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

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.