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Parkinson’s disease (PD) is one of the most prevalent and debilitating neurodegenerative conditions, and is currently on the rise. Several dysregulated pathways are behind the pathogenesis of PD; however, the critical targets remain unclear. Accordingly, there is an urgent need to reveal the key dysregulated pathways in PD. Prevailing reports have highlighted the importance of mitochondrial and cross-talked mediators in neurological disorders, genetic changes, and related complications of PD. Multiple pathophysiological mechanisms of PD, as well as the low efficacy and side effects of conventional neuroprotective therapies, drive the need for finding novel alternative agents. Recently, much attention has been paid to using plant secondary metabolites (e.g., flavonoids/phenolic compounds, alkaloids, and terpenoids) in the modulation of PD-associated manifestations by targeting mitochondria. In this line, plant secondary metabolites have shown promising potential for the simultaneous modulation of mitochondrial apoptosis and reactive oxygen species.
- neurodegenerative disease
- Parkinson’s disease
- secondary metabolites
- phytochemicals
- mitochondria
- signaling pathway
1. Introduction
Humans have always been affected by various neurological complications [1][2][1,2]. Neurodegenerative diseases greatly influence the central and peripheral nervous system and lead to the loss of both physical and mental functions [3][4][3,4]. Several mechanisms are behind neurodegeneration, including neuronal inflammation, oxidative stress, apoptosis, autophagy which cause cell death [1][3][5][1,3,5].
Considering the involvement of multiple dysregulated pathways in the pathogenesis of neurodegenerative diseases, revealing the critical signaling pathways in such disorders seems to pave the road for developing alternative therapies. Accordingly, mitochondria-associated disorders, as well as interconnected oxidative stress, and reactive oxygen species (ROS) seem to be common mediators involved in neurodegeneration [1][5][1,5]. In this line, targeting mitochondria-associated signaling pathways could open new roads in combating Parkinson’s disease (PD), ischemic brain injury (IBI), spinal cord injury (SCI), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS) and amyotrophic lateral disease (ALS) [6][7][8][6,7,8].
Mitochondria are vital components of eukaryotic cells, and are responsible for producing cellular energy [7][8][7,8], especially for more active cells in the body [9]. Mitochondria supply this energy through the oxidative phosphorylation mechanisms by associated complexes [10]. In addition to the task of energy production, mitochondria are also involved in the procedures related to cell survival/death, as well as maintaining the balance of ions and cell metals [5]. These various functions in the mitochondria are performed by constituent elements in normal conditions of cellular equilibrium [8]. Under neuronal dysfunctionalities, the aforementioned cellular balance is lost, and mitochondrial function in neuronal cells is impaired [8][11][8,11]. In such a situation of neuronal damage, mitochondria encounter a dysregulation in ROS production and sensitivity to oxidative stress, leading to cell damage [12][13][12,13]. Functional and morphological changes in mitochondria and abnormalities in its enzymes lead to nerve damage and subsequent neurodegenerative diseases [8]. Accordingly, mitochondrial dysfunction is one of the causes of neurodegenerative diseases [5][8][12][5,8,12].
In neurodegenerative diseases, the mitochondria play critical roles in supplying energy and stability of nerve cells to prevent the destruction of dopaminergic neurons in PD. In addition, the role of mitochondrial toxins is also undeniable. For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) blocked the activity of complex I in mitochondria, elevated ROS output, and increased the release of apoptogenic proteins, which ultimate causes cell death [14][15][14,15]. In addition, mitochondria have a close interconnection with several dysregulated pathways in PD. So, simultaneous targeting of mitochondria and close cross-talked mediators could pave the road for combating PD.
There is no certain cure for PD and other NDDs, but various strategies have been employed to control associated symptoms by influencing dysregulated mechanisms [16]. Considering the higher level of side effects and lower efficacy of synthetic therapies in combating neuronal complications, natural products have drawn attention towards novel alternative therapies [17][18][19][17,18,19]. Consequently, plant-derived secondary metabolites are of great importance in modulating the mitochondrial disorders and interconnected inflammatory/oxidative pathways in neuronal disorders [8][19][8,19]. These secondary metabolites simultaneously attenuate mitochondrial function via several mechanisms, including the inhibition of mitochondrial complexes and ROS-related pathways, the suppression of apoptotic pathways, and preventing the production of α-synuclein misfolded aggregates [20][21][20,21].
2. Modulation of PD by Phytochemicals through Targeting Mitochondria
Secondary metabolites have shown promising effects on neurodegenerative diseases, specifically on PD, by targeting the mitochondria [19][22][23][19,25,34]. PD is a complex neurodegenerative disease characterized by mitochondrial dysfunction, oxidative stress, and neuroinflammation. In this line, the effects of polyphenols, terpene/terpenoids, and alkaloids are highlighted on the mitochondria in PD through various mechanisms.2.1. Polyphenols Effects on Mitochondria in PD
Polyphenols are key secondary metabolites in modulating the mitochondria during PD. These secondary metabolites have a structure based on phenyl rings, including four main categories of flavonoids, lignans, stilbenes, and phenolic acids [6][13][22][6,13,25]. Flavonoids, in turn, have seven subunits that include flavonol, flavone, flavanone, flavanonol, flavanol, anthocyanin, and isoflavone [13][24][13,35]. Polyphenols prevent the production of α-synuclein misfolded aggregation, as well as mitigating oxidative stress, apoptotic and inflammatory processes caused by mitochondrial malfunction [21].
Baicalein is a leading active flavone element of the root of Scutellaria baicalensis and decreases the mitochondrial malfunction in an in vivo and in vitro experiment induced by 6-hydroxydopamine (6-OHDA) [25][26][36,37]. In an isolated brain mitochondrion, baicalein treatment reduced rotenone-induced ROS generation, ATP shortage, and mitochondrial swelling. Remarkably, baicalein increased mitochondrial respiratory action in isolated mitochondria. These findings imply that baicalein is a proper antioxidant with mitochondrial targeting with preventative properties against rotenone-induced neurotoxicity [27][38].
Puerarin, an isoflavone gained from Pueraria thomsonii, showed therapeutic effects on mitochondria through reducing the toxicity of 1-methyl-4-phenylpyridinium (MPP+)-induced in vitro model of PD [25][36]. In PC12 cells and primary rat midbrain neurons, puerarin reduced nitric oxide (NO)-mediated neurotoxicity in PD via upregulating mitochondrial enzyme arginase-2 for the selective regulation of mitochondrial dysfunction [28][39]. Additionally, the malfunction of the ubiquitin–proteasome system in the neuron has been extensively established as exacerbating PD. Puerarin also prevented apoptosis in MPP+-induced SH-SY5Y cells by increasing cell survival, enhancing morphological alterations, and decreasing apoptotic rate by modulating the ubiquitin–proteasome system [29][40].
In another study, flavonoids indicated therapeutic potentials on mitochondria enzyme complex I (e.g., luteolin, fisetin, robinetin, myricetin, rhamnetin and baicalein) and III (e.g., hispidulin and eupafolin) [13]. In addition, flavonoids defended against dopamine depletion and ROS initiation in PD [22][25].
Polyphenols substances such as quercetin and resveratrol in red wine also showed therapeutic potential on mitochondria by inhibiting apoptosis [13][20][13,20]. Resveratrol treatment also restored rotenone-induced mitochondrial membrane potential, altered mitochondrial dynamics, and elongated fragmented mitochondria in SH-SY5Y cells [30][41]. Quercetin also played essential roles in promoting mitochondrial biogenesis [31][42]. In SH-SY5Y cells exposed to MPP+ or lipopolysaccharides (LPS), pretreatment with quercetin substantially reduced mitochondrial damages. Tyrosine hydroxylase and mitochondrial controlling proteins were both upregulated by quercetin [32][43]. As previously described, PD is caused by mitochondrial malfunction and poor mitophagy. In a 6-OHDA-treated PC12 cells, quercetin administration enhanced mitochondrial quality control, decreased oxidative stress, and raised the levels of mitophagy markers. Furthermore, in rats with PD, quercetin alleviated the 6-OHDA-induced progression of PD-like motor abnormalities, decreased neuronal death, and reduced mitochondrial dysfunction [33][44]. Further research suggested that quercetin’s analysis was assumed to repair mitochondrial ETC abnormalities and upregulated. This activity is the foundation of neuroprotection shown in the parkinsonism caused by mitochondrial neurotoxin [34][45]. Hyperoside, a quercetin 3-o-galactoside, is a flavonolglycoside which reduced mitochondrial apoptotic signaling in PC12 cell in an in vitro experiment [35][46].
Silibilin, a flavonolignane extracted from Silybum marianum, has shown modulatory roles on mitochondrial membrane potentials (MMPs) in an in vivo experiment on a MPTP-induced PD model in mice [36][47]. Silibinin’s neuroprotective mechanism includes a decrease in mitochondrial damage and strengthening of the oxidative defense system. Dopaminergic nerve protection is achieved by stimulating mitophagy, which removes the detrimental consequences of damaged mitochondria. These data implied that silibinin has the potential to be further explored as a treatment option for PD [37][48]. In another study, silibinin significantly reduced the motor impairment and dopaminergic neuronal degeneration induced by MPTP. The findings suggest that silibinin has such benefits in MPTP-induced models of PD achieved through increasing the stability of mitochondrial membrane potential [38][49]. Another member of the lignan family, schisandrin, lessened ROS levels, decreased Ca2+’s impact and recovered mitochondrial membrane permeability capacities [22][25].
Naringenin, a flavanone, showed a regulatory effect in neurons and alleviated the function of mitochondria. This effect was exerted through increasing MMP and reducing ROS via affecting the Nrf2/ARE pathway in an in vitro experiment on the brains’ neurons of Sprague Dawley rats [39][50]. In addition, naringenin inhibited the mitochondria-related bioenergetics and redox dysfunctions caused by methylglyoxal in human neuroblastoma SH-SY5Y cells via the Nrf2/GSH pathways [40][51]. Naringin, a glycosylated naringenin, has been shown to defend against PD in animal models. In the striatum and substantia nigra pars compacta (SNpc) of rats, naringin decreased rotenone-induced dopaminergic toxicity. Subcellularly, naringin reduced the rotenone-induced reduction in mitochondrial function, stability, and bioenergetics in the animals’ SNpc, via a Nrf2-mediated path [41][52].
Isoliquiritigenin is a chalcone flavonoid gained from Glycyrrhizae uralensis. Isoliquiritigenin pretreatment fully inhibited the production of ROS as well as the dissipation of MMP and the presence of cytochrome c in the cytoplasm [42][53]. Inducers of the Nrf2/ARE pathway, such as isoliquiritigenin from licorice, showed the potential preservation of mitochondrial function in oxidative stress and neurodegenerative disease models, and also provided a unique strategy to prevent and treat aging-related neurodegenerative disorders, especially PD [43][23].
Phenolic acids, a subset of phenols, including ellagic acid and ferulic acid, affected mitochondria and thereby protected them from ROS-related pathways [44][32]. 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 [45][54]. In the MPTP animal model of PD, caffeic acid’s phenethyl ester reduced dopaminergic neurodegeneration and dopamine loss. Furthermore, it reduced MPP+-induced neurotoxicity in vitro and effectively prevented MPP+-induced mitochondrial cytochrome c and apoptosis. As a result, caffeic acid could be helpful in delaying or stopping the progression of PD [46][55].
The major antioxidants contained in virgin olive oil are phenolic products, and in terms of quantity, the class of secoiridoids is the most abundant in olive oil [6]. Oleuropein and ligstroside are two major secoiridoids found in olive oil and can product against hydroxytyrosol and tyrosol. Oleuropein decreased the rate of superoxide anion in mitochondria [47][56]. In dissolved cells of the brain from mice, hydroxytyrosol prevented mitochondrial membrane potential depolarization and reduced the functions of mitochondrial complexes I, II, and IV. Tyrosol showed a defensive function against MPP+ in dopaminergic neurons [6]. In line with that, green and black tea polyphenols have incredibly strong antioxidant-radical scavenging effects on membrane fragments of mitochondria in the brain [18]. Tea polyphenols could preserve dopamine neurons by dramatically suppressing DA-related damage, inhibiting DA oxidation, conjugating with DA quinones, scavenging ROS, and modulating the anti-oxidative signaling pathways Nrf2-Keap1 and PGC-1α [48][57]. In line with the modulation of Nrf2, pinocembrin, a flavonoid in propolis, provided mitochondrial and cellular safety by suppressing ERK1/2 and attenuation of Nrf2 [49][58].
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 [25][31][50][36,42,59] and preventing mitochondrial membrane damage in PD [18][19][23][18,19,34]. Targeting the exact mechanism, vanillin, a phenolic aldehyde, reduced rotenone-induced ROS production and mitochondrial malfunction in SH-SY5Y cells [45][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 [35][51][46,60]. Another phenolic compound, epigallocatechin gallate (EGCG), a type of catechin obtained from green tea, inhibited the mitochondrial malfunction via the stimulation of the AMP-activated protein kinase (AMPK) pathway [52][61].
Hesperidin, a flavonoid glycoside often observed in citrus fruits, showed a protective effect on mitochondria by modulating mitochondrial complex I, IV, and V in an in vivo experiment on mice [53][62]. The chemical structures of flavonoids/phenolic compounds are provided in Figure 2.
Figure 2. The chemical structure of flavonoids/phenolic compounds.
Therefore, several studies asserted that flavonoids and phenolic compounds might be useful in the prevention/treatment of PD by targeting mitochondria and related apoptotic/oxidative mediators, including MMP, ROS, Nrf2/ARE, NO, JNK, p38MAPK, Bcl-2/Bax ratio, PI3K/Akt, nuclear factor Kappa-B (NF-κB), PGC-1α and the activity of complexes I, II, and IV.
2.2. Alkaloids and Mitochondria in PD
Alkaloids are primary phytochemicals with nitrogen atoms, usually as part of a cyclic system or in combination. This class of phytochemicals affect social life, economic status, and health aspects of human life in various diseases, especially PD [54][55][63,64]. Nicotine is a naturally occurring alkaloid found in Nicotiana tabacum roots and leaves. It is also predominantly present in smaller quantities of various kinds of the Solanaceae family, such as potatoes, tomatoes, eggplants, and peppers chiles. Nicotine inhibits ETC from NADH to complex I, blocks the action of the NADH-ubiquinone reductase, resulting in a measurable reduction in oxygen intake by mitochondria. By suppressing complex I, nicotine resulted in less electron depletion and, as a result, less ROS generation [56][65]. In another study, nicotine interfered with the mitochondrial apoptotic pathway and shielded neurons against apoptosis caused by oxidative stress [44][32]. As provided by Xie et al., nicotine has been linked to a lower chance of acquiring PD. Nicotine suppressed MPP+ and calcium-induced mitochondrial high-amplitude swelling, and also cytochrome c release from intact mitochondria in SH-SY5Y cells. Their results indicate that nicotine showed a receptor-independent neuroprotective impact during PD by attenuating MPP+, calcium-induced mitochondrial, and cytochrome c [57][66]. Another report demonstrated that nicotine mediated mitochondrial dynamics and impacted mitochondrial affiliation from microtubules, greatly increased IP3 receptor clustering and modulated mitochondria-endoplasmic reticulum communication, as well as increasing mitochondrial biogenesis in cultured hippocampal neurons [58][67]. Nicotine has also shown mitochondrial impacts at small doses in vivo and in vitro, maintaining mitochondrial function in the rat CNS [59][68]. According to these findings, nicotine inhibited H2O2-induced astrocyte apoptosis, through the mitochondrial route by stimulating α7 nicotinic acetylcholine receptors (α7-nAChRs), and astrocytes which have been linked to immunological responses are associated with PD. In addition, considering the ability of α7-nAChRs expressed in astrocytes, it might be a potential therapeutic approach for neurodegenerative diseases [60][69].
Caffeine (1,3,7-trimethylxanthin) is a naturally occurring alkaloid found in coffee, tea, and cocoa plants [61][70]. Caffeine can block ROS production and enhances the activity of mitochondria. It also increases mitochondrial formation by stimulating Nrf2-keap1 and PGC-1α implicated in mitochondrial biogenesis, as well as having interconnected antioxidant and anti-inflammatory mechanisms. Additionally, caffeine reinstates transcription genes engaged in various activities such as cell death, cell cycle control, oxidative stress, and the expression of mitochondrial function-related genes [61][70].
Berberine is an isoquinoline alkaloid found in various medicinal plants, particularly those belonging to the Berberis genus [62][71]. In animal models of PD, berberine has been shown to have neuroprotective properties. To this end, researchers investigated the sub-cellular localization and blood-brain barrier (BBB) permeability of berberine in a cellular model of PD and a zebrafish PD model using a fluorescently labeled berberine derivative [63][64][72,73]. In their study, berberine’s derivative exhibited its anti-PD action by easily passing through the BBB. It also quickly and precisely accumulated in the mitochondria of PC12 cells, according to a subcellular localization analysis. Furthermore, it protected against 6-OHDA-induced cell death, alleviates MPTP-induced PD-like behavior, and increases dopaminergic neuron loss in the brain of PD-affected zebrafish [63][72].
Embelin is a natural plant product discovered in the fruits of Lysimachia punctata (Primulaceae) and Embelia ribes Burm (Myrsinaceae) [65][74]. The findings demonstrate that embelin preserved N27 dopaminergic cells from MPP+-induced oxidative stress and apoptosis. Embelin-treated cells had higher levels of pAMPK, SIRT1, and PGC1α, indicating improved mitochondrial biogenesis. Additionally, embelin provided in vivo protection against MPTP-induced decreases in striatal dopamine and the mitochondrial biogenesis pathway [66][75].
Isorhynchophylline is a significant tetracyclic oxindole alkaloid identified from the Chinese herbal remedy Uncaria rhynchophylla, used for generations in East Asia to alleviate neurological disorders [67][76]. Research found that isorhynchophylline substantially decreased MPP+-induced apoptotic cell death in PC12 cells and massively diminished MPP+-induced endoplasmic reticulum stress responses, both of which are implicated in dopaminergic neuronal death in PD [68][77]. In another study, a unique alkaloid leonurine, gained from Herba Leonuri (a traditional Chinese medicine) was shown to have a protective effect on mitochondria in PD and blocked oxidative stress [69][78].
The aforementioned studies implicated the possible application of alkaloids in targeting mitochondria toward preventing and treating PD. Accordingly, alkaloids modulate several signaling/mediators, including ROS, Nrf2-keap1, PGC-1α, pAMPK, α7-nAChRs, and SIRT1.
2.3. Terpenes and Mitochondria in PD
Terpenes are a class of plant secondary metabolites possessing neuroprotective effects by regulating mitochondrial-associated pathways. Terpene/terpenoids are made of isoprene units or modified structures. Based on the isoprene unit numbers in their molecule structure, terpene/terpenoids are classified into monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes [70][79].
Carotenoids are abundant in the photosynthetic pigments of plants, and their molecular composition is tetraterpenes (an 8-isoprene polymer). Lycopene, a natural carotenoid, improved mitochondrial structural membrane ability and ATP ratios while inhibited Bax, and the affiliated decline in Bcl-2 levels provided protection against inflammation and oxidative stress in neuronal cells [44][32]. In another study, lycopene treatment reduced mitochondrial depolarization and cytochrome c release in neurons, suggesting that mitochondrial membrane integrity was preserved [71][80]. In addition, lycopene reduced MPP+-induced mitochondrial ROS generation as well as mitochondrial morphological alterations. In their study, lycopene suppressed MPP+-induced opening of the mitochondrial permeability transition (MPT) pore. Lycopene’s preventative benefits towards MPP+-induced cytotoxicity could be due to its involvement in enhancing mitochondrial activity. These findings imply that lycopene might be a useful therapy approach for PD [72][81].
Kaur et al. also reported that lycopene inhibited the release of cytochrome c from mitochondria. The findings support the therapeutic potential of lycopene supplements in rotenone-induced PD, which showed beneficial effects in neurodegenerative diseases by modulating oxidative stress [73][82].
Astaxanthin, a keto-structure carotenoid in the microalgae Haematococcus pluvialis, prevented mitochondrial malfunction and modulated the production of ROS in an in vivo and in vitro experiment [74][83]. The docosahexaenoic acid-acylated astaxanthin ester substantially inhibited the progression of PD in an MPTP-induced mice model. It showed a potential role in regulating dopaminergic neuron death in the brain through the mitochondria-mediated route, as well as the JNK and p38MAPK pathways [75][84].
In SH-SY5Y cells, a pentacyclic triterpenoid called asiatic acid defends against cellular damage and mitochondrial malfunction caused by H2O2 or rotenone. The rotenone-induced increase in voltage-dependent anion channel and mitochondrial membrane potential dispersion was blocked by asiatic acid. Additionally, for the stability of the mitochondria membrane, asiatic acid decreased Bax production and increased Bcl-xL level [76][85]. In a rotenone-induced cellular model, asiatic acid rescued mitochondria against oxidative damage and apoptosis. Asiatic acid also increased MMP in an isolated mitochondria model, preserving membrane integrity and ATP generation. The findings show that mitochondria are essential in PD, and asiatic acid is a promising option for PD prevention and treatment [77][86].
Andrographolide, a diterpenoid lactone, showed a protective effect on mitochondria by blocking ROS production and modulating the mitochondrial malfunction by balancing the level of ATP in both in vivo and in vitro models. Andrographolide also enhanced the deletion of depolarized mitochondria via a parkin-dependent pathway [78][87]. In MPTP-exposed mice, andrographolide treatment alleviated behavioral impairments and decreased dopaminergic neuron loss, as well as rotenone-induced cell death in vitro. During PD, andrographolide prevented excessive mitochondrial fission and neuronal damage [79][88].
Carnosic acid, a diterpene in rosemary, stimulated the mitochondria fusion protein, mitofusin 1 and 2 (MFN1 and MFN2), and optic atrophy 1 (OPA1). It also blocked the fission protein dynamin-related protein 1 (DRP1). Additionally, parkin activated the IKK/NF-κB pathway and increased OPA1 protein production by carnosic acid [80][89]. In this line, carnosic acid reduced the negative impact of the paraquat model of PD on mitochondrial activity, while reducing ROS/reactive nitrogen species (RNS) generation. Consequently, carnosic acid stimulated Nrf2 in SH-SY5Y cells by modulating the PI3K/Akt pathway, resulting in higher antioxidant enzymes [81][90]. The MMP was disturbed, the voltage-dependent anion channel 1 (VDAC1) protein was blocked, and cytosolic cytochrome c was increased in SH-SY5Y cells after treatment with 6-OHDA; however, carnosic acid prevented such effects. By stimulating PINK1/parkin-mediated mitophagy, carnosic acid seems to mitigate the neurotoxicity of 6-OHDA [82][91]. As a result, carnosic acid might be considered a neuroprotective drug for treating PD through mitochondria-associated pathways.
Boswellic acids, a group of pentacyclic triterpenes, from the genus Boswellia, have been shown to reduce rotenone-induced mitochondrial malfunction by inhibiting the interleukin (IL)-6/signal transducer and activator of transcription-3 (STAT3)/NF-κB signaling pathways [83][92]. Tormentic acid is a triterpene found in medicinal plants, including Rosa rugosa and Potentilla chinensis that significantly suppressed ROS’s intracellular aggregation and Bax/Bcl-2 ratio induced by MPP+ in SH-SY5Y cells. This effect was primarily exerted through the stimulation of the PI3K/Akt/GSK-3β signaling pathway. Their results show that tormentic acid could be a possible contender for more preclinical research regarding the prevention and treatment of PD [84][93].
Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa Libosch, reduced mitochondrial malfunction via decreasing ATP production and enhancing the MPP+ level. It also reduced the calcium input of the neuronal cells, ROS buildup, and MPT pores [85][86][94,95].
Among the other terpenoids, ginsenosides-Rg1, a triterpenoid with a leading role in the efficacy of ginseng, may have a preventive effect on oxidative stress against mitochondrial malfunction in an in vivo experiment [87][88][96,97]. Ginseng, the root of Panax species (Araliaceae), is a traditional Chinese herbal medicine and a common and highly utilized natural medicine in contemporary times. Ginsenosides are the main pharmacologically active components in ginseng, and they are associated with the majority of ginseng’s actions [89][98]. Ginsenosides-Rg1 (G-Rg1) have been shown to possess therapeutic benefits with lower in vitro and in vivo toxicity. It also helps with various neurological disorders, particularly progressive neurodegenerative diseases such as PD [90][99]. Such effects of ginsenosides-Rg1 include enhancing the anti-inflammatory, antioxidation, and antiapoptotic roles. It has also shown the potential to suppress excitotoxicity and Ca2+ over-influx into neurons, maintain cellular ATP concentrations, and protect neuronal structural integrity. Excess hydrogen peroxide and other ROS produced by highly reactive iron concentrations can result in mitochondrial malfunction and enhanced dopamine metabolism. Ginsenosides-Rg1(G-Rg1) reduced the number of iron-staining cells in the SN of MPTP-treated mice [87][96]. It was also discovered that ginsenoside Rb1 (at 10 M) considerably improved cell survival compared to controls by recovering MMP and lessening Ca2+ over-influx into the mitochondria, resulting in an increase in the energy produced by mitochondria in primary cultured dopaminergic mouse neurons. In addition, ginsenoside Re was found to repair and offset particular mitochondrial complex IV deficiencies in PINK1-null dopaminergic cell lines by increasing the expression levels of chaperones LRPPRC, Hsp90, and Hsp60 through the restoration of optimum NO signaling. Notoginsenoside R2 (NGR2), a notoginsenoside isolated from P. notoginseng, reduced mitochondrial death in SH-SY5Y cells via the MEK1/2–ERK1/2 pathways and suppressing 6-OHDA-induced oxidative stress. Water extract of P. ginseng root also inhibited cell death in MPP+-treated SH-SY5Y cells by reducing ROS excessive synthesis and inhibiting the mitochondria-dependent apoptotic pathway, as indicated by a reduced Bax/Bcl-2 ratio, cytochrome c release, and caspase-3 activity [91][100]. The chemical structures of alkaloids/terpenoids are provided in Figure 3.
Figure 3. The chemical structure of alkaloids/terpenoids.
Altogether, terpene/terpenoids displayed auspicious anti-PD effects by targeting mitochondria, thereby suppressing complex I–III activity, PINK1/parkin, ROS, Bax, JNK/p38MAPK, IKK/NF-κB, VDAC1, PI3K/Akt/GSK-3β, and IL-6/STAT3/NF-κB.
Table 1 shows the modulatory effects of plant secondary metabolites on mitochondria and interconnected mediators toward PD prevention/treatment.
Table 1. Modulating mitochondria by plant secondary metabolites in PD.
| Compound(s) | Class | In Vivo/In Vitro Models | Mechanisms and Outcomes | Reference |
|---|---|---|---|---|
| Pinocembrin | Flavonoid | In vitro: SH-SY5Y cells | Blocking ERK1/2 or silencing of Nrf2 | [49][58] |
| Naringin | In vivo: adult male Wistar albino rats | ↓Rotenone-induced dopaminergic toxicity, ↓mitochondrial function, stability, and bioenergetics in the animals’ SNpc via a Nrf2-mediated path | [45][54] | |
| Naringenin | In vivo/ In vitro: brains’s neurons of Sprague Dawley rats | ↑MMP, ↓ROS via affecting the Nrf2/ARE pathway | [39][50] | |
| In vitro: SH-SY5Y cells | ↓Mitochondria-related bioenergetics and redox dysfunctions via the Nrf2/GSH pathways | [42][53] | ||
| Hesperidin | In vivo: Mice | Attenuation of mitochondrial complex I, IV, V activity | [53][62] | |
| Isoliquiritigenin | In vitro: dopaminergic neuronal SN4741 cells | ↓Production of ROS as well as the dissipation of MMP and the presence of cytochrome c in the cytoplasm | [42][53] | |
| In vitro: dopaminergic neuronal SN4741 cells | ↓ROS, ↓NO, ↓JNK and p38 MAPK, ↑Bcl-2/Bax ratio, ↑MMP, ↑BDNF, ↓ cytochrome c, ↓caspase 3 and modulating PI3K/Akt |
[92][101] | ||
| Luteolin | In vitro: SH-SY5Y cells | Preventive effect on ROS production and keep the activity of mitochondria in a normal way | [35][51][46,60] | |
| Baicalein | Flavone |
In vivo/ in vitro: mice/ rat/ SH-SY5Y cells | ↓Mitochondrial malfunction in 6-OHDA-induced | [25][36] |
| In vitro: PC12 cells | Modulating ROS production, ↓rotenone-induced apoptotic in PC12 cells via ameliorating the mitochondrial dysfunction | [27][38] | ||
| Apigenin | In vivo: Rat | ↑Performance of mitochondrial enzyme | [93][102] | |
| Chrysoeriol | In vitro: SH-SY5Y cells | ↓Toxicity of MPP+—induced via PI3K/Akt | [94][22] | |
| Puerarin | Isoflavone | In vitro: PC12 neuronal cells | ↓Toxicity of MPP+—induced | [25][36] |
| In vitro: PC12 cells and primary rat midbrain neurons | Regulation of NO-mediated mitochondrial dysfunction | [28][39] | ||
| In vitro: SH-SY5Y cells | ↓Caspase-3 in MPP+-induced through modulating the activity of the ubiquitin proteasome system | [29][40] | ||
| Genistein | In vivo: ovariectomized rats | ↓Activity of ROS-induced NF-κB/ recovered the production of Bcl-2 mRNA | [18] | |
| Hyperoside | Flavonol glycoside |
In vitro: PC12 neuronal cells | ↓Mitochondrial apoptotic pathway | [93][102] |
| In vitro: PC12 neuronal cells | ↓Mitochondrial apoptotic signaling | [37][48] | ||
| Schisandrin | Lignan | In vivo: Rat cortical cells | ↓Ca2+, ↓ROS, ↓cytochrome C | [22][25] |
| Ellagic acid | Phenolic acid |
In vitro: Rat cortical neurons | Modulating ROS production, ↑Bcl-2/Bax | [44][32] |
| Ferulic acid | In vivo: Mice | Modulating ROS production by blocking p38MAPK,caspase-3, and COX-2, ↓Bax/Bcl2 | [44][32] | |
| Protocatechuic aldehyde | 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 | [45][54] | |
| In vivo: male C57BL/6 mice | ↓Dopaminergic neurodegeneration and dopamine loss | [46][55] | ||
| Curcumin | Polyphenol | In vivo/ In vitro: mice / PC12 neuronal cell line | ↓MPP+ toxicity and ROS production | [25][31][50][36,42,59] |
| Tea polyphenols | In vitro: Human HEK293T and SH-SY5Y cells | Preserving DA neurons via inhibiting DA oxidation, conjugating with DA quinones (DAQ), scavenging ROS, and modulating Nrf2-Keap1 and PGC-1α | [48][57] | |
| Oleuropein | Secoiridoid | In vitro: PC12 neuronal cell line cells | ↓Superoxide anion, ↓complexes I, II, and IV activity, defensive function against MPP+ | [6] |
| Hydroxytyrosol | Phenolic compound | In vitro: dopaminergic SH-SY5Y cells | ↓Complexes I, II, and IV activity, defensive function against MPP+ | [6] |
| Quercetin | Flavonoid | In vivo/ In vitro: aged rats/ mice | ↓Apoptosis by downregulation of PI3K/Akt pathway, ↓mitochondrial fission | [31][42] |
| In vitro: SH-SY5Y cells | ↓Mitochondrial damage, ↑tyrosine hydroxylase, and mitochondrial controlling proteins | [32][43] | ||
| In vitro: PC12 cells | ↑Mitochondrial quality control, ↓ oxidative stress, ↑mitophagy markers | [33][44] | ||
| In vivo: adult Sprague-Dawley rats | Repair mitochondrial electron transport abnormalities | [34][45] | ||
| Silibinin | Flavonolig-nan | In vivo: mice | Modulating MMP and mitochondrial activity | [36][47] |
| In vivo: | ↓Mitochondrial damage, and strengthening of the oxidative defense system | [37][48] | ||
| In vivo: Male C57B/6 mice | ↓Motor impairment and dopaminergic neuronal degeneration, ↑stability of MMP | [38][49] | ||
| Resveratrol | Stilbene | 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 | [30][41] | ||
| Vanillin | Phenolic aldehyde |
In vitro: SH-SY5Y | ↓ROS production | [45][54] |
| α-Mangostin | Phenolic xanthone |
In vitro: SH-SY5Y | Recovered mitochondrial membrane potential and cellular ATP | [93][102] |
| Nicotine | Alkaloid | In vivo/ In vitro: rats | ↓complex I activity, ↓ROS, Attenuating mitochondrial apoptosis pathway | [44][56][32,65] |
| In vitro: SH-SY5Y cells | ↓MPP+ and Ca2+-induced mitochondrial high amplitude swelling, ↓cytochrome c release from intact mitochondria | [57][66] | ||
| In vitro: cultured hippocampal neurons | Mediating mitochondrial dynamics, ↑ IP3 receptor clustering, modulating mitochondria-endoplasmic reticulum communications | [58][67] | ||
| In vivo/ In vitro: rats | Maintain mitochondrial function | [59][68] | ||
| In vivo/in vitro: C57BL/6 mouse | ↓H2O2-induced astrocyte apoptosis through the mitochondrial route and α7-nAChRs | [60][69] | ||
| Caffeine | In vivo/ In vitro: mice/ dopaminergic neurons | ↓ROS production, ↑mitochondrial formation by stimulating Nrf2-keap1 and PGC-1α pathway | [61][70] | |
| Leonurine | In vivo: mice | Modulating mitochondrial activity | [69][78] | |
| Berberine | In vitro: SH-SY5Y cells/ mice | ↓6-OHDA-induced cell death, ↓MPTP-induced PD-like behavior, ↓dopaminergic neuron loss | [63][72] | |
| Embelin | In vitro: Rat dopaminergic cell line, N27 | ↑pAMPK, ↑SIRT1, ↑PGC-1α, ↑mitochondrial biogenesis | [66][75] | |
| Isorhynchophylline | In vitro: PC12 cells | ↓MPP+-induced apoptotic cell death, ↓endoplasmic reticulum stress responses | [68][77] | |
| Lycopene | Carotenoid | In vivo: small mammals | Improving mitochondrial structural membrane ability, ↓Bax | [44][71][32,80] |
| In vitro: SH-SY5Y cells | ↓MPP+-induced mitochondrial ROS generation, ↓MPP+-induced opening of the mitochondrial permeability transition pore | [72][81] | ||
| In vivo: Adult male Wistar rats | ↓cytochrome c from mitochondria | [73][82] | ||
| Crocin | In vivo: an idiopathic Drosophila | ↓complex I_III activity | [95][103] | |
| Astaxanthin | In vivo/ In vitro: Rat/ SH-SY5Y | ↓Production of ROS | [74][83] | |
| Docosahexaenoic acid-acylated astaxanthin ester | Regulating dopaminergic neuron death in the brain through the mitochondria-mediated route and JNK and p38 MAPK pathways. | [75][84] | ||
| Asiatic acid | Pentacyclic triterpenoid | In vitro: SH-SY5Y cells/ mice | ↑Bcl-xL, ↓Bax, ↓H2O2 and rotenone adverse effects | [76][85] |
| In vitro: SH-SY5Y cells | ↓ROS, ↓cytochrome c, ↑MMP, preserving membrane integrity and ATP generation | [77][86] | ||
| Catalpol | Iridoid glucoside |
In vivo: mouse | ↓Mitochondria malfunction via decreasing ATP | [85][86][94,95] |
| Ginsenosides-Rg1 | Triterpenoid | In vivo: mice | ↓Oxidative stress | [87][88][96,97] |
| Bacosides and Bacopasides |
Triterpenoid saponin | in vivo/ in vitro: Drosophila /SH-SY5Y cells | ↓Mitochondrial malfunction and oxidative stress, Modulating complex I activity | [96][97][104,105] |
| Andrografolide | Diterpenoid lactone | In vivo/ In vitro: mice brain, N9 mouse microglia (RRID CVCL_0452) cell line | ↓ROS, balancing the level of ATP, ↑deletion of depolarized mitochondria via parkin dependent pathway | [78][87] |
| Alleviating behavioral impairments, ↓dopaminergic neuron loss and preventing excessive mitochondrial fission | [79][88] | |||
| Carnosic acid | Diterpene | In vitro: Human SH-SY5Y cells | ↑Fusion protein in mitochondria, ↓fission protein activity, ↑OPA1 protein production by parkin in IKK/NF-κB pathway | [80][89] |
| In vitro: SH-SY5Y cells | ↓ROS, ↓RNS, ↑Nrf2 via modulating the PI3K/Akt pathway, ↑GSH | [81][90] | ||
| In vitro: SH-SY5Y cells | ↑VDAC1, ↓cytosolic cytochrome c, ↑ PINK1/parkin-mediated mitophagy | [82][91] | ||
| Tormentic acid | Triterpene | In vitro: SH-SY5Y cells | ↓ROS, ↓Bax/Bcl-2 ratio through stimulation of the PI3K/Akt/GSK-3β signaling pathway | [84][93] |
| Boswellic acids | Pentacyclic triterpene | In vivo: Rats | ↓Rotenone-induced mitochondrial malfunction by inhibiting the IL-6/STAT3/NF-κB signaling pathways | [83][92] |
| Ginsenosides-Rg | Ginsenoside | In vivo: SN of MPTP-treated mice | Reducing iron-staining cells | [87][96] |
| Ginsenoside Rb1 | In vivo: mice primary cultured dopaminergic neuron | Recovering MMP and lessening Ca2+ over-influx into the mitochondria | [91][100] | |
| Ginsenoside Re | In vitro: PINK1-null dopaminergic cell line | Repair and offset particular mitochondrial complex IV deficiencies | ||
| Notoginsenoside R2 | In vitro: SH-SY5Y cells | ↓Mitochondrial death via the MEK1/2–ERK1/2 pathways | ||
| P-ginseng | In vitro: SH-SY5Y cells | ↓ROS excessive synthesis and inhibiting the mitochondria-dependent apoptotic pathway |
ARE: antioxidant responsive element, ATP: adenisine triphosphate, Bcl-2: B-cell lymphoma-2, Bcl-xl: B-cell lymphoma-extra-large, Bax: BCL2-Associated X Protein, BDNF: brain-derived neurotrophic factor, DAQ: DA quinones, ERK1/2: extracellular signal-regulated kinas1/2, GSH: glutathione, IKK: IκB kinase, NF-κB: nuclear factor-kappa B, IL-6: interleukin-6, IP3 receptor: inositol 1,4,5-trisphosphate receptor, Keap1: Kelch-like ECH-associated protein 1, MMP: mitochondrial membrane potential, NO: nitric oxide, Nrf2: nuclear factor erythroid 2-related factor 2, pAMPK: phospho-AMP-activated protein kinase, PC12 cells: pheochromocytoma cell, PGC-1α: peroxisome proliferator-activated receptor γ coactivator 1α, PI3K: phosphatidylinositol 3-kinase, Akt: protein kinase B, PLK2: polo-like kinase 2, p-GSK-3β: phosphorylated glycogen synthase kinase-3β, p38MAPK: p38 mitogen-activated protein kinases, RNS: reactive nitrogen species, ROS: reactive oxygen species, SIRT1: sirtuin 1, SNpc: substantia nigra pars compacta, STAT3: signal transducer and activator of transcription 3, 6-OHDA: 6-hydroxydopamine, α7-nAChR: nicotinic acetylcholine receptors.