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Mechanisms underlying the neuromodulatory properties of Selaginella and its flavonoids in cell and animal models of neurodegeneration.

Girish, Chandran (2014) Mechanisms underlying the neuromodulatory properties of Selaginella and its flavonoids in cell and animal models of neurodegeneration. PhD thesis, University of Mysore.

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Abstract

Neurodegeneration is a progressive damage of structure and function of neurons involving numerous cellular pathways leading to a condition termed as neurodegenerative disease (NDD) affecting the normal functioning of motor activity and cognition. Irrespective of the various pathways and cascades involved in initiation and progression of NDD, oxidative stress, emerges as a chief runner in executing the severity of NDD. In general, oxidative stress and mitochondrial dysfunction are known to play key roles in the pathophysiology of NDD. The current incurable status of major CNS disorders leads to huge socio-economic impact. Hence there exists a constant need for developing newer and efficient therapeutic approaches, which act on multiple biochemical targets, without detrimental side reactions and minimal or no toxicity. New drug therapy for NDD must involve neuroprotective agents that protect the brain from the deleterious effects of oxygen free radicals and slow down the disease progression. Several lines of evidence suggest that the propensity of polyphenols to attenuate the redox status in vivo can be successfully exploited to achieve neuroprotection. Hence consistent with this conceptual thinking, various plant products are being explored as therapeutic adjuvants. Since mitochondria play a significant role in oxidative stress and associated neurodegeneration, various chemical compounds that induce mitochondrial dysfunctions are used for mimicking neurodegeneration in laboratory animals. In recent times, Drosophila melanogaster and cell lines are also employed in elucidating the pathophysiology and molecular mechanism/s of NDD and also to screen and develop novel therapeutic approaches. The primary objective of this thesis was to comprehensively assess the neuromodulatory propensity of Selaginella (Sanjeevani, the mythical resurrection herb) and its flavonoids in Drosophila, cell and animal models of neurotoxicity. For this purpose, S. delicatula (Desv. Alston) was selected. Evidence obtained in the chemical systems in vitro clearly demonstrated the potential antioxidant Abstract xiii propensity of S. delicatula extracts viz., SDAE (aqueous) and SDME(methanolic) Both extracts exhibited multiple free radical scavenging ability which was attributable to the presence of wide variety of polyphenols and biflavonoids. Based on these data, it was hypothesized that the extracts can exert significant neuroprotective potency under in vivo conditions. Initially, the hypothesis was tested in a Drosophila model (adult flies and II instar larva) of neurotoxicity employing the neurotoxin, rotenone, a mitochondrial (complex I) inhibitor. Interestingly both the extracts of S. delicatula markedly diminished the endogenous levels of oxidative markers in adult flies (head/ body) and larvae. Further, extracts robustly offset ROT-induced lethality, locomotor phenotype, and significantly ameliorated oxidative stress in Drosophila with concomitant restoration of antioxidant enzyme activity. Further, evidence obtained in larvae emphasized the vital role of GSH under ROT-induced neurotoxicity and suggested the utility value of the model. As a proof of principle, the neuroprotective efficacy of S. delicatula extracts was validated in animal models of ROT (Parkinson’s model) and 3NP (Huntington model) which were validated in N27 dopaminergic cells. In the rotenone model of neurotoxicity both extracts, markedly alleviated the locomotor phenotype, motor dysfunctions, and alleviated oxidative stress, restored antioxidant defenses and mitochondrial function in cerebellum and striatum. Further cholinergic and dopaminergic functions were restored to varying degree in the ROT model. Likewise, the prophylactic neuroprotective efficacy of extracts was demonstrable in the 3NP model as evidenced by attenuation of neurobehavioral alterations, and specific biochemical perturbations. Taken together, experimental data clearly demonstrate the neuromodulatory potential of SDAE/ SDME in experimental models of neurotoxicity alleviating NDD-related symptomatic manifestations and striatal oxidative stress. Owing to the mythical reference and neuromodulatory efficacy in the experimental systems, S. delicatula may be exploited in the management of NDD like PD and HD.

Item Type: Thesis (PhD)
Uncontrolled Keywords: Neurodegeneration, Selaginella, neurotoxicity, Drosophila
Subjects: 500 Natural Sciences and Mathematics > 10 Plants
600 Technology > 01 Medical sciences > 17 Toxicology
Divisions: Dept. of Biochemistry
Depositing User: Food Sci. & Technol. Information Services
Date Deposited: 19 Mar 2015 10:23
Last Modified: 19 Mar 2015 10:23
URI: http://ir.cftri.com/id/eprint/11757

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