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.

Targeting Mitochondria by Plant Secondary Metabolites: A Promising Strategy in Combating Parkinson’s Disease

“…Protocatechuic aldehyde is another phenolic acid gained from the root of Salvia miltiorrhiza, which has a protective effect on mitochondria by blocking ROS production and keeping the activity of complex I in MPP + -incubated SH-SY5Y cells evaluated in an in vitro experiment [15]. In this line, another phenolic acid, caffeic acid, obtained from tea, wine, coffee, etc., blocked the production of ROS and normalized the activity of mitochondria in the 6-OHDA-induced SH-SY5Y cellular model of PD [54]. In the MPTP animal model of PD, caffeic acid's phenethyl ester reduced dopaminergic neurodegeneration and dopamine loss.…”

“…Curcumin, a polyphenol gained from Curcuma longa, protected mitochondrial function in PD by blocking the activity of MPP + and ROS production in an in vivo and in vitro experiment [36,42,59] and preventing mitochondrial membrane damage in PD [18,19,34]. Targeting the exact mechanism, vanillin, a phenolic aldehyde, reduced rotenone-induced ROS production and mitochondrial malfunction in SH-SY5Y cells [54]. As another phenolic compound, luteolin, obtained from the ripe seed of Perilla frutescens, also played a preventive role in ROS production and maintained mitochondria's activity at a normal level [46,60].…”

“…In vivo/ In vitro: Male C57BL/6 mice/ SH-SY5Y cells ↓ROS, Modulating complex I's activity in PLK2/p-GSK-3β/Nrf2 pathway [15] Caffeic acid In vitro: SH-SY5Y cells ↓ROS production and keep the mitochondrial activity normal [54] In vivo: male C57BL/6 mice ↓Dopaminergic neurodegeneration and dopamine loss [55] Curcumin Polyphenol In vivo/ In vitro: mice / PC12 neuronal cell line ↓MPP + toxicity and ROS production [36,42,59] In vitro: SH-SY5Y cells ↓Mitochondrial damage, ↑tyrosine hydroxylase, and mitochondrial controlling proteins [43] In vitro: PC12 cells ↑Mitochondrial quality control, ↓ oxidative stress, ↑mitophagy markers [44] In vivo: adult Sprague-Dawley rats Repair mitochondrial electron transport abnormalities [45] Silibinin Flavonolig-nan…”

“…In vivo/ In vitro: aged rats/ mice ↓Apoptosis by downregulation of PI3K/Akt pathway [20] In vitro: SH-SY5Y cells ↑MMP, ↑mitochondrial dynamics, elongated fragmented mitochondria [41] Vanillin Phenolic aldehyde In vitro: SH-SY5Y ↓ROS production [54] α-Mangostin Phenolic xanthone In vitro: SH-SY5Y Recovered mitochondrial membrane potential and cellular ATP [102] Nicotine…”

Novel Hydroxytyrosol-Donepezil Hybrids as Potential Antioxidant and Neuroprotective Agents

“…During the last decades many reviews and papers have demonstrated the role of oxidative stress in the pathogenesis of these neurodegenerative diseases, and the administration of both natural and synthetic antioxidant molecules was studied in diverse clinical trials ( Blesa et al, 2015 ; Kim et al, 2015 ; Ganguly et al, 2021 ). The beneficial effects of the Mediterranean diet against age-related cognitive decline have been highlighted ( Gardener and Caunca, 2018 ; Balakrishnan et al, 2021 ), and they were associated to the high consumption of olive oil ( Kalatsbari, 2013 ). It was recently revealed that the poly(phenolic) components of extra virgin olive oil could be neuroprotective and ameliorative against these diseases, by working on several clinical biomarkers and molecular targets ( Spagnuolo et al, 2016 ; Dinda et al, 2019 ).…”