Parkinson's disease (PD) is the second most common neurodegenerative disorder caused due to loss of dopaminergic neurons in substantia nigra pars compacta, which occurs the presence of Lewy bodies made up of Alpha-synuclein (ASN) aggregation resulting in neuronal death. This study aims to identify potent 7,8-Dihydroxyflavone (DHF) derivatives to inhibit the ASN aggregation from in silico analysis. Molecular docking study reveals that carbamic ester derivatives of DHF [DHF-BAHPC (8q), DHF-BAHPEC (8s), DHF-BAHEC (8p), DHF-BDOPC (8c), DHF-BAPEC (8n) and DHF-BAMC (8h)] have good binding affinity towards ASN, when compared with DHF and L-DOPA; their docking score values are −16.3120, −16.1875, −15.2223, −14.3118, −14.2893, -14.2810, −14.0383, and −9.1560 kcal/ mol respectively.The in silico pharmacological evaluation shows that these molecules exhibit the druglikeness and ADMET properties. Molecular dynamics simulation confirms the stability of the molecules with ASN. The intermolecular interaction analyzed under the dynamic condition, allows to identify the candidate which potentially inhibits ASN aggregation. Hence, we propose that DHF derivatives are the potential lead drug molecules and preclinical studies are needed to confirm the promising therapeutic ability against PD.Parkinson's disease (PD) is a common neurodegenerative disorder characterized by impairment of motor functions due to complete loss of dopamine in the midbrain. Clinically, PD characterized by behavioral impairments such as rigidity, tremor, postural instability and bradykinesia 1 . Alpha-synuclein (ASN), a PD associated protein, misfolds and accumulates in the brain through protein aggregation. Post-mortem studies showed that these aggregated filamentous termed as a Lewy body, the neurotoxicity is a main factor involved in PD and other disorders such as Alzheimer and Prion disease 2 . Studies report that the loss of dopaminergic neurons in PD is partly due to the overexpression of ASN in the cytoplasm of neurons. ASN expression increases in the substantia nigra with the response of age in rhesus monkeys and humans 3 . The unfolded ASN protein does not have a secondary structure under the physiological condition. However, changes in various environmental factors (agitation, ion strength, pH) induces the formation of amyloid-like fibrils and ASN aggregates in vitro 4 . Comparatively, ASN has more cytotoxicity than the amyloid proteins, which generate amyloid-like fibrils 5 . To prevent the aggregation

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The present study was carried out to investigate the neuroprotective effects of isolongifolene (ILF), a tricyclic sesquiterpene of Murraya koenigii, against rotenone-induced mitochondrial dysfunction, oxidative stress and apoptosis in a cellular model. SH-SY5Y human neuroblastoma cells were divided into four experimental groups (control, rotenone (100 nM), ILF (10 microM) + rotenone (100 nanoM), ILF 10 microM alone treated) based on 3-(4, 5-dimethyl 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The results of the present study showed that the ILF treatment significantly alleviated rotenone-induced cytotoxicity, oxidative stress and mitochondrial dysfunction in SH-SY5Y cells. Moreover, ILF attenuated rotenone induced toxicity by down-regulating  Bax, caspases-3, 6, 8 and 9 expression and up-regulating of Bcl-2 expression. Furthermore regulation of p-P13K, p-AKT and p-GSK-3 beta expression by ILF, clearly confirmed its protective effects. Taken together, our results suggested that ILF attenuated rotenone-induced oxidative stress, mitochondrial dysfunction and apoptosis through the regulation of P13K/AKT/GSK-3 beta signaling pathways. However further pre-clinical studies are warranted in rodents to use ILF as a promising therapeutic agent for PD in future.

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Background and Objective: This investigation explored the neuroprotective effect of PIASA a newly designed peptide - VCSVY in in-silico and in opposition to rotenone stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in an SH-SY5Y cellular model. Methods: Docking and visualization of the PIASA and rotenone was progressed against mitochondrial respiratory complex I (MCI). The in-silico analysis showed that PIASA had interaction to the binding sites of rotenone which may reduce the rotenone interaction and its toxicity too. The SH-SY5Y cells were segregated into four experimental groups: Group I: untreated control cells; Group II: rotenone-only (100 nM) treated cells; Group III: PIASA (5 µM) + rotenone (100 nM) treated cells; and Group IV: PIASA-only (5 μM) treated cells. Results: We evaluated the cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), apoptosis (dual staining technique), nuclear morphological changes (Hoechst staining technique), expression of BAX, Bcl-2, cyt c, pro-caspase 3, and caspases 3, -6, -8, -9 and cleaved caspases 3 by western blot analysis. In SH-SY5Y cells, we further observed the cytotoxicity, oxidative stress and mitochondrial dysfunction in rotenone-only treated cells, whereas pretreatment of PIASA attenuated the rotenone mediated toxicity. Moreover, rotenone toxicity is caused by complex I inhibition, which leads to mitochondrial dysfunction, increased BAX while down regulating the Bcl2 expression and cyt c release and then finally caspases activation. PIASA pretreatment prevented the cytotoxic effects via the normalization of apoptotic marker expressions influenced by rotenone. In addition, pre-clinical studies are acceptable in rodents to make use of PIASA as a revitalizing remedial agent especially for PD in future. Conclusion: Collectively, our results proposed that PIASA mitigated rotenone stimulated oxidative stress, mitochondrial dysfunction, and apoptosis in rotenone induced SH-SY5Y cells.

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