Department of Pharmacy
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Item The gut-brain connection in the pathogenicity of Parkinson disease: Putative role of autophagy(Elsevier, 2021-05) Taliyan, RajeevParkinson disease (PD) is a progressive movement functionality disorder resulting in tremor and inability to execute voluntary functions combined with the preponderant non-motor disturbances encompassing constipation and gastrointestinal irritation. Despite continued research, the pathogenesis of PD is not yet clear. The available class of drugs for effective symptomatic management of PD includes a combination of levodopa and carbidopa. In recent past, the link between gut with PD has been explored. According to recent preclinical evidence, pathogens such as virus or bacterium may initiate entry into the gut via the nasal cavity that may aggravate lewy pathology in the gut that eventually propagates and progresses towards the brain via the vagus nerve resulting in the prodromal non-motor symptoms. Additionally, experimental evidence also suggests that alpha-synuclein misfolding commences at a very early stage in the gut and is transported via the vagus nerve prior to seeding PD pathology in the brain. However, this progression and resultant deterioration of the neurones can effectively be altered by an autophagy inducer, Trehalose, although the mechanism behind it is still enigmatic. Hence, this review will mainly focus on analysing the basic components of the gut that might be responsible for aggravating lewy pathology, the mediator(s) responsible for transmission of PD pathology from gut to brain and the important role of trehalose in ameliorating gut dysbiosis related PD complications that would eventually pave the way for therapeutic management of PD.Item Neuroprotective Effects of Trehalose and Sodium Butyrate on Preformed Fibrillar Form of α-Synuclein-Induced Rat Model of Parkinson’s Disease(ACS, 2021-07) Taliyan, RajeevTherapeutic options for Parkinson’s disease (PD) are limited to a symptomatic approach, making it a global threat. Targeting aggregated alpha-synuclein (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.Item Fibroblast growth factor 21 and autophagy: A complex interplay in Parkinson disease(Elsevier, 2020-07) Taliyan, RajeevParkinson disease (PD) is a progressive and an age-dependent neurodegenerative disorder that predominantly affects the dopaminergic (DA) neuronal system in the substantia nigra (SN) region of the brain causing its deterioration over time. This deterioration gives rise to motor abnormalities in a PD affected patient causing tremor, bradykinesia, akinesia, postural instability, slurred speech etc. Recent research also enlightened that occurrence of non-motor dysfunctions in an individual initiate in the advanced stage of PD. It comprises mainly of cognitive dysfunction, constipation, sleep disorder, depression, anxiety etc. PD is known to affect at least 0.3% of the worldwide population and over 3% of those over 80 years of age. The predominant pathological hallmark of PD is aggregation of misfolded forms of alpha-synuclein (α-syn) in intraneuronal inclusions known as lewy bodies (LBs) in cell soma and in lewy neurites (LNs) in neuronal processes. α-syn is a presynaptic protein involved in neurotransmission. It is normally degraded by ubiquitin-proteasome system (UPS) and autophagy-lysosome system (ALS) [1]. UPS is responsible for the selective degradation of short-lived proteins and its dysfunction leads to the activation of ALS [2]. Exceptionally high affinities of the mutant forms of α-syn blocks the lysosomal uptake and inhibits its degradation via ALS [1]. This very well explains that ALS dysfunction is an important mechanism in neurodegeneration especially PD. Subsequently, blockage of ALS can aggravate various factors that can further complicate PD, the most important being endoplasmic reticulum (ER) stress [3]. ER stress is mainly a compensatory mechanism that is intended to preserve cellular function and neuronal survival [4] by activating PKR-like ER kinase (PERK), activating transcription factor(ATF)-6, inositol-requiring enzyme(IRE)-1 [5]. Phosphorylation of eukaryotic initiation factor 2-α (eIF2α), via activation by PERK, leads to translational induction of ATF4. Several studies have proved that stressors like starvation, autophagy dysfunction activates ATF4 which is also known to upregulate Fibroblast growth factor 21 (FGF21) [6].