Parkinson's disease (PD) is a common progressive neurodegenerative disorder commonly affecting elderly people [1]. It is characterized by motor deficiencies such as resting tremors, rigidity, bradykinesia, and postural instability [2]. These motor symptoms are attributed to dopamine deficiency in the striatum following degeneration of dopaminergic neurons in the substantia nigra, which, in turn, is prompted by the accumulation of α-synuclein aggregates, the pathological hallmark of PD [3,4]. Impairment in the ubiquitin proteasome system (UPS) and autophagy can play a major role in the build-up of α-synuclein aggregates, since both are implicated in the removal of aggregated proteins before triggering detrimental effects and apoptosis [5,6]. In this context, deficiency in UPS function and autophagic activity contributes to PD pathology; thus, maintenance of their activities is crucial for α-synuclein aggregate clearance. It is worth mentioning that alteration in histone-3 acetylation has recently been correlated to the pathogenesis of PD [7]. Histone-3 acetylation is identified as a dominant controller of the transcriptional machinery involved in cellular functions, which is regulated by histone acetyltransferase and histone deacetylase (HDAC) enzymes [8,9]. Upon deacetylation via HDAC, histone becomes tightly bound to DNA with subsequent transcriptional repression of neuroprotective proteins required for neuronal survival [10]. Notably, α-synuclein accumulation has been shown to contribute to histone-3 hypoacetylation by disguising acetylation zones on histone substrates [11]. In harmony, several studies have revealed dysregulation in histone-3 acetylation in PD patients' brains, and that modulation of histone-3 acetylation via inhibition of HDAC enzymes could endorse cell survival along with protection against neurotoxic insults [7,12,13]. Interestingly, the HDAC6 enzyme was shown to be involved in autophagy, and its inhibition is associated with the induction of autophagy [7,14,15]. Thus, inhibitors of HDAC6 can promote autophagy with consequent clearance of α-synuclein aggregates, and they can modulate histone-3 acetylation with subsequent elevation in the level of survival genes, hence supporting their role as neuroprotective remedies for PD.

In addition to motor symptoms, non-motor symptoms are also noted to occur in PD, which significantly affects the quality of life of patients [16,17]. Depression is the supreme non-motor disorder; it affects approximately 40–50% of PD patients and augments the overall disability [17]. It is believed to result from deterioration of noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe, which accompanies the loss of dopaminergic neurons in the substantia nigra (SN) [18]. Remarkably, depression may precede or concurrently occur with PD, and its occurrence has also been regarded as a risk factor for later development of PD [19]. In this context, a therapy that could treat depression in PD would significantly impact the quality of life of patients with PD. Venlafaxine is defined as a mixed antidepressant that prevents the reuptake of both norepinephrine and serotonin [20]. It was suggested to be effective in the treatment of depression in PD [17]. Interestingly, venlafaxine treatment was recently shown to inhibit HDAC expression in the hippocampus of depressive rats [21]. Considering these previous findings, this study was conducted to investigate the neuroprotective effect of venlafaxine in PD by inhibiting HDAC6 and enhancing the removal of α-synuclein aggregates via activating UPS function and autophagy in an animal model of PD.

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