Mitochondrial dysfunction-targeting therapeutics of natural products in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting millions globally, with prevalence significantly increasing in aging populations. Characterized clinically by bradykinesia, tremor, postural instability, and cognitive impairment, PD's pathological hallmarks include the loss of dopaminergic neurons in the substantia nigra striatum, α-synuclein accumulation, and Lewy body formation. Its complex pathogenesis involves mitochondrial dysfunction, oxidative stress, and neuroinflammation. Current treatments, including levodopa, dopamine agonists, and anticholinergics, along with non-drug interventions, offer limited efficacy and often present significant side effects. The development of novel, safe, and effective therapies remains a crucial unmet need. Mitochondria, essential for energy production in dopaminergic neurons, are central to PD pathogenesis. Mitochondrial dysfunction, manifested as ATP depletion, oxidative stress, and apoptosis, plays a critical role in disease progression. This highlights the potential of targeting mitochondrial dysfunction as a therapeutic strategy. Natural products, derived from diverse natural sources, have demonstrated therapeutic potential across various diseases. Many natural products, such as flavonoids and polyphenols, show promise in treating PD by targeting mitochondrial dysfunction. This review focuses on various natural products and their mechanisms of action in mitigating mitochondrial dysfunction in PD, paving the way for novel therapeutic development.

The paper conducted a comprehensive literature search of PubMed, Web of Science, Elsevier, Wiley, and Springer databases (2012-2022), focusing on original research exploring the use of natural products against PD via mitochondrial dysfunction restoration. Existing literature supports the critical role of mitochondrial dysfunction in PD progression, encompassing ATP deficiency leading to decreased dopamine uptake and increased degradation in PD neurons, ROS-mediated oxidative stress, impaired mitochondrial biogenesis and mitophagy imbalance, and mitochondrial fission leading to neuronal death. The review extensively cites prior research demonstrating the neuroprotective potential of natural products in PD models, emphasizing their effects on mitochondrial function.

The study employed a systematic review methodology. A comprehensive search of PubMed, Web of Science, Elsevier, Wiley, and Springer databases was performed, focusing on original research publications between 2012 and 2022. The search terms centered on natural products, Parkinson's disease, and mitochondrial dysfunction. Inclusion criteria were limited to original research articles published in English, examining the neuroprotective effects of natural products against PD by targeting mitochondrial dysfunction. Studies utilizing in vitro (cell culture) and in vivo (animal) models were included. The selected papers were critically reviewed to extract information on the type of natural products used, their mechanisms of action in relation to mitochondrial dysfunction, in vitro and in vivo experimental designs and results, and reported dosages and treatment durations. The information extracted was then organized and presented in a tabular format (Table 1) along with textual descriptions, categorized by the primary target of mitochondrial function (respiration, biogenesis, dynamics, and apoptosis). The mechanisms of action were categorized and described in detail. Additionally, existing toxicology data on several natural products were reviewed to assess their safety profiles.

The review identified a wide range of natural products demonstrating neuroprotective effects by targeting different aspects of mitochondrial dysfunction in PD. **Targeting Mitochondrial Respiration and Bioenergetics:** Various flavonoids (naringenin, calycosin, nobiletin, silibinin, baicalein, hyperoside, myricitrin, quercetin), phenols/polyphenols (resveratrol, mangiferin, demethoxycurcumin, paeonolum, α-Arbutin, Sativex, oleuropein, polydatin, curcumin), terpenoids (ginsenoside Re, ursolic acid, celastrol, mogroside V), glycosides (echinacoside, astragalus polysaccharide, cordycepin), quinones (anthraquinone, embelin), and numerous plant extracts (Calyptranthes grandifolia, Sargassum muticum, Codium tomentosum, Ulva compressa, Eucommia ulmoides, Zizyphus spinachristi, Citrus bergamia, Acanthopanax senticosus, Ganoderma lucidum, Bacopa monnieri, tomato seed extracts, Morinda citrifolia, Centella asiatica, Selaginella delicatula, Piper longum, Trifolium pratense, Mucuna pruriens, Decalepis hamiltonii, Theobroma cacao, Artemisia argyi) were found to improve mitochondrial function by increasing ATP production, maintaining mitochondrial membrane potential (MMP), and reducing reactive oxygen species (ROS). Specific examples include naringenin's increase of MMP and ATP levels in MG-treated SH-SY5Y cells, resveratrol's enhancement of complex I activity and ATP production, and mangiferin's elevation of MMP and ATP in rotenone- or MPTP-treated cells. **Targeting Mitochondrial Biogenesis and Mitophagy:** Flavonoids (baicalein, silibinin, calycosin), phenols/polyphenols (resveratrol, vanillic acid, urolithin A, polydatin), terpenoids (ursolic acid), alkaloids (piperine, piperlonguminine, nicotine, caffeine), quinones (embelin), and various plant extracts (Huperzia selago, Diphasiastrum complanatum, ginseng total protein, Theobroma cacao, Artemisia argyi) demonstrated effects on mitochondrial biogenesis and mitophagy. Silibinin increased the expression of PINK1 and Parkin, promoting mitophagy. Resveratrol upregulated PGC-1α, TFAM, and COX1, enhancing mitochondrial biogenesis. **Targeting Mitochondrial Dynamics:** Flavonoids (silibinin, quercetin), phenols/polyphenols (resveratrol, oleuropein, mangiferin), and plant extracts (Mucuna pruriens, Decalepis hamiltonii, Theobroma cacao, Artemisia argyi) influenced mitochondrial dynamics. Silibinin decreased Drp1 and increased Mfn1 expression, restoring mitochondrial dynamic balance. Resveratrol reversed mitochondrial fragmentation. Mangiferin inhibited Drp1 translocation to mitochondria. **Targeting Mitochondrial Apoptosis:** Flavonoids (baicalein, quercetin, naringenin, calycosin), phenols/polyphenols (oleuropein, mangiferin, green tea polyphenols, demethoxycurcumin), terpenoids (mogroside V), glycosides (astragalus polysaccharide), alkaloids (piperine, piperlonguminine), alkenes (isolongifolene), and various plant extracts (Edible bird's nest, Calyptranthes grandifolia, seaweeds, Echium amoenum, Ganoderma lucidum, Zizyphus spinachristi, Paeonia suffruticosa, Eucommia ulmoides, Morinda citrifolia, Theobroma cacao, Humulus japonicus, Citrus bergamia) exhibited effects on mitochondrial apoptosis by regulating Bcl-2, Bax, caspase-3, caspase-9, and cytochrome c release. Baicalein inhibited caspase-3 activity and prevented cleaved caspase-3 expression. Quercetin reduced the Bax/Bcl-2 ratio and prevented cytochrome c release. **Other Effects:** Ganoderma lucidum extract regulated mitochondrial mobility. Piperine and piperlonguminine blocked mitochondrial permeability transition pore opening.

This review demonstrates the significant potential of diverse natural products in treating PD by targeting mitochondrial dysfunction. The mechanisms of action involve multiple pathways, including the regulation of mitochondrial respiration, biogenesis, dynamics, and apoptosis. Many natural products successfully improved mitochondrial function in both in vitro and in vivo models of PD. The broad range of natural products with differing chemical structures exhibiting neuroprotective effects underscores the potential of natural product-based therapies. However, the precise structure-activity relationships require further investigation. The variability in efficacy and dosage across different studies points to the need for standardization and optimization in the development of these therapeutic approaches. The review highlights the importance of further mechanistic studies and clinical trials to validate the efficacy and safety of these natural products in humans with PD.

Natural products offer promising therapeutic avenues for PD by targeting mitochondrial dysfunction. The review revealed multiple mechanisms of action, impacting mitochondrial respiration, biogenesis, dynamics, and apoptosis. However, more research is needed to establish structure-activity relationships, standardize efficacy and dosage, and conduct large-scale clinical trials to evaluate safety and efficacy in human patients. Future research should prioritize synthesizing potent natural compounds for more controlled and safe therapeutic applications.

The primary limitation is the predominantly preclinical nature of the studies reviewed. Many findings are based on in vitro or animal models, and the translation to human efficacy requires rigorous clinical investigation. Another limitation is the heterogeneity in experimental designs, dosages, and assessment methods across the included studies. This makes direct comparison and generalization of findings challenging. Furthermore, while many natural products exhibit neuroprotective effects, comprehensive toxicology studies and long-term safety data are lacking for many of the compounds.