Natural Products as Novel Medications for Parkinson’s Disease: History
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Contributor:
Yu-Jin So
,
Jae-Ung Lee
,
Ga-Seung Yang
,
Gabsik Yang
,
Sung-Wook Kim
,
Jun-Ho Lee
,
Jong-Uk Kim

As the global population ages, the prevalence of Parkinson’s disease (PD) is steadily on the rise. PD demonstrates chronic and progressive characteristics, and many cases can transition into dementia. This increases societal and economic burdens, emphasizing the need to find effective treatments. Among the widely recognized causes of PD is the abnormal accumulation of proteins, and autophagy dysfunction accelerates this accumulation. The resultant Lewy bodies are also commonly found in Alzheimer’s disease patients, suggesting an increased potential for the onset of dementia. Additionally, the production of free radicals due to mitochondrial dysfunction contributes to neuronal damage and degeneration. The activation of astrocytes and the M1 phenotype of microglia promote damage to dopamine neurons. The drugs currently used for PD only delay the clinical progression and exacerbation of the disease without targeting its root cause, and come with various side effects. Thus, there is a demand for treatments with fewer side effects, with much potential offered by natural products. 

  • Parkinson’s disease
  • natural products
  • alpha synuclein
  • neuroinflammation
  • oxidative stress
  • mitochondrial dysfunction
  • neurodegeneration

1. Introduction

Parkinson’s Disease (PD) is the second most common neurodegenerative disease worldwide [1]. The incidence rate of PD in women shows an increasing trend from 2.94 per 100,000 persons in the age group 40–49 years to a peak of 104.99 per 100,000 between 70–79 years, which then declines to 66.02 per 100,000 in those aged 80 and above. For men, it rises from 3.59 per 100,000 in the 40–49 years age group to a peak of 132.72 per 100,000 between ages 70 and 79, and then drops to 110.48 per 100,000 in those 80 and older. Both genders display an increased incidence rate with age [2]. The prevalence of PD in Asia is lower compared to the West. According to the age-standardized 2000 WHO population, the prevalence of PD in Asian studies was found to be 51.3–176.9/100,000 from field surveys and 35.8–68.3/100,000 from record-based surveys, whereas Western studies reported higher prevalence rates of 101–439.4/100,000 from field surveys and 61.4–141.1/100,000 from record-based surveys [3]. The number of workdays lost due to PD increased from 27.6 days three years before diagnosis to 61.5 days three years after diagnosis, and indirect costs increased from $3549 to $7892. Caregivers also took more time off work after the diagnosis, resulting in an indirect cost rising from $302 to $850 [4]. With increasing longevity, the prevalence of PD is expected to double within the next 20 years. Without more effective treatments, the social and economic burdens associated with PD are anticipated to grow [5].

2. Evidence of Natural Products from Pre-Clinical Studies

Currently, drugs designed to treat PD only aim at alleviating the symptoms. However, there are no drugs that target the root cause of the disease. The most common treatment approach involves replenishing the dopamine levels in the brain. Yet, there are no therapies available that can repair the damaged brain cells. Especially in the realm of Western medicine, drugs are synthetic. The usual approach is to design a drug to act on one specific target pathway to minimize adverse side effects. However, there are some challenges where patients develop tolerance upon continued usage and increasing the dosage that leads to additional side effects. Given these challenges, there is a growing need for the development of new drugs. The research explored alternative natural products to surpass the constraints of the current medicinal approach. Herbal medicines, made from plant-derived natural substances, have a diverse composition (Table 1). This means it is possible to address multiple pathways using a single drug, which may be a potential treatment avenue for PD.

2.1. Duzhong Fang

Duzhong Fang is a traditional Chinese medicine formula that consists of four ingredients: dried Eucommia ulmoides, Dendrobium, Rehmanniae Radix, and dried ginger. These ingredients are mixed in a specific weight ratio of 200:2:3:3 [6]. Duzhong Fang can regulate microglial morphology and reactivity, reducing microglial reactivity and inflammation in the central nervous system. Additionally, Duzhong Fang can directly inhibit the POMC gene, which is an upstream target for regulating inflammation and proinflammatory cytokines. By inhibiting POMC levels, Duzhong Fang can restore the homeostatic signature of microglia in Parkinsonian rats, leading to the alleviation of neuroinflammation and improvement of motor function. Duzhong Fang demonstrated anti-inflammatory effects in a mice model of PD, playing a role in managing neuroinflammation in PD by modulating microglial reactivity [7].

2.2. Kyung-Ok-Ko (KOK)

KOK’s original formula comprises juice from the root of Rehmannia glutinosa Liboschitz var. purpurae Makino (9.6 g), powder of dried fruit of Poria cocos Wolf (1.8 g), powder from the root of Panax ginseng C.A. Meyer (0.9 g), and honey (6 g). As a traditional composite herbal remedy, KOK has been employed to treat a wide range of diseases and conditions due to its action on multiple targets [8]. The MAPK (extracellular signal-regulated kinase ½ (ERK), c-Jun NH2-terminal kinase (JNK), and p38) and NF-κB signaling pathways, associated with neuronal loss, neuroinflammation, and BBB disruption in PD, can be potentially inhibited by KOK treatment according to the anti-inflammatory properties of KOK, similar to its role as a protective agent against MPTP-induced neurotoxicity [9].

2.3. Da-Bu-Yin-Wan (DBYW)

DBYW is composed of Amur corktree bark (Phellodendron chinense Cortex; Huang-Bai) 12 g, common Anemarrhena rhizome (Anemarrhenae Rhizoma; Zhi-Mu) 12 g, prepared rehmannia root (Radix Rehmanniae Praeparata; Shu-Di-Huang) 18 g, and tortoise shell (Carapax et Plastrum Testudinis; Gui-Jia) 18 g, as described in a prior study [10]. This study has shown that DBYW can elevate the expression of tyrosine hydroxylase (TH), enhance levels of monoamine neurotransmitters, and minimize mitochondrial DNA damage. The study demonstrates that DJ-1 overexpression increases Akt phosphorylation, leading to improved mitochondrial function and cell survival in a cellular model of Parkinson’s disease. Furthermore, DBYW was found to augment this process by enhancing the effects of DJ-1 on mitochondrial function through Akt phosphorylation. Additionally, DBYW enhances mitochondrial protection in PD by elevating cellular ATP content and decreasing the expression of ATP-sensitive potassium channel subunits [11].

2.4. Bee Venom Phospholipase A2 (BvPLa2)

BvPLa2 is an enzyme present in bee venom. This enzyme breaks down membrane phospholipids, producing free fatty acids and lysophospholipids. BvPla2 is known for its varied pharmacological effects, including anti-HIV activity, myotoxicity, and the promotion of neurite growth [12][13]. As a significant component of bee venom, BvPla2 stimulates regulatory T cells, mitigating neuroinflammatory reactions. This leads to the improvement of movement disorders and a reduction in α-Syn levels [14].

2.5. Hesperetin

Hesperetin is a flavonoid found in citrus fruits. It has shown protective effects against 6-hydroxydopamine (6-OHDA) lesions in rat striatum. Hesperetin treatment in 6-OHDA lesioned rats resulted in a reduction in apomorphine-induced rotational asymmetry, indicating an improvement in motor function. Additionally, hesperetin decreased the latency to initiate and the total time on the narrow beam task, suggesting an enhancement in motor coordination and balance. These effects indicate that hesperetin has the potential to improve motor function and coordination in rats with 6-hydroxydopamine-induced damage, possibly through its protective effects on the dopaminergic system and related motor pathways. It was found to provide protective effects in early models of PD by reducing behavioral disorders, alleviating oxidative stress, and reducing astrogliosis. Furthermore, hesperetin can be considered a potential adjunct therapy for PD management by preventing cell death and loss of dopaminergic neurons in the substantia nigra [15].

2.6. Paeonol

Paeonol is a major phenol compound from the Chinese herb Cortex Moutan, known for its antioxidant, anti-inflammatory, and anticancer properties [16]. This study showed that paeonol treatment significantly restored the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) in the midbrain, thereby alleviating oxidative stress induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p). Additionally, Paeonol treatment decreased the levels of microglia and interleukin-1β (IL-1β), indicating a reduction in neuroinflammation, and increased the levels of brain-derived neurotrophic factor (BDNF), indicating neurotrophic effects on dopaminergic neurons. It has shown therapeutic effects against MPTP-induced PD in mice by improving behavioral tests, enhancing TH expression, reducing oxidative stress, and inhibiting microglial activation. Paeonol’s capability to promote neuronal survival and delay PD progression suggests its possibility as a treatment for PD [17].

2.7. Gastrodin

The Chinese herb Rhizoma Gastrodiae contains Gastrodin, a phenol glycoside known for its neuroprotective, antidepressant, and antiepileptic properties [18]. Gastrodin protects dopaminergic neurons, reduces the accumulation of α-Syn protein, and inhibits amyloid-β production and aggregation. In this study, Gastrodin rescued the climbing ability of Pink1 mutant flies, indicating an improvement in their motor function. Moreover, Gastrodin delayed the progressive loss of a cluster of dopaminergic neurons in the protocerebral posterial lateral 1 region of Pink1 mutant flies, and increased the dopamine content in the brain of Pink1 mutant flies. In other words, Gastrodin demonstrated potential anti-aging effects by extending lifespan, enhancing antioxidant capacity, and delaying PD-like phenotypes [19].

2.8. Trehalose

Trehalose is a natural disaccharide found in invertebrates, fungi, and many plants. It has value in various potential applications; has anti-inflammatory, antioxidant stress, and anti-cell death effects; and is a non-toxic compound [20][21]. In an AAV α-synuclein rat model of PD, animals that received unilateral AAV1/2 A53T α-synuclein showed a deficit in the use of their paw contralateral to the site of vector injection 3 weeks post-surgery, compared with empty vector controls. Neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration, including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system, by commencing 5 and 2% trehalose at the same time as delivery of AAV. Trehalose protects against α-synuclein-mediated DA degeneration by enhancing autophagy in the striatum, which leads to the reduction of α-synuclein aggregates, improved DA neuronal survival, and prevention of behavioral asymmetry. Trehalose stimulates autophagy in an mTOR-independent manner, which helps in the clearance of α-synuclein aggregates [22].

2.9. Bu-Shen-Jie-Du-Fang (BSJDF)

BSJDF is a composite traditional Chinese medicine made up of Rehmannia glutinosa, Cistanche deserticola, Paeonia lactiflora Pall, Radix Angelica sinensis, Puerariae Radix, Rhizoma Coptidis, Radix Scutellariae, Antelope Horn Powder, and Glycyrrhizae Radix in a weight ratio of 5:5:4:4:5:4:4:1:2 [23][24]. BSJDF was found to protect PC12 cells by inducing autophagy in an MPP+-induced cell model of Parkinson’s Disease. The BSJDF group had the greatest surviving cell counts compared with all other treated cell groups except the normal group. Autophagy was observed in the BSJDF group by transmission electron microscopy (TEM), and protein expression of Atg12 and LC3 in the BSJDF group was upregulated compared to the PD model group. BSJDF was found to improve cell survival in an MPP+-induced cell model of Parkinson’s Disease by inducing autophagy, as evidenced by increased protein expression of Atg12 and LC3, and upregulated Atg12 mRNA expression. The study suggests that autophagy plays an important role in cell fate and maintaining cellular metabolic balance in Parkinson’s disease. These findings highlight the potential role of BSJDF in modulating autophagy and its implications for the development of treatments for Parkinson’s disease [25].

2.10. Nerolidol (NRD)

NRD is a sesquiterpene alcohol found in the essential oils of Baccharis dracunculifolia, Amaranthus retroflexus, and Canarium schweinfurthii. It exhibits various biological properties, including antioxidant and anti-inflammatory effects. NRD’s ability to easily cross the BBB enhances its potential as a treatment for neurodegenerative diseases like PD [26]. This study does not explicitly address whether NRD can be used as a standalone treatment for PD or if it needs to be combined with other medications. However, it is important to note that the neuroprotective effects of NRD against neuroinflammation and oxidative stress were demonstrated in an experimental model of PD induced by rotenone. NRD exerts its neuroprotective effects by reducing oxidative stress and neuroinflammation. It has been reported to increase the activities of antioxidant enzymes such as SOD and CAT, and to decrease the level of the antioxidant tripeptide GSH. Additionally, NRD inhibits the release of proinflammatory cytokines and inflammatory mediators, and prevents the activation of glial cells, ultimately attenuating neurodegeneration induced by rotenone. Furthermore, NRD has been shown to reduce the level of lipid peroxidation and nitrite content in the hippocampus, protecting against oxidative stress. NRD supplementation demonstrates promising neuroprotective effects by attenuating dopaminergic neurodegeneration, enhancing antioxidant enzyme activity, and inhibiting brain inflammatory mediators and lipid peroxidation [27].

2.11. Vanillic Acid (VA)

Vanillic acid, 4-hydroxy-3-methoxybenzoic acid, is the oxidized form of vanillin, and can be isolated from Gastrodia [28]. Co-treatment with VA and Levodopa–Carbidopa in a rotenone-induced Parkinson’s disease rat model showed significant effects on various Parkinson’s symptoms [29]. The co-treatment led to a significant reduction in muscle rigidity and catalepsy, along with a significant increase in body weight, rearing behavior, locomotion, and muscle activity in a dose-dependent manner, with the maximum effect observed at the 50 mg/kg dose of VA. Additionally, the co-treatment resulted in a significant increase in the level of dopamine in the VA plus standard drug-treated animals compared to the rotenone-treated group. Furthermore, histopathological evaluation showed a reduction in the number of eosinophilic lesions in the VA co-treated group compared to the rotenone group, indicating protection against neuronal damage due to oxidative stress and attenuation of motor defects. Furthermore, the study indicates a reduction in various oxidative stress markers in the brain, including increased lipid peroxidation and decreased GSH and catalase [28].

2.12. Vanillin

Vanillin, 4-hydroxy-3-methoxybenzaldehyde, an aromatic organic phenol molecule that can be extracted from Gastrodia, is widely used as a fragrance in the food, beverage, cosmetics, and pharmaceutical industries. This study demonstrated that Vanillin administration significantly increased striatal tissue dopamine content in 6-OHDA lesioned animals, which is a key indicator of nigrostriatal neurodegeneration. Additionally, Vanillin administration showed that attenuated 6-OHDA-induced rotations during apomorphine challenge, indicating its potential efficacy in reducing the phenotypic behavior associated with 6-OHDA lesion [30].
Table 1. Effect of natural products for PD.
Origin of Extraction Mechanism Cell or Animal Model Inducer Mode of Action and Target Signal Site of Action (Figure 1) Ref.
Duzhong Fang Inflammation C57bl/6 mice MPTP ↓ locomotor dysfunction, inflammation, Iba1, microglia reactivity state
↑ striatal dopamine content, dopaminergic neurons, TH		 3 [7]
KOK Inflammation C57BL/6 mice MPTP ML385 ↓ neurological dysfunction and motor impairments, the loss of dopaminergic neurons and fibers, Iba1, the upregulation of inflammatory mediators (IL-6, TNF-α, COX-2, and iNOS), neurotoxicity (microglial activation and inflammatory response ↓), BBB disruption markers (PECAM-1 and GFAP), neurotoxicity and inflammation (phosphorylated forms of ERK, JNK, and p38 & IκB and NF-κB ↓), ROS, MAPKs and NF-κB signaling pathways
↑ Nrf2 signaling (decreases the expression levels of Keap1 (a repressor protein that binds to Nrf2), and increases the expression levels of Nrf2 transcription factor, Nrf2 targeting genes HO-1 and NQO-1)		 3 [9]
DBYW Mitochondrial dysfunction Rat PC-12 cells pDJ-1
transfection
MPP+		 ↓ DJ-1, mitochondrial dysfunction
↑ mitochondrial mass, total ATP content, the Akt phosphorylation		 2 [11]
BvPLA2 Inflammation Human A53T α-Syn Transgenic mice A53T Transgenes ↓ motor dysfunction, α-Syn, the activation and numbers of microglia, and the ratio of M1/M2 3 [14]
Hesperetin Inflammation Wistar rats 6-OHDA ↓ astrogliosis (GFAP ↓), apoptosis (nigral DNA fragmentation ↓), the loss of SNC dopaminergic neurons
↑ striatal catalase activity and GSH content, Bcl2		 3 [15]
Paeonol Inflammation C57BL/6 mice MPTP ↓ motor dysfunction, oxidative stress (the activity levels of SOD, CAT, and GSH ↑), neuroinflammation(the number of Iba1-positive and IL-1β-positive cells ↓),
↑ TH-positive neurons, BDNF, dopaminergic neurons protection		 3 [17]
Gastrodin Mitochondrial dysfunction Drosophila melanogaster PINK1 gene mutant ↓ the loss of dopaminergic neurons, the onset of Parkinson-like phenotypes
↑ lifespan, climbing ability, resistance to oxidative stress, enzyme activities of superoxide dismutase (SOD) and catalase (CAT), the expression of anti-oxidative genes		 2 [19]
Trehalose Lysosomal Disorders Human A53T α-Syn Transgenic mice A53T Transgenes ↓ α-Synuclein-Induced
Behavioral Impairment, α-Synuclein Accumulation
↑ DA Neuronal Survival, protection against the reduction of TH protein expression, autophagosome formation, LC3-II levels		 1 [22]
BSJDF Lysosomal Disorders Pheochromocytoma12 (PC12) MPP+
(MPTP)		 improved cell survival in the PC12 cell PD model
activated the autophagic process in PC12 cells.
increased expression of Atg12 and LC3 proteins and upregulated Atg12 mRNA.		 1 [25]
NRD inflammation Wistar
rats		 Rotenone ↑ level of superoxide dismutase, catalase, and glutathione
↓ level of malondialdehyde
inhibited the release of proinflammatory cytokines and inflammatory mediators
prevented ROT-induced glial cell activation and the loss of dopaminergic neurons and nerve fibers
attenuated rotenone-induced dopaminergic neurodegeneration.		 3 [27]
Vanillic acid Mitochondrial dysfunction Sprague Dawley rats Rotenone ↓ Weight gain, Catalepsy, Rearing
TBARS level (at 25 mg/kg and 50 mg/kg)
SAG(superoxide anion generation)
↑ behaviour, CAT		 2 [28]
Vanillin Inflammation Male Wistar rats 6-OHDA ↓ apomorphine-induced rotations, free radical release, expression of pro-inflammatory cytokines, lipid peroxidation
↑ striatal dopamine content, glutathione and superoxide dismutase enzyme
protection of dopaminergic neurons		 3 [30]

3. Evidence of Natural Products from Clinical Trials

Recently, clinical trials utilizing various natural substances for the improvement of PD symptoms have been conducted. These studies collectively suggest that natural products can potentially reduce neurotoxicity caused by oxidative stress and improve various symptoms associated with Parkinson’s disease.
Natural substances applied in the clinical trials include Licorice root, Origanum majorana L., and Pingchan. The trial results suggested that these natural substances are effective in reducing neurotoxicity caused by oxidative stress and improving motor symptoms. We, hereby, hypothesize that natural substances can be utilized in PD treatment [31].
According to Persian traditional literature [32], Licorice root was used for neurological conditions like headaches as a neuroprotective agent. In Persian folk medicine, formulations including Licorice extracts were used as neuroprotective herbal treatments for preventing disabilities associated with strokes or PD. In modern medicine, Licorice has shown various biological activities, such as anti-inflammatory, antioxidant [33], anti-tumor [34], antidepressant [35], memory-enhancing [36], neuroprotective [37], and anti-apoptotic effects. In a clinical trial involving 39 PD patients, patients were randomly divided into two groups and given either Licorice or a placebo syrup twice daily for six months. The results showed that adding Licorice extract as an adjunctive therapy can improve the overall Unified Parkinson’s Disease Rating Scale score of PD patients, improving daily activities, tremor and motor ability tests, and rigidity scores [31].
Origanum majorana L, known as sweet marjoram or simply marjoram, is an evergreen plant that belongs to the Lauraceae family. It is believed to have originated in the Mediterranean, North Africa, Egypt, and Asia and is widely used for culinary or medicinal purposes. In a clinical trial with 51 PD patients, patients who consumed Origanum majorana tea showed significant improvement in non-motor symptoms such as depression, anxiety, gastrointestinal and urinary symptoms, restlessness, and fatigue compared to the placebo group. Furthermore, consuming Origanum majorana tea daily for a month did not have adverse effects on liver and kidney functions. Notably, Origanum majorana L is rich in antioxidants like polyphenols and monoterpenes. Hence, this plant can neutralize reactive oxygen species and delay neurodegeneration [38].
Pingchan granule, a traditional Chinese herbal formulation, is composed of nine widely recognized herbs. These include Lycium barbarum L., Taxillus chinensis (DC.) Danser, Gastrodia elata Blume, Paeonia lactiflora Pall., Arisaema erubescens (Wall.) Schott, and Curcuma phaeocaulis Valeton. Additionally, it incorporates Bombyx mori Linnaeus, Buthus martensii Karsch, and Scolopendra subspinipes mutilans L. Koch. Each of these herbs has been carefully selected for their unique medicinal properties and synergistic effects in this composite herbal remedy. A randomized double-blind placebo-controlled trial was conducted on a cohort of 292 mild-to-moderate PD patients across multiple centers. This trial demonstrated the superiority of Pingchan granule over the placebo in managing both motor and non-motor symptoms of PD over a treatment period of 24 weeks. This effect persisted during the 12-week follow-up period. The Pingchan granule group showed better improvements in motor outcomes at timepoints 1, 2, and 3 compared to the placebo group, and demonstrated efficacy across a range of both motor and non-motor symptoms, suggesting the long-term beneficial effects of Pingchan granule on both motor and non-motor symptoms [39] of PD. The results of these trials can provide as strong evidence that the development of natural product-based medicines would be expected to have a very positive effect on PD treatment. However, further research with larger sample sizes and longer study durations is necessary to fully understand their long-term effects and potential in PD treatment.

This entry is adapted from the peer-reviewed paper 10.3390/ijms25021071

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