Emerging Nondopaminergic Medications for Parkinson’s Disease: Focusing on A_2A Receptor Antagonists and GLP1 Receptor Agonists

Article information

JMD. 2021;14(3):193-203

Publication date (electronic) : 2021 August 18

doi : https://doi.org/10.14802/jmd.21035

Pei Shang ¹

, Matthew Baker ¹

, Samantha Banks ²

, Sa-Ik Hong ¹

, Doo-Sup Choi^,¹^,³^,⁴

¹Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA

²Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA

³Department of Psychiatry and Psychology, Mayo Clinic, College of Medicine, Rochester, MN, USA

⁴Department of Neuroscience Program, Mayo Clinic, College of Medicine, Rochester, MN, USA

Corresponding author: Doo-Sup Choi, PhD Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, 200 1st SW, MN 55905, USA / Tel: +1-507-284-5602 / Fax: +1-507-266-0824 / E-mail: choids@mayo.edu

Received 2021 March 13; Revised 2021 May 21; Accepted 2021 June 10.

Abstract

Parkinson’s disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A_2A receptors (A_2AR) and dopamine D₂ receptors (D₂R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A_2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A_2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A_2AR antagonists and GLP1R agonists in clinical practice.

Keywords: A_2A receptor antagonist; GLP1 receptor agonist; Parkinson’s disease

INTRODUCTION

Parkinson’s disease (PD) is a progressive and degenerative disorder characterized pathologically by a substantial loss of dopaminergic neurons in the substantia nigra. PD is a relatively wellcharacterized disorder, and objective clinical assessment provides accurate diagnosis and analysis of disease severity. To reverse the dopamine deficiency that drives symptoms in PD, levodopa (L-DOPA), a precursor of dopamine that readily crosses the blood-brain barrier (BBB), revolutionized PD treatment since its Food and Drug Administration (FDA) approval in 1962. Many additional therapeutic drugs used as combinatory treatments work through different mechanisms, such as inhibiting L-DOPA or dopamine metabolism or activating dopamine receptors [1]. Although the efficacy of dopamine-based treatment for PD symptoms is broadly well accepted and tolerable, the fluctuation in dopamine levels in the brain may result in potential side effects, including levodopa-induced dyskinesia (LID), impulsivity, and sleep disturbance [2,3]. Numerous novel drugs have been tested in clinical trials to mitigate dopamine-based treatment shortcomings or reverse or compensate for dopamine deficiency. In 2019, the FDA approved a novel nondopaminergic medication, istradefylline, an adenosine A_2A receptor (A_2AR) antagonist, as an adjuvant drug to treat off-episodes of PD symptoms [4]. Interestingly, the glucagon-like peptide-1 receptor (GLP1R) agonist exenatide is another emerging nondopaminergic receptor-based treatment option and shows promising preclinical and clinical outcomes. In this review, we discuss how these two G-protein coupled receptor (GPCR) ligands may improve L-DOPA-based treatment with minimized side effects or provide alternative nondopaminergic options for patients who would benefit from early treatment.

ADENOSINE A_2AR ANTAGONISTS

Adenosine and adenosine receptors in movement

Adenosine and its receptors have been considered important therapeutic targets for PD due to their neuromodulatory and homeostatic functions in the human brain [5]. Generally, adenosine receptors have been divided into subtypes, including A₁, A_2A, A_2B, and A₃. As an endogenous purine nucleoside, adenosine modulates several physiological functions in the central and peripheral nervous systems. Under basal conditions, adenosine mainly acts on inhibitory A₁ receptors (A₁R) and excitatory A_2ARs to integrate dopamine and glutamate signaling, which controls the synaptic plasticity associated with learning, memory, and cognition [5]. Adenosine preferentially acts at A₁R because of its widespread distribution and high expression levels [6]. The A_2AR is a GPCR that can activate adenylyl cyclase [7]. Of note, A_2AR is always distributed and colocalized with dopamine D₂R and D₃R on striatopallidal neurons in the striatum. A_2AR can also interact with dopamine D₂R and reduce the expression of D₂R (Figure 1) [8,9]. Due to their localization in the basal ganglia, A_2AR modulates the indirect pathway by modulating gamma-aminobutyric acid (GABA) and glutamate release, both of which are highly involved in the control of voluntary movements [10].

Figure 1.

Possible mechanisms of A_2AR antagonists on PD. A_2A receptors and dopamine D₂ receptors interact with each other, and A_2A receptor activation inhibits the function of the D₂ receptor under normal conditions. A_2A receptor antagonists can be adjuvants to D₂R agonists, diminishing the inhibition of the D₂ receptor by adenosine. Thus, A_2AR antagonists block the effects of adenosine and facilitate D₂R agonist effects on lowering cAMP levels and then dampens PKA activity, which may result in neuroprotective effects. Meanwhile, the combination of an A_2A receptor antagonist and mGluR5 antagonist also promotes neuroprotection and activates the indirect corticostriatal circuit while reducing PD-like symptoms. The synergistic effect of A_2AR antagonist, D₂R agonist, and 5-HT_1A/1BR agonist also prevents L-DOPA-related dyskinesia-like behaviors. Figure 1 was modified from Nazario et al. [118] 5-HT: serotonin, A_2AR: adenosine A_2A receptor, cAMP: cyclic adenosine monophosphate, D₂R: dopamine receptor D₂, L-DOPA: levodopa, LTP: long-term potentiation, mGluR5: metabotropic glutamate receptor 5 receptor, PD: Parkinson’s disease, PKA: protein kinase A.

Adenosine A_2AR antagonists and PD

D₂/D₃Rs have long been considered efficient therapeutic agents for the management of PD [11]. However, L-DOPA and its analogs usually function in an early phase of PD, and patients may develop tolerance with long-term treatment [12]. Side effects, including dyskinesias, “on-off” syndromes, and psychotic disorders, can emerge after long-term utilization of dopaminergic agonists [12]. Although surgical interventions such as deep brain stimulation (DBS) can effectively relieve bradykinesia, rigidity, and tremor in PD patients, DBS has several limitations, including the risk of surgical complications and affordability [13]. Istradefylline, an A_2AR antagonist, was approved by the FDA as an anti-PD drug in 2019 [14]. Importantly, istradefylline exhibited powerful increases in locomotor activity and potentiated dopaminergic agonist motor effects in animal models of PD (Table 1) [15]. Indeed, dysfunction in adenosinergic transduction is associated with neurological disorders ranging from epilepsy to neurodegenerative disorders [16]. Not surprisingly, the adenosinergic system was identified to be dysregulated in patients with PD [17]. Researchers also demonstrated increased A_2AR density in the caudate-putamen from PD subjects in a postmortem study [18,19]. Consistently, pharmacological inhibition by A_2AR antagonists has been found to improve motor behavior deficits in PD and dyskinesia [20]. Interestingly, a photoactive adenosine A_2AR antagonist also showed potential to remotely control movement disorders such as PD [21].

Table 1.

Summary of clinical trials of A_2AR antagonists for PD with symptom improvements

A_2AR antagonism was first identified for potential therapeutic effects in patients with PD with the antimalarial drug mefloquine, which contains an A_2AR antagonist [22]. Experimentally, periodically interrupted or long-lasting administration of an A_2AR antagonist such as SCH58261 combined with L-DOPA may restore normal motor function in PD animal models [23]. Interestingly, long-acting L-DOPA treatment also results in an enhanced biosynthesis of A_2ARs in patients with PD-induced dyskinesias, especially in brain networks involving the striatum and substantia nigra [24].

Interactions between adenosine A_2AR and other GPCRs in PD

The hypothesis for A_2AR antagonist utilization in PD is based on adenosine-dopamine antagonism in the striatum, which has the highest expression of A_2AR in the human body [25,26]. Accumulated evidence has verified the functional relationships between A_2AR and D₂R in the basal ganglia (Figure 1) [27,28]. Researchers have also identified D₂R/A_2AR oligomers in the mouse and monkey striatum via proximity ligation assays, immunoelectron microscopy, and ligand fluorescence resonance energy transfer (FRET)-based approaches [29-31]. In addition, D₂R/A_2AR oligomers in the striatum have been postulated to appear at the onset of PD and could interrupt selective dopaminergic denervation [32]. Furthermore, A_2AR mRNA has been detected in striatal cholinergic interneurons according to a previous study [33]. Due to structural associations, A_2AR activation can inhibit Gi/o protein (G protein α subunit, which inhibits adenylyl cyclase activity and thereby decreases cAMP levels) coupled with D₂R, further validating the existence of the A_2AR-D₂R heteroreceptor complex [34,35].

Meanwhile, D₂R activation can lead to the formation of D₂R-NMDAR heteroreceptor complexes and subsequent inhibition of NMDAR signaling [36]. Overactivity of astroglial A_2AR induces extrasynaptic and postsynaptic mGluR1 and mGluR5 coupling to Gq protein (G protein α subunit, which activates phospholipase β and thereby increases diacylglycerol and inositol-triphosphate levels) by enhancing astroglial glutamate release, which can further increase intracellular calcium levels and lead to inhibition of D₂R signaling in A_2AR-D₂R and A_2AR-mGluR5 complexes (Figure 1) [37]. The A_2AR-D₂R and A_2AR-mGluR5 complexes may inhibit D₂R promoter recognition and activate intracellular MAPK and CREB signaling pathways, mainly relying on antagonistic allosteric receptor-to-receptor interactions [38,39]. Nonetheless, A_2AR activation by adenosine may have an excitatory effect on striatopallidal neurons in a D₂R-independent manner [40,41].

During the early phase of PD, L-DOPA and D₂R agonists can prevent D₂R promoter inhibition induced by the basal A_2AR promoter since more D₂R homoreceptor complexes are expressed than A_2AR-D₂R complexes [42]. 5-HT_1A/1B agonists combined with A_2AR antagonists were also reported as an advanced therapy for PD with antidyskinetic effects, implicating a potential synergic effect between the two receptors (Figure 1) [43].

Adenosine A_2AR antagonists on cognition

Cognitive impairment frequently occurs in patients with PD and usually reduces patient quality of life and comfort [44]. Early cognitive deficits in PD were hypothesized to be associated with deficits in dopaminergic innervation of the cortex and alterations in striatum-thalamocortical loop function, which is difficult to manage using dopaminergic medications [45,46]. Interestingly, A_2AR antagonists improve cognitive functions, including memory. The A_2AR antagonist SCH58261 improved memory performance and social recognition memory in rodent models with memory deficits [47]. However, A_2AR antagonist administration into the posterior cingulate cortex impaired the process of memory retrieval in rats [48], suggesting region-specific effects. In practice, donepezil, an acetylcholinesterase inhibitor, is commonly prescribed for patients with PD to manage cognitive impairment and memory loss and might be an adjuvant to A_2AR antagonists to alleviate side effects [49].

A_2AR antagonists, including ZM241385 and istradefylline, may restore social recognition and cognitive deficits in rats [50,51]. Similarly, A_2AR antagonists or genetic deletion of A_2AR were shown to improve short-term memory, working memory, reversal learning, goal-directed behavior, and fear conditioning in animal models used for different neurological diseases [51-56].

Adenosine A_2AR antagonists: efficacy and limitations

It has been clinically verified that A_2AR antagonists can improve motor dysfunction in patients with PD as monotherapy or in combination with L-DOPA and other antiparkinsonian drugs (Table 1) [57,58]. Previous clinical trials have also shown that A_2AR antagonists are effective in shortening the off-time without worsening troublesome dyskinesia and increasing on-time in patients with advanced stage PD and L-DOPA treatment [59]. However, with the exception of istradefylline, almost all of the other clinical trials with novel therapeutics have failed in recent years, including preladenant, vipadenant, and the nonxanthine SCH58261 [59,60]. Clinical trials of the A_2AR antagonist named preladenant were discontinued due to the lack of efficacy [61]. Side effects induced by A_2AR antagonists, including insomnia, headache, constipation, hallucinations, and cardiac failure, merit attention from caregivers [62]. Targeting A_2AR with classic pharmacology has shown some drawbacks, including slow and imprecise drug delivery and low specificity and efficacy [21]. A_2AR antagonists generally have higher molecular weights and are difficult to synthesize due to the complexity of structures, poor water solubility, and furan groups that preclude replacement by classic chemistry [63]. Caffeine is an adenosine analog and has been shown to confer neuroprotection against dopaminergic neurodegeneration via modulation of A_2AR pathways and neuroinflammation in PD models [64]. Furthermore, caffeine was demonstrated to improve motor function in PD patients by targeting A_2AR [65]. Chronic caffeine treatment can largely attenuate α-synuclein-induced microglial activation and astrogliosis in mice, similar to A_2AR antagonists [66,67]. However, a clinical trial has shown that caffeine intake twice daily (200 mg) over 6 months did not produce significant symptomatic benefits for patients with PD [68]. Therefore, further studies are required to clarify the benefits of caffeine for the prevention or improvement of early or moderate PD symptoms.

Interestingly, our preclinical experiment showed that A_2AR inhibition increases alcohol-seeking behaviors [69] through enhanced goal-directed cognitive function. Consistent with this finding, pharmacological activation of A_2AR or optogenetic activation of A_2AR-expressing neurons in the dorsomedial striatum (DMS) decreases alcohol-seeking behaviors [70]. In corticostriatal circuits, A_2AR-expressing neurons consist of indirect and inhibiting circuits, as discussed in the previous section. Adenosine is known to mediate the intoxicating effect of alcohol [71-75], and A_2AR inhibition may increase reward-seeking behaviors when subjects are introduced to addictive substances or activities. As noted above, A_2AR inhibition increases cognitive function through enhanced goal-directed behavior. Even though istradefylline was suspected to positively affect cognitive dysfunction and postural abnormalities in patients with PD, short-term clinical trials did not show benefits on cognition [76]. Meanwhile, based on preclinical studies, A_2AR inhibition may increase the risk of addiction. Therefore, it is important to monitor the behavioral patterns of PD patients when A_2AR antagonists are prescribed.

GLP1R AGONISTS

Glucagon-like peptide and GLP1R-mediated signaling in insulin regulation

Glucagon-like peptide-1 (7-36) amide (GLP1) is secreted from intestinal enteroendocrine L cells in response to food intake and controls systemic blood glucose homeostasis in the human body [77]. The intestinal wall secretes GLP1 to activate enteroenteric reflexes, control gastric motility, and slow gastric emptying [78]. GLP1 also activates vagal sensory nerve terminals and initiates vagal-vagal autonomic reflexes by controlling the endocrine function of the pancreas [79]. The islets of Langerhans in the pancreas can be stimulated by GLP1 and release insulin to inhibit glucagon production. GLP1Rs are usually expressed in hypothalamic neurons and vagal afferent ganglion neurons [80]. Due to rapid degradation and short half-lives, only 10–15% of GLP1 reaches circulation after release [81]. Peripheral injection of GLP1R antagonists facilitates food intake and diminishes the efficacy of circulating GLP1, suggesting that the feeding process induced by GLP1 relies on peripheral GLP1R, which activates vagal afferents after stimulation [82,83]. Notably, the glucose-lowering function of GLP1 is highly dependent on the concentration of glucose [84]. This property of GLP1 prevents it from lowering blood glucose after fasting [85]. Therefore, GLP1R agonists are clinically used as a new class of glucose-controlling agents for treating type 2 diabetes (T2D) without introducing the side effects of hypoglycemia [86,87].

Based on previous findings, GLP1 may not influence the metabolome or directly interact with rodent β cells, and short-term exposure to GLP1 did not induce changes to glycolytic or TCA cycle intermediates in vitro [88,89]. The binding between GLP1 and GLP1R on various cells can activate adenylyl cyclase and increase cAMP levels, which further stimulates protein kinase A and cAMP-regulated guanine nucleotide exchange factor 2 pathways and insulin secretion [90,91]. A previous study also found that GLP1 may stimulate the secretion of insulin in β cells and induce glucose catabolism via the mTOR-dependent HIF-1α activation pathway (Figure 2) [92].

Figure 2.

Possible mechanisms of GLP1 agonists on PD. Exenatide activates the GLP1 receptor and further promotes PI3K/AKT pathway signaling. PI3K/AKT activates the mTOR pathway but inhibits the FoxO1/O3, GSK-3β, and NF-κB pathways. Activation of the PI3K/AKT pathway enhances neurogenesis, LTP, and mitochondrial function with a decrease in apoptosis and microglial activation. Moreover, GLP1R agonists activate adenylate cyclase and facilitate cAMP biosynthesis with CREB. CREB further promotes Bcl-2 and Bcl-XL transcription to prevent apoptosis. cAMP also activates the PKA/MAPK pathway and increases synaptic plasticity. PKA-dependent phosphorylation of L-type calcium channels potentiates calcium influx and increases neuronal activities. Bcl-2: B-cell lymphoma 2, Bcl-XL: B-cell lymphoma-extra large, cAMP: cyclic adenosine monophosphate, CREB: cAMP-response element-binding protein, FoxO1/O3: forkhead box transcription factor 1/3, GLP1R: glucagon-like peptide-1 receptor, GSK-3β: glycogen synthase kinase-3β, LTP: long-term potentiation, MAPK: mitogen-activated protein kinase, mTOR: mammalian target of rapamycin, NF-κB: nuclear factor kappa B, PD: Parkinson’s disease, PI3K: phosphoinositide 3-kinase, PKA: protein kinase A.

As a promising therapeutic strategy for the management of T2D, GLP1 efficacy has been compared with different insulin formulations, including glargine and detemir, in multiple clinical trials [93,94]. Long-acting GLP1R agonists have shown better glycemic efficacy than basal insulin. For instance, a once-weekly regimen of semaglutide significantly decreased the HbA1c levels compared with glargine therapy [95].

GLP1R and dopaminergic neurons

While GLP1R plays an important peripheral role in glucose-dependent insulin secretion and gene expression, there is increasing evidence of its central role in feeding and satiety-related behaviors. GLP1R expression has been observed throughout the brain in both rodents and humans. In particular, GLP1R is highly expressed in mesolimbic reward pathways, including the hypothalamus, ventral tegmental area, lateral septum, nucleus of the solitary tract, and many others. GLP1 and other GLP1R agonists have been shown to cross the BBB. GLP1R is a Gα-coupled GPCR that activates adenylyl cyclase, leading to increased intracellular cAMP levels (Figure 2). GLP1R activation has been shown to directly interact with the dopamine system by decreasing phasic dopamine release and facilitating a reduction in feeding and reward-seeking behaviors [96]. Additionally, GLP1R stimulation has been shown to exert neuroprotective and neuroproliferative effects in response to stroke, neurodegeneration, and other neurologic injuries (Figure 2).

In particular, exenatide, a novel GLP1R agonist that was discovered in the saliva of the Gila monster (Heloderma suspectum), was shown to reduce dopaminergic cell loss in the substantia nigra in a methyl-phenyl tetrahydropyridine (MPTP)-induced mouse model of PD and restore normal dopamine levels and motor function [97]. Similarly, exenatide treatment was shown to reduce dopaminergic cell loss and motor function in rats injected with 6-hydroxydopamine (6-OHDA), another toxin that selectively causes dopaminergic cell death. In addition to motor effects, GLP1R has been shown to have a neuroprotective role in cognitive function through enhanced synaptic plasticity. While GLP1R null mouse models have shown evidence of impaired long-term potentiation (LTP) and learning and memory deficits, GLP1R stimulation increases LTP and restores cognitive function in neurodegenerative mouse models.

The extended-release form of the protease-resistant and brain-penetrating exenatide was approved by the FDA for T2D in 2018. Following this, Dr. Foltynie’s group in England demonstrated that weekly administration of exenatide for 48 weeks significantly improved PD symptoms in a phase II clinical trial [98]. Recently, improved extended-release forms of exenatide with increased brain penetration and longer bioavailability were developed [99-101]. Since various forms of exenatide were comprehensively tested in humans through T2D clinical studies, the new application of exenatide in PD will be available for PD treatment in the near future.

GLP1R agonists: efficacy and limitations

GLP1 function is hypothesized to be a pivotal molecular pathway in glucose regulation via the gut-brain axis. Interestingly, GLP1R is expressed not only in peripheral organs such as the pancreas but also in the brain [97,102-104]. In line with this theory, GLP1R agonists showed positive impacts on controlling cardiovascular diseases, especially in patients with diabetes [105,106]. Liraglutide, a GLP1R agonist, has been implicated as an efficient weight-loss agent in patients with or without T2D [107]. GLP1R agonists such as exenatide have also been demonstrated to exert neuroprotective and neurotrophic effects and have shown therapeutic efficacy in PD management in several clinical and preclinical trials (Table 2 and 3) [98,108]. Another GLP1R agonist, lixisenatide, can cross the BBB and increase cAMP levels at a low dose [109]. GLP1R activation elicited neurite outgrowth of SH-SY5Y cells, similar to the function of nerve growth factors, further validating its potential role in neurogenesis and neurotrophy [110]. Meanwhile, exenatide induces approximately twofold changes in doublecortin-positive cells in the medial striatum and bromodeoxyuridine-positive cells in the subventricular area in adult mice, both of which are highly involved in the process of neurogenesis [111]. Exenatide also improves Mattis dementia rating scale scores in patients with PD [108]. The follow-up study showed that the benefits lasted for 12 months after the cessation of exenatide [112,113].

Table 2.

Summary of preclinical trials of GLP1R agonists for PD

Table 3.

Summary of phase 2 clinical trials of GLP1R agonists for PD

The neuroprotective mechanisms of GLP1R agonists have not been elucidated until now. The brain-penetrant long-acting GLP1R agonist NLY01 prevented the loss of dopaminergic neurons and improved behavioral deficits in an α-synuclein-treated fibril model mimicking sporadic PD [114,115]. NLY01 prolonged life expectancy and alleviated neurodegeneration and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model [116]. The neuroprotective effects of the GLP1R agonist are likely correlated with the MAPK (ERK) and PI3K/AKT pathways (Figure 2) [90,117].

CONCLUSIONS

This review provides current perspectives on the recently approved istradefylline and the recently investigated exenatide as new treatment options for PD. Ongoing postmarketing clinical studies on istradefylline will reveal optimal dosing and treatment timing for PD symptom management. Regarding exenatide, as it is clinically used for T2D, additional trials will inform the potential benefits in PD and T2D. Furthermore, various suspended release forms of exenatide will be available for once weekly or every other week treatment regimens. More user-friendly routes of administration (pencil-type syringe or oral form) will increase the accessibility of this novel medication. Importantly, we need to develop personalized treatment methods for PD based on more precise phenotyping and genotyping, which may correlate with the treatment outcomes associated with existing and novel medications. Big-data-driven artificial intelligence will eventually aid physicians’ treatment strategies with improved symptom monitoring systems.

Notes

Conflicts of Interest

D.S.C. is a scientific advisory board member for Peptron Inc. Peptron had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. All the other authors declare no biomedical financial interests or potential conflicts of interest.

Funding Statement

This work was supported by the Samuel C. Johnson for Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, and National Institute on Alcohol Abuse and Alcoholism (K01 AA027773 to SK; R01 AA018779, R01 AA029258, and R01 AG072898 to DSC).

Author Contributions

Conceptualization: Pei Shang, Doo-Sup Choi. Funding acquisition: Doo-Sup Choi. Investigation: all authors. Project administration: Pei Shang, Doo-Sup Choi. Resources: Pei Shang, Matthew Baker, Samantha Banks, Doo-Sup Choi. Supervision: Doo-Sup Choi. Writing—original draft: all authors. Writing—review & editing: all authors.

Acknowledgements

We thank all the Choi laboratory members for their discussions. Figure 1 and 2 were created with BioRender.com.

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Medication	Trial design	Subjects	Treatment doses	Outcomes	Reference
Istradefylline	A phase 2, 12-week, double-blind, placebo-controlled study of istradefylline in PD patients on L-DOPA/carbidopa	790 PD patients with an average OFF time at least 2 h/day and approximately 3.2 years after diagnosis	20 (for 163 subjects) or 60 mg (for 155 subjects) per day	Significant reduction in the awake time per day spent in OFF state	[119]
Istradefylline	A phase 3, multicenter, open-label, long-term (52 w) study of istradefylline in PD patients experiencing wearing-off	313 PD patients approximately 7.5 years after onset and 3.3 years after showing motor complications	20 mg as starting dosage with/o adjustment to 40 mg	Significant OFF time reduction since the 2nd week	[120]
Istradefylline	Istradefylline as adjunctive treatment to levodopa for 12 weeks in a phase 3, double-blind manner in PD patients with motor complications	373 PD patients 3.3 years after showing motor complications	20 or 40 mg per day	Istradefylline markedly reduced daily OFF time and was well-tolerated in patients with motor complications	[121]
Istradefylline	A phase 3 randomized, 12-week, double-blind, placebo-controlled parallel-group study of istradefylline with different doses in patients on levodopa therapy	610 PD patients with an average OFF time at least 3 h/day. 9 years after diagnosis, and 3.6 years after motor fluctuations	10, 20, and 40 mg per day	Istradefylline did not impact daily OFF time but significantly improved motor scores at 40 mg per day	[122]
Tozadenant	A phase 2, double-blind, randomized, placebo-controlled study of the safety and efficacy of SYN115 as adjunctive therapy in L-DOPA- treated PD subjects	337 PD patients with an average OFF time at least 6 h/day and 8.7 years after diagnosis	60 or 120 or 180 or 240 mg/BID	Tozadenant significantly reduced daily OFF time and improved motor signs without increasing dyskinesia	[123]
Preladenant	A phase 2, 36-week, open-label, follow-up safety study of SCH420814 in subjects with PD	140 PD patients with moderate to severe PD > 5 years	5 mg/BID	Long-term preladenant treatment are well-tolerated and sustained the OFF time reduction	[124]

GLP1R agonist	PD models	Treatment details	Experimental results	Reference
Ex-4	6-OHDA/LPS-treated rat model	Ex-4 (0.1 and 0.5 µg/kg) was given 7 days after the intracerebral toxin injection, BID for 7 days	Circling behavior was attenuated in Ex-4 group; striatal tissue dopamine level increased in Ex-4 group	[125]
Ex-4	6-OHDA-treated rat model	Ex-4 (0.1 μg/kg) was given 5 weeks after the intracerebral toxin injection, BID for 21 days	Ex-4 promoted neurogenesis and normalized the imbalance in dopamine levels; Ex-4 also increased the dopaminergic neurons in substantia nigra	[111]
Ex-4	MPTP-treated mouse model	Ex-4 (20 nM, 0.25 μL/h) was given 7 days 2 hour before MPTP treatment via left ventricle administration	Ex-4 protected dopaminergic neurons, preserved dopamine levels and improved motor functions	[97]
Extended-release Ex-4 (PT302)	6-OHDA-treated rat model	Ex-4 (0.4 or 2 mg/kg) was given every 2 weeks for 10 weeks starting 16 days before the unilateral lesion induced by 6-OHDA	PT302 increased tyrosine hydroxylase levels in the lesioned substantia nigra and striatum; PT302 reduced the neurodegeneration of nigrostriatal dopaminergic neurons	[126]
Lixisenatide	MPTP-treated mouse model	Lixisenatide (10 nmol/kg) was given after the 7-day MPTP treatment, once a day for 14 days	Lixisenatide prevented MPTP-induced motor impairment, reduction in tyrosine hydroxylase levels in substantia nigra, and reduction in pro-apoptotic signaling	[127]

GLP1R agonist	Treatment details	Subjects	Study design	Primary outcome measures	Conclusions	Reference
Ex-4	Self-administer twice-daily subcutaneous injections of 5 µg for 1 month and 10 µg for 11 months	45 patients: moderate PD approximately 7.5 years since disease onset	Single-blind, placebo-controlled. 21-Ex-4 and 24-placebo	MDS-UPDRS and nonmotor tests at baseline, 6 months, 12 months, and 14 months	MDS-UPDRS scores in the Ex-4 treated group improved 2.7 points compared with 2.2 in the control group; motor and cognitive functions also improved in Ex-4 treated group	[108]
Ex-4	Once-weekly subcutaneous injections of 2 mg for 48 weeks	62 patients: moderate PD with DAergic treatment with wearing-off effects	Single-center, randomized, double-blind, placebo-controlled. 32-Ex-4 and 30-placebo.	MDS-UPDRS motor subscale (part 3)	Ex-4 significantly improved MDS-UPDRS scores of patients in the OFF time	[98]
Ex-4	2 mg of once weekly or placebo for 48 weeks followed by a 12-week washout period	60 patients: moderate PD; patients were receiving dopaminergic treatment	Single-center, randomized, double-blind, placebo-controlled. 31-Ex-4 and 29-placebo	MDS-UPDRS and serum were collected after 12-week withdrawal; insulin and PKB-related pathways were tested	Ex-4 treated group showed increased phospho-IRS1 and elevated expression of total AKT and phospho-mTOR; improvement of MDS-UPDRS was correlated to total and phospho-mTOR level	[113]