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Assessment of neuroprotective efficacy of phytochemicals against oxidatiive stress mediated neurodegeneratiion in Drosophilla mellanogaster

Ravikumar, Hosamani (2010) Assessment of neuroprotective efficacy of phytochemicals against oxidatiive stress mediated neurodegeneratiion in Drosophilla mellanogaster. PhD thesis, University of Mysore.

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Abstract

Currently, there has been an increased interest globally to identify antioxidant compounds that are pharmacologically potent and have low or no side effects for use in preventive medicine. As plants produce significant amount of antioxidants to prevent oxidative stress, they represent a potential source of new compounds of therapeutic use. Numerous clinical and experimental studies have also demonstrated the putative positive benefits of antioxidants in altering, reversing or forestalling the neuronal and behavioral dysfunctions. Involvement of oxidative stress is well accepted concept among pathophysiology of various neurodegenerative diseases (NDD). Owing to the existence of rich background literature, coupled with easy culture methods and short lifespan, Drosophila have been extensively utilized in the recent past to understand human NDD. In general studies in Drosophila have translated well to mammalian systems. To the best of our knowledge, the Drosophila system has not been employed as a model to understand the neuroprotective effects of phytochemicals. Hence, it is hypothesized that Drosophila can be utilized as a rapid model system to test the efficacy of putative neuroprotective compounds. Utilizing Drosophila melanogaster, screening of phytochemicals for their potency to modulate neurotoxicant (Rotenone, Paraquat and Acrylamide) induced lethality response revealed the higher potential of Bacopa monnieri (BM) extract. Chronic systemic exposure to rotenone, a specific mitochondrial complex I inhibitor and a prime risk factor in PD pathogenesis has been exploited to understand oxidative stress -mediated neurodegeneration. Using this model specific question/s related to the possible neuropharmacological properties of BM leaf powder against rotenone-induced oxidative stress and neurotoxicity have been addressed. Biochemical evidences revealed that dietary feeding of BM to Drosophila for a short duration has the propensity to attenuate rotenone induced oxidative stress owing to its antioxidative nature and its ability to modulate the activity of antioxidant defenses. Additional evidences viz., lower incidence of rotenone induced mortality and higher resistance to paraquat among flies given BM prophylaxis clearly support such a Abstract mechanism/s. Further, its neuro-modulatory potency was ascertained by its ability to significantly improve the locomotor performance among rotenone exposed flies and restoration of Dopamine levels. Several evidences related to the neuroprotective efficacy of BM prophylaxis was obtained in the paraquat (PQ) model in Drosophila. BM prophylaxis markedly attenuated the PQ induced lethality, oxidative stress and mitochondrial functions determined in terms of the activities of TCA cycle and ETC enzymes. These neuroprotective effects of BM in the Drosophila model were validated in a mice model employing both acute and chronic paradigms of PQ. Interestingly prepubertal mice given BM prophylaxis (200 mg/kg bw /d, 4 weeks) were more resistant to acute PQ induced oxidative stress and mitochondrial damage. Differential protective effects were evident in different brain regions. Further, BM treatment of mice in a ‘Chronic PQ intoxication regimen’ rendered marked protection to cerebellum and striatum in terms of oxidative impairments, cholinergic function, and mitochondrial dysfunction. The findings in the fly model were reproducible in the rodent model suggesting the utility value of Drosophila to screen the neuroprotective efficacy of phytochemicals. Since several NDD involve multiple cellular mechanisms, a combination of two or more potential compounds may yield additive or synergistic neuroprotective effects. Such an attempt was made in the Drosophila model by testing a combination of BM extract and creatine, a well known ergogenic nutritional supplement. The neuroprotective efficacy of creatine-enriched diet in Drosophila system was clearly evidenced by its ability to modulate endogenous oxidative markers, its propensity to mitigate rotenone-induced mitochondrial oxidative stress, restoration of dopamine levels and attenuation of neurotoxicity. Interestingly, a combination of BM extract and creatine at lower concentrations appeared to completely offset rotenone-induced neurotoxic effects suggesting a clear synergistic effect. Collectively these evidences confirm the utility value of Drosophila as a primary tool to rapidly screen compounds suspected to possess neuropharmacological properties prior to their testing in mammalian models and further therapeutic use in humans.

Item Type: Thesis (PhD)
Uncontrolled Keywords: neurodegenerative diseases, NDD, Drosophila, Bacopa monnieri
Subjects: 600 Technology > 01 Medical sciences > 17 Toxicology
Divisions: Dept. of Biochemistry
Depositing User: Food Sci. & Technol. Information Services
Date Deposited: 15 May 2012 06:49
Last Modified: 30 Jun 2015 12:34
URI: http://ir.cftri.com/id/eprint/10755

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