Neuroprotective activities of Nepalese and Native American traditional medicine in Parkinson's disease models

Aurelie de Rus Jacquet, Purdue University

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease with 5% of the population being affected by age 85. The disease involves a loss of dopaminergic neurons from the substantia nigra in the midbrain, and this loss of neurons is largely responsible for motor symptoms such as the inability to initiate movement, resting tremor, and reduced balance. Molecular phenomena underlying neurodegeneration in PD include oxidative stress, loss of mitochondrial function, aggregation of the pre-synaptic protein alpha-synuclein (aSyn), and neuroinflammation. Current therapeutic strategies for PD only alleviate symptoms and do not reverse the neuronal death. Hence, patients and health care providers are in need of safe and effective neuroprotective therapies that can slow the neurodegenerative process. Traditional medicine is the primary form of healthcare for 80% of the population in developing countries. This form of medicine results from empirical determination of the safest and most efficient plant preparations to achieve desired health-promoting benefits. A number of in vitro and in vivo studies have led to the identification of polyphenols (including isoflavones and anthocyanins (ANC)) as a major class of plant-derived compounds with potential neuroprotective activities. As a result of these observations, we hypothesized that medicinal plants used in Nepalese and Native American traditional medicine to treat symptoms related to PD or other CNS disorders are potential neuroprotective candidates for the development of PD therapies. The studies outlined in this thesis were aimed at identifying traditional herbal medicines used to treat PD and CNS-related disorders in (i) Nepalese communities living in three eco-geographical areas, and (ii) two Native American tribes (the Pikuni-Blackfeet and Lumbee tribes) with different cultural identities and traditional practices. Our ethnopharmacological study yielded insight into the strong influence of the surrounding environment on the practice of traditional medicine. In all three study areas, we observed and reported on the impact of cultural, historical and environmental pressures on the evolution of traditional medicine. Our study led to the identification of medicinal plants across various botanical families with potential neuroprotective activities. We developed a primary screen to test the ability of 23 botanical extracts to activate Nrf2, a transcription factor that acts as a master regulator of the cellular antioxidant response. Extracts that produced the most robust activation of Nrf2 signaling were further studied to determine their neuroprotective effects against toxicity elicited by PD-related insults. The extracts of garlic, juneberry, elderflower, red clover, Mucuna pruriens and Tinospora sinensis alleviated neurodegeneration induced by the pesticide rotenone, the herbicide paraquat, and/or the A53T genetic mutant of aSyn. Following the observation that isoflavones-rich extracts (red clover) and ANC-rich berry extracts (juneberry) are potent neuroprotective agents, we carried out two studies aimed at understanding the beneficial role of isoflavones and ANC in PD models. In these studies we characterized several isoflavone-rich extracts, individual isoflavones, and ANC-rich extracts in terms of their ability to prevent dopaminergic cell loss, activate the Nrf2/ARE response, and alleviate mitochondrial dysfunction. We found that the extracts and compounds alleviated neurodegeneration by modulating different pro-survival pathways. The red clover and ANC-rich extracts, but not the soy extract or individual isoflavones, activated the Nrf2/ARE pathway. Interestingly, Nrf2 activation mediated by ANC-rich extracts was ROS-dependent, whereas activation by the red clover extract was dependent on UPS inhibition. Furthermore, the red clover, soy, and ANC-rich extracts mitigated rotenone-induced mitochondrial impairment, and the amelioration of mitochondrial dysfunction by the red clover extract apparently involved the displacement of rotenone from its complex I binding site. Collectively, our data indicate that ethnopharmacological studies are an effective strategy to identify botanical specimens with neuroprotective activity. Polyphenol-rich herbal extracts achieve neuroprotection via multiple pro-survival mechanisms including activation of the Nrf2/ARE antioxidant response and maintenance of mitochondrial function. Our findings suggest that plant-based extracts with neuroprotective activity could potentially reduce the risk of PD and slow disease progression in patients.

Degree

Ph.D.

Advisors

Rochet, Purdue University.

Subject Area

Neurosciences|Pharmacology

Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server
.

Share

COinS