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Synergistic neuroprotective effects of Withania somnifera with specific dietary derived polyphenols

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Relation http://ir.cftri.com/12170/
 
Title Synergistic neuroprotective effects of
Withania somnifera with specific
dietary derived polyphenols
 
Creator Manjunath, M. J.
 
Subject 09 Human Physiology
04 Medicinal Plants
 
Description Neurodegeneration is a progressive damage of both structure and
function of neurons involving numerous cellular pathways leading to a condition
designated as neurodegenerative disorders (NDD). These affect the normal
functioning of motor activity as well as cognition. Although various pathways
and cascades are demonstrated to be involved in initiation and progression of
NDD, oxidative stress mechanism/s emerges as a chief runner in executing the
severity of NDD. Both, oxidative stress and mitochondrial dysfunction are
known to play key roles in the pathophysiology of various NDD.
Owing to the incurable status of major CNS disorders which has a huge
socio-economic impact, researchers are constantly attempting to develop
newer and efficient therapeutic approaches, which act on multiple biochemical
targets, without detrimental side reactions. Both epidemiological and
experimental evidence suggest that the propensity of phytomedicines and
polyphenols to attenuate the redox status in vivo can be successfully exploited
to achieve neuroprotection. Accordingly, various plant extracts in Ayurvedic
medicine 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 rodent and other
laboratory models. In recent times, Drosophila melanogaster is employed as an
experimental model in elucidating not only the pathophysiology and molecular
mechanism/s of NDD, but also as a primary screening platform to develop
novel therapeutic approaches.
The primary objective of this thesis was to comprehensively assess the
neuromodulatory propensity of Withania somnifera (Ashwagandha, Indian
ginseng) and its flavonoids in Drosophila, and mice models of neurotoxicity. For
this purpose, a standardized extract of Withania somnifera was chosen.
Evidence obtained in the chemical systems in vitro clearly demonstrated the
potential antioxidant activity of WSE. Initially, the hypothesis was tested in a
Drosophila model (adult flies) of neurotoxicity employing the neurotoxin,
Rotenone, a mitochondrial (complex I) inhibitor. Interestingly WSE markedly
diminished the endogenous levels of oxidative markers in adult flies. Further,
Abstract
extracts robustly offset ROT –induced lethality, locomotor phenotype, and
significantly ameliorated oxidative stress in Drosophila with concomitant
restoration of antioxidant enzyme activity. Ferulic acid a well-known polyphenol
offered significant protection in the Rotenone model of neurotoxicity. Further,
significant synergistic protections was evidenced in flies exposed to ferulic acid
(FA) enriched with WSE neurotoxicity and suggested the utility value of the
model.
As a proof of principle, the neuroprotective efficacy of WSE was
validated in animal models of ROT (Parkinson’s model). WSE prophylaxis
significantly modulated the endogenous levels of brain oxidative markers in the
mice model. Further, in the Rotenone model of neurotoxicity WSE, markedly
alleviated the locomotor phenotype, motor dysfunctions, and alleviated
oxidative stress, restored antioxidant defenses and mitochondrial function in
cerebellum and striatum. Interestingly, both cholinergic and dopaminergic
functions were restored to varying degree in this model clearly suggesting the
neurorestorative efficacy of WSE under neurotoxicant exposure. The
neuroameliorative effect of WSE was also evaluated in a Streptozotocin
diabetic mice model. Involvement of oxidative stress, mitochondrial
dysfunctions are known to be involved in the development of diabetic
complications such as encephalopathy and neuropathy. In the mice model, the
neuroprotective effects of WSE were evidenced in terms of restoration of
behavioral phenotype, attenuation of brain oxidative stress, and mitochondrial
dysfunctions and neurotransmission.
Collectively, these experimental data clearly demonstrate the
neuromodulatory potential of WSE in experimental models of neurotoxicity in
alleviating NDD–related symptomatic manifestations and striatal oxidative
stress.
 
Contributor Dr., Muralidhara
 
Date 2015
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Language en
 
Rights —
 
Identifier http://ir.cftri.com/12170/1/Manjunath.pdf
Manjunath, M. J. (2015) Synergistic neuroprotective effects of Withania somnifera with specific dietary derived polyphenols. PhD thesis, University of Mysore.