Natural Phytochemicals as Novel Therapeutic Strategies to Prevent and Treat Parkinson's Disease: Current Knowledge and Future Perspectives

Abstract

Parkinson's disease (PD) is the second-most common neurodegenerative chronic disease affecting both cognitive performance and motor functions in aged people. Yet despite the prevalence of this disease, the current therapeutic options for the management of PD can only alleviate motor symptoms. Research has explored novel substances for naturally derived antioxidant phytochemicals with potential therapeutic benefits for PD patients through their neuroprotective mechanism, targeting oxidative stress, neuroinflammation, abnormal protein accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, neurotrophic factor deficit, and apoptosis. The aim of the present study is to perform a comprehensive evaluation of naturally derived antioxidant phytochemicals with neuroprotective or therapeutic activities in PD, focusing on their neuropharmacological mechanisms, including modulation of antioxidant and anti-inflammatory activity, growth factor induction, neurotransmitter activity, direct regulation of mitochondrial apoptotic machinery, prevention of protein aggregation via modulation of protein folding, modification of cell signaling pathways, enhanced systemic immunity, autophagy, and proteasome activity. In addition, we provide data showing the relationship between nuclear factor E2-related factor 2 (Nrf2) and PD is supported by studies demonstrating that antiparkinsonian phytochemicals can activate the Nrf2/antioxidant response element (ARE) signaling pathway and Nrf2-dependent protein expression, preventing cellular oxidative damage and PD. Furthermore, we explore several experimental models that evaluated the potential neuroprotective efficacy of antioxidant phytochemical derivatives for their inhibitory effects on oxidative stress and neuroinflammation in the brain. Finally, we highlight recent developments in the nanodelivery of antioxidant phytochemicals and its neuroprotective application against pathological conditions associated with oxidative stress. In conclusion, naturally derived antioxidant phytochemicals can be considered as future pharmaceutical drug candidates to potentially alleviate symptoms or slow the progression of PD. However, further well-designed clinical studies are required to evaluate the protective and therapeutic benefits of phytochemicals as promising drugs in the management of PD.

Figure 1

Structures of phytochemicals present in dietary sources (chrysin, vanillin, ferulic acid (FA), thymoquinone (TQ), ellagic acid (EA), caffeic acid (CA), epigallocatechin-3-gallate (EGCG), and theaflavin (TF)) and other plant-derived phytochemicals (asiatic acid (AA) and α- and β-asarone), belonging to different classes of phenolics and nonphenolics. These phytochemicals have demonstrated several mechanisms of action by which they protect the brain from neurodegeneration. The structures were regenerated from http://molview.org/. Here, the different colors of different atoms in the structures represent specific molecules, where grey = carbon, white = hydrogen, and red = oxygen.

Figure 2

Oxidative stress and its implications in the pathogenesis of neurodegeneration in PD. When the production of ROS generation overwhelms intracellular antioxidant defenses, brain cells are exposed to oxidative stress, which may lead to mitochondrial dysfunction and further ROS production. Oxidative stress impairs the protein degradation system and hinders the clearance and results in the subsequent deposition of misfolded protein, which in turn results in lipid peroxidation, protein oxidation, and DNA damage, leading to neuronal death. These events constitute the pathological basis of PD. CAT: catalase; SOD: superoxide dismutase; GPx: glutathione peroxidase; GSH: glutathione; MDA: malondialdehyde; 8-OHdG: 8-hydroxydeoxyguanosine.

Figure 3

Intracellular targets of neuroprotective antioxidant phytochemicals by activation of Keap1/Nrf2/ARE signaling pathways to increase the expression of antioxidant enzymes. The modulation of these pathways by natural antioxidant phytochemicals such as chrysin, vanillin, asiatic acid (AA), ferulic acid (FA), thymoquinone (TQ), ellagic acid (EA), caffeic acid (CA), epigallocatechin-3-gallate (EGCG), α- and β-asarone, and theaflavin (TF).