It was found that abnormal aggregation of mutant huntingtin (mHtt) proteins could cause toxic effects in neurons, followed by a cascade of pathogenic mechanisms associated with bioenergetic defects and subsequent excitotoxicity, mitochondrial dysfunction, oxidative stress, transcriptional alterations, and apoptosis [3,4]. Mitochondrial toxin 3-nitropropionic acid, which selectively inhibits complex II of the electron transport chain (ETC), produces clinical and pathologic manifestations of disorders that look like HD symptoms in rodents, primates, and humans [7].

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