Background & Objective:
Imbalance in histone acetylation levels and consequently the
dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone
proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases
and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of
neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level
of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be
a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of
repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression
due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical
and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative
diseases has been widely explored.
Conclusion:
In this review, we focus on the putative role of HDACs in neurodegeneration and further
discuss their potential as a new therapeutic avenue for treating neurodegenerative diseases.
Therapeutic options for Parkinson's disease (PD) are limited to a symptomatic approach, making it a global threat. Targeting aggregated alphasynuclein (α-syn) clearance is a gold standard for ameliorating PD pathology, bringing autophagy into the limelight. Expression of autophagy related genes are under the regulation by histone modifications, however, its relevance in PD is yet to be established. Here, preformed fibrillar form (PFF) of α-syn was used to induce PD in wistar rats, which were thereafter subjected to treatment with trehalose (tre, 4g/kg, orally), a potent autophagy inducer and sodium butyrate (SB, 300 mg/kg, orally), a pan histone deacetylase inhibitor alone as well as in combination. The combination treatment significantly reduced motor deficits as evidenced after rotarod, narrow beam walk, and open field tests. Novel object location and recognition tests were performed to govern cognitive abnormality associated with advanced stage PD, which was overcome by the combination treatment. Additionally, with the combination, the level of pro-inflammatory cytokines were significantly reduced, along with elevated levels of dopamine and histone H3 acetylation. Further, mRNA analysis revealed that levels of certain autophagy related genes and proteins implicated in PD pathogenesis significantly improved after administration of both tre and SB. Immunofluorescence and H&E staining in the substantia nigra region mirrored a potential improvement after treatment with both tre and SB. Therefore, outcomes of the present study were adequate to prove that combinatorial efficacy with tre and SB may prove to be a formidable insight into ameliorating PD exacerbated by PFF α-syn as compared to its individual efficacy.
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