Modulation of histone deacetylase, the ubiquitin proteasome system, and autophagy underlies the neuroprotective effects of venlafaxine in a rotenone-induced Parkinson's disease model in rats. (25th February 2022)

• Record Type: Journal Article
• Authors: El-Saiy, Khalid A.; Sayed, Rabab H.; El-Sahar, Ayman E.; Kandil, Esraa A.
• Is Part Of: Chemico-biological interactions. Volume 354(2022)
• Publication Date: 2022-02-25
• Subjects: Venlafaxine -- Ubiquitin proteasome system (UPS) -- Autophagy -- Histone deacetylase 6 (HDAC6) -- Parkinson's disease (PD) -- Depression; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2022.109841
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms. Impairment of the ubiquitin proteasome system (UPS) and autophagy has been suggested to contribute to α-synuclein accumulation, which is identified as the pathological hallmark of PD. Recently, alteration in histone-3 acetylation has also been found to be correlated to PD. Interestingly, the histone deacetylase 6 (HDAC6) enzyme, which regulates the acetylation of histone-3, was shown to be involved in autophagy. Venlafaxine is an antidepressant that was proposed to inhibit HDAC expression in depressive rats' hippocampi. In this study, we aimed to examine the ability of venlafaxine to inhibit striatal HDAC6 and to enhance α-synuclein clearance through the activation of the UPS and autophagy, in addition to treating depression, which is the most debilitating non-motor symptom, in a rotenone model of PD. Venlafaxine administration was noted to decrease α-synuclein accumulation and preserve dopaminergic neurons along with restoration of striatal dopamine levels and motor recovery. Its administration augmented the UPS and autophagic markers (beclin-1, p62, and LC3) with consequent modulation of apoptotic indicators (Bax/Bcl-2 ratio, cytochrome c, and caspase-3). Additionally, venlafaxine inhibited HDAC6 with further enhancement of autophagy and restoration of histone-3 acetylation with subsequent increases in survival gene expressions (Bcl-2 and brain-derived neurotrophic factor). Chloroquine (autophagy inhibitor) was used to indicate the proposed pathway. Moreover, venlafaxine hampered depressive symptoms and improved hippocampal noradrenaline and serotonin levels. Collectively, venlafaxine is suggested to display neuroprotective effects with improvement of motor and non-motor PD symptoms. Graphical abstract: Image 1 Highlights: Venlafaxine decreased α-synuclein accumulation and preserved dopaminergic neurons. Venlafaxine recovered motor activity of rats. Venlafaxine augmented the UPS and autophagic markers with consequent modulation of apoptotic indicators. Venlafaxine inhibited HDAC6 with restoration of histone-3 acetylation. The proposed pathway was evidenced by the use of autophagy inhibitor chloroquine.