6-OHDA shares structural similarities with DA and norepinephrine, rendering it selectively toxic to catecholaminergic neurons. Due to its inability to cross the BBB, 6-OHDA typically requires direct, targeted injection into the brain to induce neurotoxicity. Once inside the brain, 6-OHDA is taken up by DA/norepinephrine membrane transporters (DMT/NMT), leading to intracellular accumulation and the generation of hydrogen peroxide and ROS. This, in turn, exacerbates oxidative stress, inhibits mitochondrial complex activity, and induces mitochondrial dysfunction, ultimately culminating in neuronal degeneration within specific brain regions. Targeted injection of 6-OHDA into the SN pars compacta, striatum, or medial forebrain bundle disrupts the dopaminergic nigrostriatal system, producing classic Parkinsonian motor deficits in mice. This process effectively recapitulates the progression of pathological and clinical manifestations observed in PD, establishing 6-OHDA as a widely used neurotoxin for inducing PD animal models (Simola et al., 2007).

MPTP, due to its high lipophilicity, readily crosses the BBB to reach the CNS. Within astrocytes, MPTP is metabolized to 1-methyl-4-phenylpyridinium (MPP⁺), which then enters dopaminergic neurons via the DA transporter. Inside neurons, MPP⁺ binds to neuromelanin and is transported and stored in synaptic vesicles via the vesicular monoamine transporter type 2 (VMAT-2). Prolonged exposure to MPP⁺ activates microglia, triggering the release of proinflammatory factors that contribute to neurotoxic responses. Furthermore, MPP⁺ inhibits the activity of mitochondrial complex I and suppresses the expression of anti-apoptotic proteins, ultimately impairing ATP synthesis within the electron transport chain and disrupting mitochondrial function. This disruption leads to excessive ROS production, which further promotes the generation and aggregation of α-Syn into toxic oligomers. The cumulative effects of these mechanisms damage dopaminergic neurons in the nigrostriatal pathway, effectively simulating the pathophysiological processes of PD (Mustapha and Taib, 2021).

Curcumin (Figure 4.1), a natural polyphenolic compound found in turmeric, possesses a distinctive chemical structure of 1,6-heptadiene-3,5-dione-1,7-bis(4-hydroxy-3-methoxyphenyl)-(1E, 6E) (Goel et al., 2008). It exhibits high solubility in organic solvents but poor solubility in aqueous solutions. Additionally, curcumin remains stable in acidic environments but readily decomposes under neutral and alkaline conditions (Wang et al., 1997). Curcumin has long been recognized for its diverse biological activities, including antioxidant (Menon and Sudheer, 2007), anti-inflammatory (Menon and Sudheer, 2007), anticancer (Cheng et al., 2001), antimicrobial (Shao et al., 2024), antithrombotic (Keihanian et al., 2018), blood sugar-lowering (Nabavi et al., 2015), and cardioprotective effects (Zhang et al., 2020).

Curcumin’s remarkable ability to penetrate the BBB has led to its widespread investigation as a potential therapeutic agent for neurodegenerative diseases, including PD. Sharma et al. demonstrated in a PD animal model that curcumin treatment significantly inhibited astrocyte activation, downregulated NF-κB transcription factor expression, and suppressed the production of inflammatory factors, ultimately modulating α-Syn aggregation. Moreover, curcumin supplementation was found to inhibit the α-Syn formation and aggregation by suppressing α-Syn gene expression (Sharma and Nehru, 2018).

Several studies suggest that curcumin exerts its inhibitory effects by directly interacting with α-Syn during its phase separation. For instance, Xu et al. reported that while curcumin does not interfere with the initial formation and conformation of α-Syn condensates, it significantly inhibits their transformation into amyloid-like proteins by reducing α-Syn mobility within these condensates (Xu et al., 2022). Similarly, Ahmad et al. discovered that curcumin possesses a unique remodeling capacity. Specifically, its interaction with α-Syn monomers disrupts long-range interactions within the protein chain, leading to an increased refolding rate, prevention of α-Syn aggregation, and temperature-dependent reaction kinetics (Ahmad and Lapidus, 2012).

The dose-dependent inhibitory effect of curcumin on α-Syn aggregation was further corroborated by Pandey et al., who observed that curcumin, particularly at concentrations of 10⁻⁶–10⁻⁷ M, significantly increased the soluble fractions of α-Syn monomers, dimers, and oligomers. This increase in solubility reduces the stability of these aggregates, rendering them more susceptible to degradation (Pandey et al., 2008). These findings align with those of Ono et al., who also emphasized the importance of curcumin dosing in inhibiting α-Syn aggregation and fibril growth (Ono and Yamada, 2006). Furthermore, curcumin has been shown to bind to preformed α-Syn fibrils and aggregates, altering their hydrophobic surface structure and reducing α-Syn toxicity. Intriguingly, curcumin appears to selectively bind to the ordered structure of the protein, with the degree of binding correlating with the extent of α-Syn oligomerization (Singh D. et al., 2012).

Research on curcumin as an adjunct therapy for cancer has been extensive, consistently demonstrating its favorable safety profile. Curcumin is generally well-tolerated, even at single oral doses as high as 12 g/d. However, its clinical application and development have been hampered by its poor solubility, inherent instability, and suboptimal pharmacokinetic profile. Specifically, inadequate intestinal absorption, rapid metabolism, and rapid systematic elimination result in low plasma and tissue concentrations, limiting its therapeutic efficacy. Interestingly, co-administration with piperine, a natural alkaloid found in black pepper, has been shown to increase curcumin bioavailability by an impressive 2,000%, highlighting the potential of piperine as a bioenhancer for curcumin (Sharma et al., 2007; Anand et al., 2007).

To address the inherent limitations of curcumin, researchers have focused on synthesizing curcumin analogs with enhanced biological activity. For instance, Jha et al. synthesized a series of curcumin analogs by substituting the hydroxyl group on the phenyl ring with various functional groups. These modifications differentially reduced the hydrophobic surface exposure of α-Syn oligomers, effectively mitigating their cytotoxicity (Jha et al., 2016). Notably, 4-arylidene curcumin derivatives (Figure 4.2) exhibited superior anti-aggregation properties, effectively targeting both α-Syn fibrils and oligomers (Liu W. et al., 2023). Similarly, two other stable curcumin analogs, curcumin pyrazole (Figure 4.3) and curcumin isoxazole (Figure 4.4), have demonstrated promising anti-amyloidogenic activity, effectively preventing fibrillation, disrupting preformed fibrils, and inhibiting the formation of toxic A11 protein conformations (Ahsan et al., 2015). Furthermore, Gadad et al. synthesized curcumin-glucoside (Figures 4.5, 4.6), which also exhibited robust inhibitory effects on α-Syn aggregation and fibril formation under in vitro conditions (Gadad et al., 2012). These findings collectively suggest that curcumin and its related polyphenolic compounds hold significant promise as therapeutic candidates for PD and other related neurodegenerative disorders (Table 1).

Resveratrol (Figure 4.7), a low molecular-weight polyphenolic compound, is abundant in various plants and trees, including pine, eucalyptus, grapes, blueberries, and cranberries. It exhibits a wide range of protective activities, including antioxidant, anti-inflammatory, free radical scavenging, and neuroprotective effects, establishing its potential as a dietary supplement for neurodegenerative diseases (Bastianetto et al., 2015). Kinetic modeling experiments employing hydrogen/deuterium exchange mass spectrometry have revealed that resveratrol significantly remodels α-Syn aggregation (Illes-Toth et al., 2024).

In PD models induced by 6-OHDA, MPTP, and rotenone, resveratrol effectively ameliorates motor deficits in mice (Zhao X. et al., 2017; Jin et al., 2008; Lu et al., 2008; Liu D. et al., 2019). It reduces α-Syn expression and toxicity while enhancing cell survival, likely through the activation of sirtuin 1, which promotes α-Syn degradation via autophagy (Guo S. S. et al., 2016). Resveratrol analogs have also demonstrated comparable neuroprotective effects. For instance, the resveratrol derivative AM17 (Figure 4.8) and piceatannol (Figure 4.9) both inhibit α-Syn monomer aggregation and disassemble preformed α-Syn oligomers and fibrils, independent of copper ions (Temsamani et al., 2016; Chau et al., 2021).

Although resveratrol readily crosses the BBB (Marier et al., 2002), its rapid metabolism, low bioavailability, and inherent chemical instability limit its clinical utility, even at high concentrations (Calamini et al., 2010). While resveratrol exhibits an oral absorption rate of approximately 75%, it undergoes rapid first-pass metabolism and elimination, resulting in low systemic exposure. Furthermore, circadian rhythms may influence resveratrol bioavailability. Studies suggest that morning administration may enhance its absorption. The recommended oral dosage range for resveratrol is 100–1,000 mg. Doses exceeding 2 g/d may lead to adverse effects such as diarrhea, nausea, vomiting, or headaches (Vesely et al., 2021).

To overcome these limitations, structural modifications aimed at improving bioavailability, metabolic stability, and biological activity without compromising its protective effects are being actively pursued. Current modification strategies include hydroxylation, amination/amidation/imination, methoxylation, prenylation, and glycosylation. Notably, resveratrol derivatives and analogs, such as oxyresveratrol, piceatannol, and imine resveratrol derivatives, exhibit more favorable pharmacokinetic profiles compared to the parent compound, demonstrating faster absorption, higher bioavailability, and greater metabolic stability (Li S. Y. et al., 2014; Setoguchi et al., 2014; Jung et al., 2009). Moreover, novel drug delivery systems, such as nanoparticle-loaded resveratrol and vitamin E-loaded resveratrol nanoemulsions, have shown reduce oxidative stress, enhance intracranial drug concentrations, and diminish degenerative lesions, demonstrating promising therapeutic effects against PD (Pangeni et al., 2014) (Table 1).

The major polyphenolic compounds found in green tea are collectively known as catechins (flavan-3-ols). Catechins have demonstrated a wide array of beneficial health effects, including anti-inflammatory, antioxidant, antibacterial, anticancer, infection-preventive, cognitive-enhancing, memory-improving, and neuroprotective properties. These compounds have been implicated in the treatment of chronic diseases such as cardiovascular diseases, diabetes, obesity, and neurodegenerative disorders. Green tea catechins primarily include (-)-epicatechin (EC) (Figure 4.10), (-)-epigallocatechin (EGC) (Figure 4.11), (-)-epicatechin-3-gallate (ECG) (Figure 4.12), and (-)-epigallocatechin-3-gallate (EGCG) (Figure 4.13). The antioxidant activity of these catechins varies depending on the number of hydroxyl groups and the structure of their substituent groups. EGCG is the most abundant catechin in green tea, followed by EGC (Musial et al., 2020).

Studies have shown that green tea catechins can mitigate α-Syn pathology in PD models. For instance, in MPTP-induced PD monkeys, administration of catechin-rich tea polyphenol extracts significantly reduced α-Syn aggregation in the striatum and hippocampus, attenuating α-Syn-induced dopaminergic neurons loss and motor dysfunction (Chen et al., 2015). Using parallel mass spectrometry to analyze green tea metabolites, Williams et al. found that, in addition to EGCG, both catechin and EC not only inhibited the formation of α-Syn fibrils but also destabilized preformed α-Syn fibrils (Williams et al., 2007).

To date, EGCG (Figure 4.13) is one of the most extensively studied and bioactive catechins extracted from green tea. In preformed α-Syn fibril models, EGCG disrupts the structural integrity of α-Syn fibrils by interfering with hydrogen bonds, aromatic stacking, and cation-π interactions, thereby inhibiting α-Syn fibrillation. In cellular models, EGCG directly binds to the β-sheet structure of α-Syn aggregates, inducing conformational changes that inhibit aggregation and promote the breakdown of aggregates into smaller, less toxic, and more disordered species (Andrich and Bieschke, 2015; Bieschke et al., 2010; Dominguez-Meijide et al., 2020). The destabilizing effect of EGCG on α-Syn fibrils is closely associated with the disruption of the E46-K80 salt bridge (Yao et al., 2020). Moreover, EGCG interaction with α-Syn reduces the affinity between α-Syn and lipid membranes, thereby mitigating hydrophobic surface exposure and cytotoxicity (Zhao J. et al., 2017; Lorenzen et al., 2014; Jha et al., 2017; Andrich and Bieschke, 2015; Yang Z. et al., 2023).

Furthermore, EGCG has been shown to interfere with copper (II) (Cu(II))-induced ROS generation, protecting cells from the toxic effects of α-Syn overexpression and fibrillation (Teng et al., 2019). Additionally, EGCG may influence α-Syn expression in vivo by modulating both the expression of the SNCA gene and the methylation status of CpG sites within its promoter region (Ramakrishna et al., 2016). In MPTP-treated mice, EGCG attenuates α-Syn accumulation and reduces neuronal death, potentially through mechanisms involving increased Bcl-2 protein expression, suppressed Bax protein expression, and upregulation of the PKC pathway (Mandel et al., 2004).

Ion mobility-mass spectrometry (IM-MS) confirmed that EGCG binds to α-Syn in a non-specific manner, inducing a more compact protein structure that resists conformational changes and reduces fibrillar aggregate formation (Liu et al., 2011). Interestingly, EGCG oxidation products exhibit even stronger inhibitory effects on α-Syn aggregation than the parent compound. Paradoxically, some studies have reported that both EGCG and its oxidation products can accelerate α-Syn fibril formation. This discrepancy may be attributed to variations in experimental conditions and warrants further investigation (Sternke-Hoffmann et al., 2020) (Table 1).

Despite its potent neuroprotective properties, the therapeutic application of EGCG is hindered by its inherent instability and poor bioavailability. The rapid metabolic degradation of EGCG often necessitates high doses to achieve therapeutic efficacy. However, such high doses may lead to toxicity, presenting a significant challenge for clinical transition. To overcome these limitations, researchers are actively exploring strategies to enhance EGCG bioavailability and reduce its toxicity, including chemical modification and nanoparticle-based delivery systems (Mehmood et al., 2022).

Flavonoids, the most abundant and diverse group of polyphenolic compounds, are found ubiquitously in plants and dietary sources. They share a common structural backbone consisting of a 2-phenyl-benzo-alpha-pyran or flavan nucleus, comprising two benzene rings (A and B) linked by a C heterocyclic pyran ring. Based on variations in the pyran ring structure, flavonoids are classified into six major subclasses: flavonols, flavanones, flavanols, flavones, anthocyanins, and isoflavones. Recognized for their wide-ranging biological activities, flavonoids are often consumed as dietary supplements, offering numerous health benefits. The recommended daily dosage for flavonoids typically ranges from 500 to 1,000 mg (Billowria et al., 2024).

Shikonin (SHK) (Figure 6.1) is a bioactive naphthoquinone compound extracted from the roots of Lithospermum erythrorhizon (Andújar et al., 2013). It is well-known for its free radical scavenging, antioxidant, and anti-inflammatory properties (Chen X. et al., 2001). Srivastava et al. demonstrated that SHK dose-dependently inhibits α-Syn aggregation both in vivo and in vitro. Increasing concentrations of SHK prolonged the lag phase of α-Syn aggregation, the lag phase of α-Syn aggregation can be extended to 26.14 h in the presence of equimolar α-Syn and SHK. Mechanistically, SHK binds to the C-terminus of α-Syn, preserving its helical and disordered secondary structures while reducing β-sheet content. This interaction stabilizes α-Syn monomers, reduces the complexity of aggregated structures, and delays fibril elongation. In C. elegans model, SHK significantly reduced α-Syn aggregation, improved motor deficits, and attenuated dopaminergic neurons degeneration (Srivastava et al., 2023) (Table 3).

These neuroprotective effects highlight SHK’s potential as a therapeutic agent for synucleinopathies, including PD. However, SHK’s limited solubility and chemical stability hinder its biological activity. Pharmacokinetic studies have revealed a half-life of 630.7 ± 124.9 min, a maximum concentration of 83.6 ± 8.8 ng/mL, and a time to maximum concentration of 1.0 ± 0.0 min. Importantly, prolonged or rapid administration, particularly at high doses, can lead to hepatotoxicity and nephrotoxicity (Sun et al., 2022).

Vitamin K, a fat-soluble vitamin found abundantly in green leafy vegetables, encompasses various forms, including Vitamin K₁ (Figure 6.2), Vitamin K₂ (Figure 6.3), Vitamin K₃ (Figure 6.4), Vitamin K₄ (Figure 6.5), and other forms (Mladěnka et al., 2021). While initially recognized for its essential role in blood clotting (Mishima et al., 2023), recent studies have highlighted the potential of vitamin K, particularly 1,4-NQ (Figure 6.6), in treating neurodegenerative diseases. These therapeutic benefits likely stem from vitamin K’s antioxidant, anti-inflammatory, and anti-demyelination properties (Santos et al., 2023; Emekli-Alturfan and Alturfan, 2023; Diachenko et al., 2024; Sandeep et al., 2023). Fernanda et al. demonstrated the inhibitory effects of vitamin K and 1,4-NQ on α-Syn aggregation. Both compounds effectively decelerated α-Syn fibrillation by interacting with the N-terminal repeat domain of α-Syn monomers. Treatment with vitamin K or 1,4-NQ resulted in the formation of smaller, fragmented fibrils and amorphous aggregates, which exhibited a reduced capacity to induce vesicle leakage (Table 3).

Interestingly, a case-control study found significantly lower serum vitamin K levels in PD patients compared to healthy controls. Moreover, serum vitamin K levels were higher in early-stage PD patients than in those with later-stage disease, suggesting that vitamin K deficiency may contribute to PD pathogenesis and that vitamin K supplementation may hold therapeutic and preventive potential (Liu L. et al., 2023; Yu et al., 2020). Given that inhibiting MAO activity is a key pharmacological target in PD treatment, and based on the structural features of 1,4-NQ, vitamin K, shows promise for developing MAO inhibitors and represents a promising avenue for developing inhibitors of α-Syn fibrillation and aggregation (da Silva et al., 2013).

Natural alkaloids represent a promising source of bioactive compounds for modulating α-Syn aggregation. In a study investigating the relationship between alkaloids and α-Syn aggregation, six out of nine alkaloids tested (Figures 8.1–8.6), all derived from medicinal herbs, exhibited inhibitory effects on α-Syn seed fibril formation and seed-induced toxicity (Ghanem et al., 2021). Similarly, previous studies have shown that 2-(quinoline-8-carboxamido)benzoic acid (2-QBA) (Figure 8.8), a natural quinoline alkaloid isolated from Aspergillus sp. SCSIO06786, enhances proteasome activity, reduces the toxicity associated with α-Syn aggregates, and ameliorates motor dysfunction in a nematode model of PD (Lee et al., 2023). Moreover, Harmine (Figure 8.4), a β-carboline alkaloid found in Peganum harmala, and Lycorine (Figure 8.7), an isoquinoline alkaloid extracted from Amaryllidaceae plants, acts as natural enhancers of the UPS, can significantly enhance the phosphorylation of PKA, thereby activating the UPS to promote the degradation of pathogenic α-Syn in both in vitro and in vivo models of PD (Zhu et al., 2021; Cai et al., 2019). Furthermore, tetracyclic oxindole alkaloids, such as isorhynchophylline (Figure 8.9), corynoxine B, and corynoxine (an enantiomer of corynoxine B) (Figure 8.10), isolated from the Chinese herbal medicine Uncaria rhynchophylla, function as natural autophagy inducers. These alkaloids have been shown to mitigate α-Syn aggregation by inducing autophagy (Chen et al., 2014; Lu et al., 2012). Corynoxine B acts through the autophagy-regulating factor Beclin 1, whereas corynoxine exerts its effects through the AKT/mTOR pathway (Table 5). These findings provide compelling evidence for the potential of natural alkaloids as valuable leads for developing novel autophagy enhancers for the treatment of PD.

Epidemiological studies have consistently revealed a negative correlation between smoking and the incidence of PD (Quik, 2004). Nicotine (Figure 9.1), the primary alkaloid found in Solanaceae plants, has been shown to exert neuroprotective effects through the activation of nicotinic receptors located at dopaminergic terminals, which modulates DA release (Ma et al., 2017; Quik et al., 2012).

Studies suggest that nicotine can influence α-Syn dynamics and potentially modulate PD pathogenesis. Nicotine has been shown to stabilize soluble α-Syn oligomers, thereby inhibiting the formation of α-Syn fibrils and reducing the instability of preformed fibrils (Ono et al., 2007; Hong et al., 2009). It interacts extensively with α-Syn, engaging nearly all of its structural domains through van der Waals forces. This interaction helps maintain the helical structure of α-Syn and prevents detrimental conformational changes (Tavassoly et al., 2014; Alıcı, 2021). Moreover, nicotine can prolong the rate of aggregate nucleation, effectively delaying the conversion of α-Syn monomers into oligomers (Kardani et al., 2017). Interestingly, studies using synaptic vesicle glycoprotein 2 knockdown in Drosophila models suggest that nicotine may influence PD pathology by modulating vesicle release (Olsen et al., 2023) (Table 5). Collectively, these findings highlight the therapeutic potential of nicotine, and other agents targeting nicotinic acetylcholine receptors, as potential disease-modifying agents for PD.

Smoking represents the most rapid and efficient route for delivering nicotine to the bloodstream and brain, achieving stable concentrations within 30 min of intake. Due to the first-pass metabolism of the liver, the bioavailability of oral nicotine is about 20%–45%, while the bioavailability through inhalation is substantially higher (Hukkanen et al., 2005). While nicotine exhibits promising neuroprotective properties, its delivery via smoking is inextricably linked to the detrimental effects of tobacco smoke. The addictive and stimulant properties of nicotine, primarily attributed to its action on nicotine acetylcholine receptors, necessitate a cautious approach to its therapeutic application. This is particularly relevant for individuals with PD, especially elderly patients who may be more susceptible to nicotine addiction. Therefore, determining the effective dosage, optimal route of administration, and long-term safety of nicotine for PD treatment remains a significant challenge that warrants further investigation.

Caffeine (Figure 9.2), a xanthine alkaloid primarily derived from coffee, tea, and cocoa, has been linked to a reduced incidence of PD (Qi and Li, 2014). As a non-selective adenosine A_2A receptor antagonist, caffeine may exert its neuroprotective effects on dopaminergic neurons by inhibiting A_2A receptor signaling pathways (Ren and Chen, 2020; Qi and Li, 2014; Chen J. F. et al., 2001). Several studies have explored the intricate relationship between caffeine and α-Syn. Caffeine has been shown to induce conformational changes in α-Syn by binding to its N-terminal and C-terminal regions, thereby hindering its aggregation and preserving its lipid-binding properties (Tavassoly et al., 2014). Intriguingly, caffeine appears to modulate the aggregation kinetics of α-Syn in a complex manner. It has been reported to increase the formation of α-Syn oligomers and accelerate the conversion of oligomers into fibrils, ultimately leading to the formation of new, stable fibrils with reduced oligomer presence. This observation is significant because these newly formed fibrils exhibit lower toxicity compared to their oligomeric counterparts (Kardani and Roy, 2015). Furthermore, caffeine has demonstrated autophagy-enhancing properties. Chronic caffeine treatment has been shown to rescue macroautophagy defects induced by the A53T α-Syn mutation, accelerate the clearance and degradation of α-Syn, and alleviate α-Syn fibril-induced apoptosis in mice (Luan et al., 2018) (Table 5).

Moreover, caffeine’s dual solubility in water and lipids, along with its high BBB permeability, makes it a promising therapeutic agent for brain disorders. With an absorption rate of up to 99% in the gastrointestinal tract, a half-life of 2.5–4.5 h, and good oral bioavailability and tolerance, caffeine demonstrates favorable pharmacological properties (Fredholm et al., 1999). These characteristics, coupled with its ability to enhance autophagy and modulate α-Syn aggregation, suggest potential for targeted therapy in PD. However, despite its generally safe profile, excessive caffeine intake (exceeding grams) can lead to adverse effects, even fatal consequences, especially in individuals with certain metabolic disorders, liver diseases, or cardiovascular conditions (Musgrave et al., 2016). Therefore, careful evaluation of caffeine’s optimal dosage, adverse effects, and long-term toxicity remains crucial.

Squalamine (Figure 9.3), a water-soluble aminosterol isolated from the dogfish shark (Squalus acanthias), is well-known for its potent antibacterial properties (Moore et al., 1993). As a cationic amphipathic steroid, squalamine exhibits a high affinity for phospholipid membranes containing negatively charged headgroups (Selinsky et al., 1998; Brunel et al., 2005). Michele et al. demonstrated in vitro that squalamine’s positive charge mediates strong binding to anionic groups on LM, thereby inducing the dissociation of α-Syn from the LM. This competitive interaction effectively blocks α-Syn binding sites on the LM, inhibiting the formation of α-Syn aggregates. Furthermore, in a C. elegans model of α-Syn, squalamine treatment significantly reduced the cytotoxicity associated with α-Syn aggregates and ameliorated the behavioral and motor deficits (Perni et al., 2017). These findings suggest that squalamine inhibits α-Syn aggregation by targeting the kinetics of the aggregation process, a mechanism distinct from the previously reported inhibitory effects of NPs.

Squalamine has emerged as a promising therapeutic candidate for PD. Notably, ENT-01 (patent: CN106535902), the first squalamine-based drug, entered human clinical trials for PD in 2018 (NCT03781791). Phase II results indicated that ENT-01 exhibits a favorable safety profile, and 80% of patients experienced significant relief from constipation, a common NMS of PD, following ENT-01 treatment. Further evaluations of ENT-01’s effects on other neurological symptoms are planned for future studies (Hauser et al., 2019). Previous studies have provided evidence supporting the efficacy of squalamine in PD treatment, with preliminary findings suggesting that an oral dose of 500 mg/m²/day is relatively safe. However, further studies are needed to assess the potential for adverse effects associated with long-term or frequent squalamine administration (Hao et al., 2003).

Like squalamine, trodusquemine (Figure 9.4) is an aminosterol isolated from the liver of Squalus acanthias. Structurally similar to squalamine (Rao et al., 2000), trodusquemine also exerts inhibitory effects on α-Syn aggregation by displacing it from LM. However, in addition to inhibiting the initial nucleation event, trodusquemine can directly bind to preformed α-Syn fibrils, thereby preventing amplification of aggregation through secondary nucleation. This dual inhibition of nucleation processes may confer superior cytoprotective properties to trodusquemine compared to squalamine (Perni et al., 2018). Although experimental data regarding its pharmacokinetics, bioavailability, safety, and toxicological profile are currently limited, trodusquemine’s reported ability to penetrate the BBB and promote tissue regeneration makes it an attractive candidate for treating synucleinopathies, including PD.