Although several strategies have been explored for PD treatment (Troncoso-Escudero et al., 2020), the identification of α-syn accumulation as one of the key pathological features of this disease has led to the development of pharmacological strategies that directly or indirectly target α-syn misfolded to prevent its aggregation and all the toxic events associated to aggregate formation (Savitt and Jankovic, 2019; Teil et al., 2020). One example of small molecules that directly modulates protein aggregation is NPT200-11, a totally synthetic small molecule derivative of NPT100-18A, a de novo synthetized molecule modeled to target specific regions of the α-syn protein that are key players in oligomer formation (Wrasidlo et al., 2016). Although treatment with NPT100-18A showed the effect of decreasing the α-syn accumulation in vitro and in vivo models of PD (Wrasidlo et al., 2016), its poor bioavailability led to the later development of NPT200-11, which retained its effects over α-syn aggregation with improved physicochemical and pharmacokinetic properties (Price et al., 2018). Recently, oral treatment with NPT200-11 showed the ability to reach the brain and to exert positive effects over neuropathological and behavioral endpoints related to its ability to reduce α-syn aggregation in a transgenic mouse model of PD (Price et al., 2018). The safety and tolerability of NPT200-11 have already been analyzed in a clinical trial where the drug was administered to healthy subjects (NCT02606682, Table 1), but its safety and efficacy in PD patients remains to be elucidated. Interestingly, UCB0599, the R-enantiomer of NPT200-11, has shown an acceptable safety and tolerability profile (Smit et al., 2022) and is currently under a phase 2 clinical trial to determine its effects over clinical symptoms of PD (NCT04658186, Table 1).

Cu (II) ATSM is a cupper-containing radiolabeled imaging agent that has shown to inhibit α-syn aggregation in vitro, which mediated cell toxicity, and dopaminergic neuron loss in preclinical models of PD (Hung et al., 2012). In a study aiming to analyze other pathways involved in the neuroprotective activities of Cu (II) ATSM, a RNAseq whole transcriptome sequencing approach was utilized to evaluate the changes in the SNpc upon treatment with Cu (II) ATSM in a mouse model of PD (Cheng et al., 2016). Results showed a set of genes related to brain and cognitive development, neuroplasticity, regulation and cellular response, whose expression was recovered upon oral treatment with Cu (II) ATSM in PD animals (Cheng et al., 2016), thus the beneficial effects of Cu (II) ATSM treatment are not only related to its indirect effects over protein aggregation but might also be related to its ability to restore gene expression. The safety and tolerability of Cu (II) ATSM treatment in PD patients has recently been analyzed in a multicenter phase 1 clinical trial (NCT03204929, Table 1), although results haven't been posted yet.

Although it was not developed as a disease-modifying treatment, IRL790 (Mesdopetam) is a novel compound that has already been tested in clinical trials to analyze its safety and tolerability in PD patients (Svenningsson et al., 2018) and, recently, its efficacy in the treatment of PD-related dyskinesia has also been evaluated (NCT03368170, Table 1). IRL790 is a dopamine antagonist that was rationally developed to antagonize the D3/D2 receptors (Waters et al., 2020). Upon oral treatment, IRL790 was able to exert anti-dyskinesic and anti-psychotic effects in preclinical models without having a negative impact on the normal dopamine transmission and, in consequence, in the normal motor function (Waters et al., 2020). Hence, IRL790 treatment might have a positive impact on the quality of life of PD patients suffering from dyskinesia and psychosis.

NYX-458 is another example of a non-disease-modifier drug being developed for the treatment of PD. Specifically, NYX-458 is a modulator of the NMDA receptor that has shown the effect of facilitating synaptic plasticity (Khan et al., 2018) and chronic low-dose oral treatment with this drug resulted in an improvement of the cognitive performance in a primate model of PD (Barth et al., 2020). The safety and tolerability of NYX-458 is being tested in a phase 2 clinical trial on PD patients with mild cognitive impairment, where the drug's effects on cognitive performance are also being explored (NCT04148391, Table 1). This clinical trial is expected to be completed by the end of 2022.

Strategies that directly or indirectly target mHTT aggregation have also been under development for HD treatment (Tabrizi et al., 2019). As in PD, the rationale behind targeting mHTT aggregation is in line with its pathogenic role in the progression of the disease. PBT2 is an orally available metal chelator with the ability to prevent protein aggregation associated with metal-mediated oxidative stress (Cherny et al., 2012). The oral treatment with PBT2 has shown to reduce neuronal damage, reverse motor dysfunction and extend lifespan in preclinical models of HD which express polyQ extended proteins that are able to form toxic aggregates (Cherny et al., 2012). The safety, tolerability, and efficacy of PBT2 has already been tested in a phase 2 clinical trial including patients with early to mid-stage HD (NCT01590888, Table 1). The results of this clinical trial showed that oral treatment with PBT2 is generally well tolerated and safe, as the incidence of serious adverse effects in all treated patients was low (Huntington Study Group Reach2HD Investigators, 2015). Furthermore, treatment with PBT2 also showed to improve the cognitive performance of treated patients, but a larger study is needed in order to confirm its beneficial effects in HD patients (Huntington Study Group Reach2HD Investigators, 2015).

Selisistat is a small molecule inhibitor of the Sirtuin 1 deacetylase (SirT1), whose use as treatment has shown to protect against mHTT toxicity in cellular and preclinical models of HD (Smith et al., 2014). Its significant effects over mHTT aggregation produced an improvement in the motor function and lifespan of treated animals (Smith et al., 2014). The effects of selisistat and other SirT1 inhibitors over protein aggregation can be explained by the requirement of post-translational acetylation for the clearance of mHTT through the autophagy machinery (Jeong et al., 2009). Four clinical trials of selisistat treatment in HD patients have already been performed (NCT01485965; NCT01485952; NCT01521585; NCT01521832, Table 1), from where its safety and tolerability have been confirmed (Süssmuth et al., 2015). Although selisistat treatment did not show adverse effects on the motor and cognitive performance of HD patients (Süssmuth et al., 2015), its efficacy as a disease-modifying treatment of HD remains to be evaluated.

As previously explained, the activation of NLRP3 inflammasome by α-syn aggregates has been related to neuronal death in PD (Gordon et al., 2018; Wang et al., 2019; Haque et al., 2020). Recently, Paladino et al showed that the expression of NLRP3 was significantly higher in R6/2 mice compared to control mice (Paldino et al., 2020). Moreover, oral treatment of R6/2 animals with Olarapib, an FDA approved drug commonly used for the treatment of ovarian cancer, significantly reduced the expression of NLRP3, the levels of neuroinflammation, and promoted neuroprotection in treated animals (Paldino et al., 2020). More recently, Chen et al. (2022), showed that oral treatment with the highly selective NLRP3 inhibitor MCC950 suppressed NLRP3 inflammasome, reduced levels of pro-inflammatory cytokines and neuronal toxicity in the R6/2 preclinical model and, more importantly, improved motor dysfunction and extended lifespan in treated animals compared to non-treated mice.

Pridopidine is a dopamine D2 receptor ligand that upon interaction destabilize the active conformation of the receptor and, consequently, acts as a dopamine antagonist increasing synthesis, release, and metabolism of dopamine in subcortical areas (Waters et al., 2018). Preclinical data shows that treatment with pridopidine has a higher affinity for the sigma 1 receptor, which is in the endoplasmic reticulum (ER), and upon interaction with pridopidine promotes neuroprotection in mouse primary cortical neurons and patient-derived induced pluripotent stem cells (Eddings et al., 2019). Furthermore, pridopidine treatment has also shown to improve behavioral symptoms and reverse the changes in gene transcription related to HD in a preclinical model of the disease (Garcia-Miralles et al., 2017; Kusko et al., 2018). The safety, tolerability, and efficacy as a symptomatic treatment of this drug has already been tested in phase 1 (NCT03019289, Table 1), phase 2 (NCT02006472, NCT01306929, Table 1) and phase 3 (NCT00724048, NCT00665223, Table 1) clinical trials. These studies demonstrated that 90 mg of pridopidine acts as selective S1R ligand (Grachev et al., 2021) and that treatment of HD patients with pridopidine results in significant reduction in the decline in Total Functional Capacity, a scale used to assess independence, perform domestic work, among other tasks (McGarry et al., 2020a,b). Further studies are needed to determine its properties as a disease modifying treatment for HD.

Previous reviews have analyzed the potential neuroprotective capacity of polyphenolic compounds, showing that these types of compounds could be acting through their antioxidant, anti-inflammatory, and anti-aggregation activities (Zhang et al., 2017; Javed et al., 2018; Kujawska and Jodynis-Liebert, 2018; Maher, 2019). One of the most studied polyphenolic compounds is resveratrol. Resveratrol is a stilbene most notably found in grapes and blueberries, whose antioxidant and anti-inflammatory activities have been extensively studied (revised in Diaz-Gerevini et al., 2016; Repossi et al., 2020). Its neuroprotective properties have also been analyzed and several mechanisms of action of this molecule have been described (Bastianetto et al., 2015; Kou and Chen, 2017; Gomes et al., 2018; Lin et al., 2018). In different in vivo PD models, resveratrol has shown the ability to delay the progression of the disease and improve motor function through the rescue of dopaminergic neurons (Huang et al., 2019), induction of α-syn degradation by autophagy (Guo et al., 2016), inhibition of α-syn oligomerization and reduction of neuroinflammation and oxidative stress (Zhang et al., 2018). Also, the concomitant use of resveratrol and L-dopa in a mouse model of PD has been effective in reducing the dopaminergic neuron loss and motor dysfunction, with the advantage of a lower administration of L-dopa, and therefore, less side effects manifestation (Liu et al., 2019). The potential applications of resveratrol in the treatment of PD and other diseases are limited by its poor solubility and extensive hepatic metabolisms which lowers its bioavailability (Salehi et al., 2018; Arbo et al., 2020). This issue has led to the development of resveratrol derivatives with improved pharmacokinetics and similar biological effects, whose potential uses in PD treatment are reviewed in (Arbo et al., 2020). BIA6-512 is a resveratrol derivative (trans-resveratrol) whose pharmacokinetics have been analyzed in clinical trials as monotherapy (NCT03095105 and NCT03093389, Table 2) and in combination with L-dopa (NCT03091543, Table 2), but no clinical trials studying the efficacy of BIA6-512 treatment, alone or in combination, have been performed to date.

Flavonoids are one of the biggest family of polyphenolic compounds found in plants with around 5000 molecules described, classified by the degree of oxidation of their central ring, their hydroxylation pattern, and the presence of substitution in C3 (Petrussa et al., 2013; Maher, 2019). These compounds can be found in a variety of foods and food products such as grapes, berries, tea and cocoa (Terahara, 2015) and their neuroprotective effects have been extensively analyzed in preclinical models (revised in Vauzour et al., 2008; Spencer, 2009; Vauzour, 2014; Flanagan et al., 2018; Gildawie et al., 2018; Bakoyiannis et al., 2019; Maher, 2019; Di Meo et al., 2020). Nevertheless, our search for clinical trials of flavonoids related to PD revealed that not many of these plant metabolites reach the clinical stage for the treatment of neurodegenerative diseases. In this context, one clinical trial in phase 2 of green tea polyphenols was found. In this clinical trial performed in China (NCT00461942, Table 2), the safety and efficacy of the treatment with a green tea extract was analyzed in PD patients not yet taking prescribed PD-specific medications, but results are not posted. The rationale behind the use of a green tea extract is the presence of catechins, specifically EGCG (epigallocatechin-3-gallate), a polyphenolic compound of the flavonoid family (Nagle et al., 2006). EGCG treatment has shown the ability to inhibit α-syn in in vitro and human postmortem tissue models of PD by directly interacting with specific amino acid sequences in the protein and blocking aggregation-prone regions by intermolecular hydrophobic interactions (Xu et al., 2016). Furthermore, EGCG oral treatment rescued striatal dopaminergic neurons by protecting them against oxidative stress related to iron in a MPTP-induced PD mouse model (Xu et al., 2016). EGCG treatment has also shown to modulate autophagy and extend cell survival (Holczer et al., 2018), a mechanism that could also be involved in its neuroprotective properties of EGCG (Limanaqi et al., 2019). The effects of the treatment with a standardized green tea extract have also been analyzed in a preclinical model of PD (Pinto et al., 2015). In this study, long-term treatment with green tea extract resulted in positive effects on motor and behavioral performance of treated animals with respect to control, and in a reversal of DA levels in the striatum and protection against oxidative stress (Pinto et al., 2015). More details on the neuroprotective mechanisms of EGCG can be found elsewhere (Wang et al., 2022). Considering the accumulated pre-clinical evidence, the disease-modifying properties of EGCG should be further analyzed in clinical trials.

Cannabinoids are a class of secondary metabolites found in Cannabis sativa, a plant whose leaves and flowers have been used since ancient times for different purposes. Cannabidiol (CBD) is the second most abundant component of the plant, behind delta9-tetrahydrocannabinol (Δ⁹-THC). The endocannabinoid system, mainly composed of CB1 and CB2 receptors, and their endogenous ligands, plays a key role in the regulation of physiological processes and its alteration has been observed in several pathological conditions, such as movement disorders (Bilkei-Gorzo, 2012; Buhmann et al., 2017, 2019). For this reason, many efforts to develop cannabinoid-based therapeutics to target the endocannabinoid system for the treatment of disease have been made, but these efforts have been challenged by the complexity and promiscuity of the cannabinoids actions (Morales and Jagerovic, 2020). In the context of PD, the role of the endocannabinoid system is still unclear (Cristino et al., 2020; Junior et al., 2020; Morales and Jagerovic, 2020). Nevertheless, treatment with different phytocannabinoids has shown neuroprotective effects in preclinical animal models of PD (García et al., 2011; Ojha et al., 2016; Espadas et al., 2020). Moreover, Nabilone, a synthetic analog of tetrahydrocannabinol, was included in 2 clinical trials (NCT03769896; NCT03773796, Table 2) to assess its efficacy and safety for the treatment of non-motor symptoms in patients with PD (Peball et al., 2019). Results from these studies indicate that Nabilone treatment has beneficial effects on sleep outcomes in PD patients that have been experiencing sleep problems at baseline (Peball et al., 2022). Whether or not phytocannabinoids or their synthetic derivatives can have a significant impact on motor performance of PD patients remains to be elucidated (Buhmann et al., 2017).

Oral treatment with resveratrol extended lifespan in both models and reversed motor impairment related to mHTT expression in treated mice compared to control, effects that can be explained by the activation of the ERK signaling pathway (Maher et al., 2011). ERK signaling alterations have been related to the development of movement disorders (Hutton et al., 2017) and, in turn, mHTT has shown to alter ERK signaling in HD models (Apostol et al., 2006), which might explain the neuroprotective effects of resveratrol treatment. Resveratrol has also shown to protect against dopamine and mHTT toxicity in a neuronal cell model of HD by preventing oxidative stress and promoting autophagy-degradation of mHTT (Vidoni et al., 2018). Also, resveratrol treatment has shown to improve mitochondrial activity in a transgenic mouse model of HD, an effect that correlated with a significant improvement in motor function of treated animals compared to control (Naia et al., 2017). The therapeutic potential of resveratrol was analyzed in a clinical trial comprising 102 participants with HD (NCT023366339, Table 2), where the primary output was to assess the rate of caudate atrophy after 1 year of treatment. This clinical trial was recently completed, but no results have been posted yet.

EGCG treatment inhibits early events of mHTT aggregation in vitro, reduces the toxicity of mHTT in a yeast model of HD, and improves motor performance in a transgenic fly model of HD (Ehrnhoefer et al., 2006). Also, treatment with a green tea infusion has shown to modestly reduce neurodegeneration related to mHTT aggregation in a fly model of HD (Varga et al., 2020). A phase 2 multicenter clinical trial of EGCG, denominated the ETON-Study (NCT01357681, Table 2), aimed to analyze the effects on cognitive function of EGCG treatment for 1 year in patients with HD and the safety and tolerability of the treatment were also studied. This study was completed in 2015, but results were not posted.

Curcumin is one of the most active polyphenolic compounds from Curcuma, has shown to possess anti-oxidant and anti-inflammatory potential in the treatment of several disorders including diabetes, cardiovascular, neurologic, metabolic, inflammatory, and skin disorders, hepatotoxicity, respiratory tract infections, and diseases of infectious origin (Zhou et al., 2011; Khan et al., 2019). Curcumin treatment has been analyzed in pre-clinical models of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), which have shown promising results (Chico et al., 2018; Voulgaropoulou et al., 2019; Mohseni et al., 2021; Lv et al., 2022). In these studies, curcumin treatment has shown to inhibit protein aggregation and decrease neuroinflammation, mechanisms that could also be promissory for PD and HD treatment. Moreover, curcumin treatment has also been analyzed in clinical trials of AD and ALS (Ringman et al., 2012; Chico et al., 2018; Voulgaropoulou et al., 2019; Mohseni et al., 2021; Lv et al., 2022). Furthermore, a chronic administration of curcumin in preclinical models of Huntington's disease has been shown to alleviate both the brain pathophysiology associated with reduced levels of huntingtin protein aggregates and to alleviate the motor symptoms described in R6/2 mice, along with reduced inflammation and intestinal damage associated with the progression of Huntington's disease (Elifani et al., 2019). Thus, curcumin treatment is a potential candidate for clinical trials in PD and HD patients.

The evidence for the use of cannabinoids as treatment for HD has been somewhat mixed given the high heterogeneity of different motor and cognitive symptoms of HD patients. Dronabinol is a synthetic form of delta-9-tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive component of cannabis. This natural product is a partial agonist at Cannabinoid-1 receptor (CB1R) and Cannabinoid-2 receptor (CB2R). In a clinical trial (NCT01502046), treatment with dronabinol showed beneficial symptomatic motor effects in HD patients with dystonia as a primary motor syndrome (rigidity or muscle contracture). It was also observed an improvement in weight and food intake in patients with more advanced disease stages, but dronabinol treatment has failed to demonstrate positive effects in the management of chorea (Saft et al., 2018).