Parkinson’s disease (PD) is a common chronic neurodegenerative disease, which results in motor symptoms such as bradykinesia, stiffness, resting tremor, and postural instability (Kalia and Lang, 2015). Most PD symptoms are caused by the degeneration and loss of dopaminergic neurons that produce dopamine in the substantia nigra (SN) of the midbrain (Dickson et al., 2009). Reduced dopamine level results in abnormal brain transmission activity, leading to impaired movement and various motor symptoms. PD also leads to non-motor symptoms such as dizziness, cognitive changes, psychiatric and sleep problems. PD affects individuals all over the globe and is the second most prevalent neurological illness after Alzheimer’s disease. According to the statistics of PD patients worldwide from 1990 to 2015, the prevalence, disability-adjusted life-years, and deaths increased substantially, making PD the fastest-growing neurological disease (Feigin et al., 2017).

The incidence of PD increases with age, particularly in elderly individuals over 50 years of age (Bloem et al., 2021). With the increase of the aging population, the prevalence of PD will continue to grow and is expected to exceed 12 million by 2040 (Dorsey and Bloem, 2018). Meta-analysis suggests that there are significant differences in PD prevalence by geographical location. The prevalence rates in North America, Europe, and Australia are 2.4 times higher than that of Asia. In addition, the prevalence in women is three-tenths of that in men (Pringsheim et al., 2014). Environmental risk factors for PD are also identified through epidemiology. Environmental chemicals such as the pesticide paraquat are found to be a risk factor in the development of PD (Clarimon, 2020). PD is a neurological ailment that worsens with age; thus, aging is considered the major driver of PD development (Antony et al., 2013). However, since PD’s etiology and pathogenic mechanisms are still poorly understood, it is challenging to develop drugs to prevent the death of dopaminergic neurons. Currently, PD drugs including levodopa preparations, dopamine receptor agonists, and monoamine oxidase inhibitors mainly work through enhancing dopamine levels, but they exhibit a large number of side effects and addiction issues (Bastide et al., 2015). Conversely, they may generate excessive dopamine action, causing the abnormal activation of the motor system and thereby generating dyskinesias. The standard oral levodopamine (l-dopa) treatment is the most effective way to relieve PD patients’ motor symptoms. However, as the disease progresses and l-dopa continues to be taken, the movement disorder caused by the drug l-dopa, known as l-dopa-induced dyskinesia (LID), are often seen in patients who are on the treatment for over 10 years (Bastide et al., 2015). Notably, these PD drugs cannot prevent or slow down the death of dopaminergic neurons. Therefore, it is particularly urgent to find drugs that have fewer side effects, can improve the PD symptoms, and prevent the death of dopaminergic neurons.

Up to now, many medicinal herbs or natural products have been developed as PD drug candidates. Some have entered in clinical trials (Figure 1) (Prasad and Hung, 2021). For example, Ganoderma (NCT03594656) has entered phase III of a trial. And the SQJZ herbal mixture (NCT02616120), a formula consisting of Cornus officinalis, Rehmannia glutinosa, Poria cocos, Ophiopogon japonicus, Cuscuta chinensis, Trichosanthes kirilowii, Semen ziziphin spinosae, Aurantii fructus immaturus, and Schisandra chinensis (Shi et al., 2017), has entered phase II. Additionally, Hypoestoxide (NCT04858074), a natural diterpenoid found in Hypoestes rosea dry leaf powder, is in phase I. These imply that medicinal herbs may have potential in the treatment of PD without serious side effects.

Gastrodia elata blume (Tianma) is a medicinal herb first found in the Classic of the Materia Medica, also known as the Shennong Ben Cao Jing (Zhan et al., 2016; Zhu et al., 2019; Heese, 2020). According to the Global Biodiversity Information Facility database (https://www.gbif.org/), Tianma has 20 synonyms and belongs to the genus Gastrodia R. Br. Family Orchidaceae. It is mainly distributed in the mountainous regions of eastern Asia, especially in Korea, Japan, China, and India (Figure 2) (Gbif Global Biodiversity Information Facility, 2022). In ancient China, this was the preferred remedy to benefit and strengthen the qi, nourish the yin, and strengthen the body and prolong life (Zhan et al., 2016). Nowadays, it is used clinically for the treatment of dizziness, spasms, epilepsy, headache, amnesia, and hypertension (Matias et al., 2016; Zhan et al., 2016). Several clinical studies showed that the famous formula Tianma Gouteng decoction could be used as an add-on therapy for PD patients (Chen et al., 2014; Yan et al., 2014; Liu, 2015; Zhao and Hu, 2017; Zuo, 2018; Wang et al., 2019; Li et al., 2020). Furthermore, a growing number of studies have shown that Tianma and its constituents show neuroprotective effects in various PD in vitro and in vivo models. The main bioactive components of Tianma such as gastrodin, vanillyl alcohol, vanillin, vanillic acid, and anisalcohol have neuroprotective activities, which have attracted strong interest in the treatment of PD. Although the neuroprotective effects of the extracts and some compounds of Tianma have been summarized in previous reviews, new evidence from recent studies support the multiple activities of Tianma in specific PD features. Thus, in this review, we update and briefly summarize studies regarding the effects of the bioactive components of Tianma on the main features of PD and explore their potential for the treatment of PD.

MPTP is a Parkinsonism-inducing neurotoxin. It is a highly lipophilic molecule that can cross the blood-brain barrier (BBB) and specifically destroy dopaminergic neurons, thus MPTP is commonly used for establishment of various animal PD models (Ke et al., 2021). In vitro PD models based on dopaminergic neuronal death are commonly used for identifying PD drug candidates. 1-Methyl-4-phenylpyridinium ion (MPP⁺) is a metabolite of MPTP catalyzed by monoamine oxidase-B (MAO-B) in the brain. It can be specifically taken up by dopaminergic neurons and neuron-like cells, which causes injury to the mitochondria and thereby leads to apoptosis. SHSY-5Y and the MN9D cell lines are commonly used in the MPP⁺ cell model since they have the ability to synthesize and release dopamine (Xie et al., 2010). They also express tyrosine hydroxylase and dopamine transporter protein (DAT) (Xie et al., 2010). In addition, these cell lines are treated with 6-OHDA and H₂O₂ to induce oxidative stress, which is a causative factor for dopaminergic neuronal death in PD (Gay et al., 2018). The changes in apoptosis-related markers such as Bcl-2, Bax, and caspases three are major indicators for evaluating the effects of drug candidates on cell death (Abushouk et al., 2017).

LPS-induced microglial activation is a classical model for identifying drug candidates to evaluate anti-neuroinflammation properties (Catorce and Gevorkian, 2016). BV-2 is a microglial cell line derived from C57/BL6 mice. After LPS treatment, it enters the M1 polarised state, which is the main cause of neuroinflammation in PD. The changes in proinflammatory factors such as nitric oxide (NO), TNF-α,IL-1β, and COX-2 are common indicators for evaluating the effects of drug candidates on neuroinflammation.

According to the ancient record of Chinese medicine, Tianma Gouteng decoction is a well-known formula containing Tianma, Uncaria Ramulus Cum Uncis, Haliotidis Concha, Gardeniae Fructus, Scutellariae Radix, Cyathulae Radix, Leonur Iherba, Eucommiae Cortex, Taxilli Herba, Caulis Polygoni Multiflori, and Zhu Fushen, originally used in the treatment of various disorders such as hypertension, migraine (Chang et al., 2014; Chong et al., 2021), and dementia (Lin et al., 2015). In preclinical studies, this formula inhibited lipid peroxidation by attenuating the lipid peroxidation-related protein ALOX15, thereby improving behavioral deficits and reducing the loss of dopaminergic neurons in MPTP-induced mice, 6-OHDA-induced rat, and α-Syn A53T overexpressed mice (Jiang Y.N et al., 2020). In clinical studies, Tianma Gouteng decoction was found to be a potential candidate for the treatment of PD. Its therapeutic effects are based on usage in combination with clinical drugs such as selegiline, levodopa, medopar, or pramipexole (Chen et al., 2014; Yan et al., 2014; Liu, 2015; Zhao and Hu, 2017; Zuo, 2018; Wang et al., 2019; Li et al., 2020). Compared to single treatment with these drugs, the combined treatment with Tianma Gouteng decoction leads to significantly lower scores in Parts I, II, III, and IV of the Unified PD Rating Scale (UPDRS). The treatment of Tianma Gouteng Decoction combined with selegiline decreased the serum levels of TNF-α, IL-6, malondialdehyde (MDA), and Cys-C when compared to the control group (Zuo, 2018). In the treatment of Tianma Gouteng decoction combined with Levodopa, it was found that the levels of IL-2, IL-6, TNF-α, MDA, and Cys-C in the treatment group decreased significantly and the SOD level increased significantly after 3 months (Gu et al., 2018). In the treatment of Tianma Gouteng decoction combined with Madopar, the levels of Glu and GABA in the treatment group were significantly increased compared to the control group (Liu et al., 2020). Serum homocysteine (Hcy) decreased, serum uric acid (UA) and adiponectin (APN) levels increased in Tianma Gouteng decoction combined with pramipexole treatment (Liu, 2020; Gui, 2021). These clinical evidences support that Tianma Gouteng decoction can be used as an add-on therapy for improving PD motor symptoms and blood biochemical parameters in PD.

Tianma is a major medicinal herb in Tianma Gouteng decoction, hinting that it may have some potential therapeutic effects for PD. Evidence suggests that Tianma display strong antioxidant properties and neuroprotection in vitro and in vivo PD models. In MPP⁺-treated SH-SY5Y cells, the ethanol extract of Tianma conferred protective effects against MPP⁺-induced cell death (An et al., 2010). Researchers also demonstrated that the water extract of Tianma is an effective treatment for alleviating the motor symptoms of parkinsonian and loss of dopaminergic neurons in the fly model with LRRK2-G2019S mutation, which is the most common familial PD mutation (Lin et al., 2021). They found that the extract of Tianma activated the Akt-Nrf2 pathway in glia but not in neurons, contributing to its neuroprotective effects. Simultaneously, the extract of Tianma also worked as a neuroprotectant to improve locomotor performance, reduce dopaminergic neuron loss, and microglial activation in mice with LRRK2-G2019S mutation (Lin et al., 2021). Tianma extract could reduce lipopolysaccharides (LPS)-stimulated neuroinflammation BV-2 microglia model by down-regulating JNK/nuclear factor-κB (NF-κB) pathway (Kim et al., 2012), supporting the anti-neuroinflammation activity of Tianma. In 6-OHDA mice, l-dopa’s adverse effect LID was alleviated by Tianma extract via normalizing FosB and ERK activation (Doo et al., 2014). On the other hand, GABA levels in the SN pars reticulata can be increased by high-frequency stimulation of the subthalamic nucleus which is a therapy for patients with severe PD (Windels et al., 2005). Tianma extract could improve cognitive impairment and recover normal GABA levels in aluminum-treated rats (Shuchang et al., 2008). Tianma also provides anxiolytic-like effects via regulating the GABAergic nervous system (Ha et al., 2000). Taken together, due to the multiple activities of Tianma, we believe the bioactive components from Tianma may have the potential to alleviate various PD characteristics and symptoms.

To present, at least 81 compounds have been isolated from Tianma, with five major groups including phenols and their glycosides, polysaccharides, sterols, organic acids, and other compounds (Zhu et al., 2019). The contents of these compounds are comprised of total phenolics (0.0485%), total polysaccharides (21.6%), total flavonoids (0.235%), total amino acids (1.92%), β sitosterol (0.113%), and other undetermined compounds (77.8%) (Zhan et al., 2016). Amongst them, the bioactive components of Tianma include gastrodin, vanillyl alcohol, vanillin, vanillic acid, and anisalcohol, which exhibit neuroprotective activities in various PD models. Gastrodin is considered as the major reference standard and the main bioactive component of Tianma. The maximum content of gastrodin reaches 0.24%, while other active components such as vanillin, vanillyl alcohol, vanillic acid, and anisalcohol belong to phenolic compounds that in total reach 0.0485% detected by the Folin-Ciocaileu colorimetric method (Zhan et al., 2016). The EtOEt extract of Tianma was subjected to the phenolic separation of compounds and showed to comprise Vanillyl Alcohol (0.00195%), Vanillin (0.00282%), and Vanillic acid (0.00195%) (Jang et al., 2010). Another report found that Tianma extracted with ethyl acetate to obtain the ethyl acetate fraction of Tianma after the crude extract of ethanol gives rise to anisyl alcohol (0.009445%) (Duan et al., 2013).

Dopaminergic neuron death, α-Syn aggregation, and neuroinflammation are major characteristics of PD and can be used as key indicators for evaluating the efficacy of promising PD drugs. In this review, we assessed the effects of five constituents of Tianma on these major features of PD (Table 1). Although all these components are phenolic compounds with similar structures, their bioactivities are different in PD models. Gastrodin and vanillyl alcohol are reported to have protective effects against MPP⁺-induced cytotoxicity by upregulating Bcl-2 protein and thereby inhibiting the apoptotic pathway in PD cell models (Kumar et al., 2013; Jiang et al., 2014; Gay et al., 2018). Comparing their working concentrations (Table 2), gastrodin (1,5 and 25 μM) works at lower concentrations than vanillyl alcohol (10 and 20 μM). In the H₂O₂ cell model, vanillic acid treatment maintains the levels of SOD2, catalase, and Bcl-2 protein expression (Kim et al., 2011), suggesting that vanillic acid works through mediating oxidative stress-induced cell death. However, evidence to support the protective effect of vanillic acid against MPP⁺-induced cytotoxicity is still lacking. In PD animal models, only gastrodin and vanillin exert neuroprotective effects, probably due to their ability to cross BBB. According to mechanistic studies, gastrodin can enhance Nrf2-mediated intracellular antioxidant system, which is critical in maintaining mitochondrial functions under oxidative damage (Jiang T et al., 2020). Therefore, current evidences do support that gastrodin is able to reduce PD neurotoxin-induced mitochondrial dysfunction and oxidative stress as well as enhance the survival of neurons in different PD models. In contrast, there is no report regarding the action mechanism of vanillin and further study is needed to identify what contributes to the neuoprotective effects of vanillin.

Gastrodin, vanillin, and anisalcohol are reported to reduce microglial activation and pro-inflammatory cytokine generation (Table 3). In the LPS/BV-2 cells, the working concentrations of anisalcohol (0.1, 1, 10 μM) were found to be much lower than those of vanillin (100, 200, 300, 400 μM) and gastrodin (20, 30, 40, 60 μM). Vanillin and gastrodin mediate anti-inflammatory activity via inhibiting LPS-induced phosphorylation of MAPK and NF-κB. Anisalcohol also inhibits p65 phosphorylation of NF-κB and JNK phosphorylation, while anisalcohol can significantly inhibit the M1 microglia marker CD16/32 and promote M2 microglia CD206 expression. These evidences support that anisalcohol has anti-inflammatory effects at the cellular level. However, there is no report regarding anti-neuroinflammation of anisalcohol in animal models. Notably, anisalcohol can promote microglia to become M2 type microglia. It is possible that gastrodin and vanillin also have similar effects on the changes of microglia polarisations. Both gastrodin and vanillin display in vivo anti-neuroinflammation activity, but the working concentration of gastrodin (200 mg/kg) is far higher than vanillin (20 mg/kg). The possible reason is that in vivo rapid metabolism of gastrodin into 4-hydroxybenzyl alcohol (4-HBA) may reduce its application in vivo because 4-HBA exhibits limited biological activity (Liu et al., 2018). Therefore, maintaining the in vivo stability of gastrodin may be a critical issue to solve for future applications.

Gastrodin is the only candidate that may clear the accumulation of α-Syn. Strikingly, gastrodin is reported to exhibit anti-aging activity in Drosophila (He et al., 2021). Since aging is the major driver of PD development, it would be interesting examine whether this activity can be observed in other species. Compared with other compounds, gastrodin not only decreases three major PD features but also slows aging, providing vital support for its potential for PD.

These studies still have limitations because none of the current experimental models can mimic all clinical features of PD (Ke et al., 2021). The classical neurotoxin (MPTP, 6-OHDA, and rotenone)-induced PD animal models can rapidly generate the loss of dopaminergic neurons and neuroinflammation without disease progression. These in vivo models help define the benefits of drug candidates to reduce PD symptoms. Cell models are treated with neurotoxins to induce oxidative stress, mitochondria dysfunction, and cell death. LPS-induced BV-2 microglia activation is commonly used for investigating neuroinflammation. Undoubtedly, these in vitro models can mimic some PD features for drug screening and mechanistic study. However, a poor understanding of PD etiology and pathogenesis still limits us from identifying the suitability of drug candidates. In addition, these models fail to reflect the impact of aging. Thus, it may be necessary to evaluate the effects of drug candidates via using more diverse models such as transgenic animal models and neurons derived from induced pluripotent stem cells of human PD patients; alternatively, establishing more precise models to mimic PD development may help assess the effects of potential drug candidates.

There are many similarities between Tianma and Ganoderma. Both have complicated components, but have been used for centuries in Chinese medicine, which may support their safety as therapeutics. In vitro and in vivo studies, they can improve motor symptoms and various major PD features (Zhang et al., 2011; Ren et al., 2019). In toxicology experiments, it was found that a 28-day oral intake of Tianma water extract (8,065 mg/kg body weight) did not have adverse effects on mortality, body weight, organ weight, behavior, hematology, and clinical biochemistry (Lu et al., 2020). Notably, gastrodin was found in a clinical study (NCT00297245) to prevent cognitive decline after cardiac surgery with cardiopulmonary bypass. Results indicated that gastrodin is an effective and safe drug for preventing the neurocognitive decline in patients (Zhang et al., 2011). These studies support that Tianma and its active compounds are safe and have the potential to relieve neurological symptoms.

So far, the exact pathogenic mechanisms of PD are not well understood, thereby resulting a lack of effective drugs for preventing PD development. The bioactive components of Tianma have various positive effects on dopaminergic neuron death, α-synuclein aggregation, and neuroinflammation, further supporting the therapeutic potential of Tianma for PD. Of these, gastrodin shows greatest potential as it reduces the characteristics of PD and displays anti-aging activity in preclinical studies. Further studies on Tianma and its major compounds are warranted to fully understand the toxicological profiles, pharmacokinetics, and the underlying molecular mechanisms of these naturally occurring compounds and their potential for the prevention and treatment of PD.