Selective degeneration of dopaminergic neurons in the substantia nigra underlies the basic motor impairments of Parkinson's disease (PD). Curcumin has been used for centuries in traditional medicines in India. Our aim is to understand the efficacy of genotropic drug curcumin as a neuroprotective agent in PD. Analysis of different developmental stages in model organisms revealed that they are characterized by different patterns of gene expression which is similar to that of developmental stages of human. Genotropic drugs would be effective only during those life cycle stages for which their target molecules are available. Hence there exists a possibility that targets of genotropic compounds such as curcumin may not be present in all life stages. However, no reports are available in PD models illustrating the efficacy of curcumin in later phases of adult life. This is important because this is the period during which late-onset disorders such as idiopathic PD set in. To understand this paradigm, we tested the protective efficacy of curcumin in different growth stages (early, late health stage, and transition phase) in adult Drosophila flies. Results showed that it can rescue the motor defects during early stages of life but is ineffective at later phases. This observation was substantiated with the finding that curcumin treatment could replenish depleted brain dopamine levels in the PD model only during early stages of life cycle, clearly suggesting its limitation as a therapeutic agent in late-onset neurodegenerative disorders such as PD.

Parkinson’s disease (PD) affects almost 1% of the population worldwide over the age of 50 years. Exposure to environmental toxins like paraquat and rotenone is a risk factor for sporadic PD which constitutes 95% of total cases. Herbicide rotenone has been shown to cause Parkinsonian symptoms in multiple animal models. Drosophila is an excellent model organism for studying neurodegenerative diseases (NDD) including PD. The aging process is characterized by differential expression of genes during different life stages. Hence it is necessary to develop life-stage-matched animal models for late-onset human disease(s) such as PD. Such animal models are critical for understanding the pathophysiology of age-related disease progression and important to understand if a genotropic drug/nutraceutical can be effective during late stages. With this idea, we developed an adult life stage-specific (health and transition phase, during which late-onset NDDs such as PD sets in) rotenone-mediated Drosophila model of idiopathic PD. Drosophila is susceptible to rotenone in dose-time dependent manner. Rotenone-mediated fly model of sporadic PD exhibits mobility defects (independent of mortality), inhibited mitochondrial complex I activity, dopaminergic (DAergic) neuronal dysfunction (no loss of DAergic neuronal number; however, reduction in rate-limiting enzyme tyrosine hydroxylase (TH) synthesis), and alteration in levels of dopamine (DA) and its metabolites; 3,4-Dihydroxyphenylacetic acid (DOPAC) and Homovanilic acid (HVA) in brain-specific fashion. These PD-linked behaviors and brain-specific phenotypes denote the robustness of the present fly model of PD. This novel model will be of great help to decipher life stage-specific genetic targets of small molecule mediated DAergic neuroprotection; understanding of which is critical for formulating therapeutic strategies for PD.

Background: Owing to the increasing aged population globally, disorders and diseases of the CNS are anticipated to increase and profoundly impact the health care. As these neurodegenerative diseases (NDD) are complex, multifactorial and do not have identified etiological factors, unfortunately, drugs developed for the purpose have not met with the expected success. Hence, there has been a constant demand for the development of natural therapeutic adjuvants which are safe and possess the potential to attenuate multiple pathways. Methods: Numerous herbal/natural products have been used as therapeutics in Ayurvedic system of medicine to treat NDD and other memory-related disorders. Withania somnifera (Ashwagandha, WS), popularly called as “Indian Ginseng” is one such plant which possesses a variety of beneficial neuropharmacological properties. In this review, we have attempted to review critically the existing literature and patents related to the neuroprotective efficacy of WS roots and the underlying mechanism/s. Results: Standardized extracts of Withania somnifera (WS) have been demonstrated to possess multidimensional neuromodulatory effects both in vitro and animal models. The spectrum of effects evidenced comprises of attenuation of oxidative damage by enhancing the antioxidant defense system with concomitant enhancement of the expression of marker proteins responsible for growth, differentiation and communication of neural cells. Specific effects of WS are attributable to its potential to modulate neurotrophic factors, cytoskeletal elements, cell adhesion molecules and synaptic proteins. Conclusion: Generation of new data by employing systematic contemporary approaches such as bioinformatics, molecular docking studies, identification of specific gene targets and epigenetic regulation would provide the necessary impetus to validate fully the neurotherapeutic potential of the phytochemicals derived from WS. More importantly, well-designed clinical trials are required to exploit the neuromodulatory propensity of WS extract/bioactives in specific neurodegenerative diseases such as AD and PD.