GLP-1 Signalling as a Therapeutic Avenue in Parkinson’s Disease: A Comprehensive Review

GLP-1 receptors (GLP-1Rs) are widely distributed throughout the brain, which underpins the diverse central effects of GLP-1 signalling. GLP-1Rs are expressed in regions relevant to PD, including the striatum and substantia nigra pars compacta (SNpc), specifically in dopaminergic neurons [13,14]. Moderate to low levels of GLP-1R expression have been detected in the hippocampus (CA1 region), cerebral cortex, thalamus, caudate nucleus, globus pallidus, and brainstem nuclei [7,15]. GLP-1Rs are also densely packed in the hypothalamus, specifically, in the supraoptic, paraventricular, and infundibular nuclei [16,17]. Notably, immunohistochemical studies confirm that tyrosine hydroxylase-positive neurons in the SNpc (the cells that degenerate in PD) do express GLP-1Rs [18]. In addition to neurons, GLP-1Rs are predominantly present on glial cells, including astrocytes and microglia [19]. This broad cellular distribution means that GLP-1R agonists could directly modulate neuronal activity as well as glial-mediated neuroinflammatory responses in the brain. Endogenous GLP-1 is produced by brainstem preproglucagon neurons (in the nucleus of the solitary tract) and can act centrally via volume transmission [16,17,18,19].

Peripherally administered GLP-1RAs (e.g., exenatide) have been shown to reach the brain parenchyma. Certain analogues penetrate the blood-brain barrier (BBB) more effectively; for instance, exendin-4 and its analogues display measurable brain uptake, whereas larger analogues like liraglutide and semaglutide cross more slowly or at lower levels in some models [7,20]. Therefore, the blood-to-brain influx rate of exedin-4 remains higher than the other GLP-1 agonists, reflecting differences in their chemical structures [20]. Non-acylated and non-PEGylated GLP-1 agonists, with a negative charge, utilize adsorptive transcytosis to effectively access brain tissue. In contrast, liraglutide's BBB penetration is limited due to acylation, which promotes oligomer formation, albumin binding, and sequestration within the capillary endothelium, thereby restricting its access and distribution to neural parenchyma [20]. Despite variable BBB permeability, the neuroprotective efficacy of different GLP-1RAs suggests that even those with limited direct brain uptake can exert central effects, possibly via circumventricular organs or indirect mechanisms (e.g., peripheral immune modulation) [7,21]. An example of this is semaglutide, whose elevated albumin affinity impairs BBB penetration. However, this property derives from its long aliphatic chain, enabling it to target GLP-1R-positive brain areas such as the brainstem, septal nucleus, and hypothalamus. Additionally, it affects central nervous system regions through tanycyte passage [22,23].

The presence of GLP-1Rs on vagal afferents and in the area postrema (AP), a circumventricular region located outside the BBB, provides a pathway for peripheral GLP-1 signals to influence the brain. To illustrate, neurons in the nucleus of the solitary tract (NTS) are thought to suppress ingestive behaviour through central GLP-1 production, triggered by vagal sensory information and gustatory input [14]. Furthermore, GLP-1 has an excitatory effect in AP neurons, also implied in food intake regulation [24,25].

Overall, the CNS distribution of GLP-1Rs provides a neuroanatomical basis for targeting this system in PD, with the potential to impact multiple brain regions involved in motor, cognitive, and autonomic aspects of the disease.

Neuroinflammation plays a pivotal role in PD progression, characterized by significant microglial activation, which leads to elevated levels of pro-inflammatory cytokines and reactive oxygen species in the nigrostriatal system. GLP-1 receptor agonists have demonstrated robust anti-inflammatory effects in the brain [26,27]. One key mechanism is the modulation of microglial activation states. GLP-1R activation suppresses the production of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α), interleukin-1β, and IL-6 by microglia [19]. This results in a shift from a neurotoxic inflammatory state to a more neuroprotective environment. Certainly, in preclinical models, GLP-1RAs prevented the transformation of astrocytes into the A1 neurotoxic phenotype that is induced by activated microglia [28]. For example, the GLP-1RA known as NLY01 (a pegylated exendin-4 derivative) was shown to directly block microglia-mediated conversion of astrocytes into A1 reactive astrocytes, thereby averting the release of neurotoxic factors and protecting neurons [29,30]. On top of that, in an α-synuclein preformed fibril model of sporadic PD, NLY01 not only inhibited astrocytes transformation but also preserved dopaminergic neurons and ameliorated associated behavioural deficits [28].

At the molecular level, GLP-1R stimulation can interfere with inflammatory signalling pathways. Elevated cAMP (from GLP-1R's G_s coupling) tends to inhibit NF-κB activation in immune cells, reducing the transcription of inflammatory genes [31]. GLP-1RAs have also been reported to inhibit Toll-like receptor (TLR)-induced inflammatory responses in the CNS [32], suggesting a broad dampening of innate immune activation. GLP-1R activation has demonstrated the ability to shift cytokine signalling toward an anti-inflammatory profile. This phenomenon was observed in a recent 2024 preclinical study, in which administration of GLP-1RAs led to a 38 ± 4.2% increase in plasma IL-10 levels. Concurrently, a significant reduction in pro-inflammatory cytokines, such as TNF-α and IL-6, was reported, showing a 42 ± 3.5% decrease compared to baseline values [32,33]. In parallel, upregulation of neurotrophic factors also contributes to inflammation resolution. Exedin-4 exemplifies this effect by promoting the expression of brain-derived neurotrophic factor (BDNF), a protein that facilitates synaptic regeneration and neuronal survival [34,35]. Furthermore, in PD animal studies, these anti-inflammatory effects correlate with reduced nigral neuron loss [3]. Liraglutide treatment in MPTP-lesioned mice, for instance, significantly attenuated microglial activation in the substantia nigra and lowered levels of inflammatory markers, accompanying improvements in motor function [36,37,38]. This finding highlights how GLP-1 signalling through multi-faceted immunomodulation counteracts the chronic neuroinflammation that contributes to dopaminergic neuron injury in PD.

Mitochondrial impairment is a central feature of PD pathology, contributing to energy failure and DA neuron death. GLP-1 receptor activation can improve mitochondrial function and biogenesis in stressed neurons. A prominent pathway involved is the PI3K/Akt signalling cascade, which GLP-1RAs trigger in neurons (often via insulin/IGF-1 signalling crosstalk). Activation of PI3K/Akt leads to downstream effects like enhanced activity of the master regulator of mitochondrial biogenesis, PGC-1α (peroxisome proliferator-activated receptor-γ coactivator 1α) [6]. Following GLP-1R activation, AKT is upregulated, resulting in reduced synthesis of pro-apoptotic proteins, such as BiM and FAS. Moreover, it has also been implicated in promoting cell survival by stimulating anti-apoptotic signalling pathways, primarily through elevated cAMP levels [8,39]. Studies show that GLP-1 treatment elevates levels of proteins involved in oxidative phosphorylation and mitochondrial dynamics (e.g., COX 5A, PGC-1α) [9,40]. In PD models, exendin-4 and dual incretin agonists were found to upregulate mitochondrial transcription factors such as NRF1 and SIRT1, promoting mitochondrial biogenesis and enhancing respiratory function [41].

GLP-1RAs also protect neurons from toxin-induced mitochondrial stress. In cellular models, exendin-4 pre-treatment protected dopaminergic cells from rotenone (a mitochondrial complex I inhibitor) by preserving mitochondrial membrane potential and preventing excessive mitochondrial fragmentation [9,42,43]. This was accompanied by an increase in markers of autophagy that clear damaged mitochondria (mitophagy), suggesting GLP-1R stimulation helps remove dysfunctional mitochondria and maintain healthy populations [44]. In vivo, GLP-1 analogues have been shown to restore levels of mitochondrial enzymes in PD models. For example, in MPTP-treated mice, drugs like liraglutide normalized complex I activity and ATP levels in nigral neurons [38].

A 2024 study reported that another GLP-1RA, PT320, delays disease progression in a MitoPark mouse model of PD. PT320 demonstrated promising therapeutic potential, exerting neuroprotective effects by preserving mitochondrial function and ultrastructure [45,46]. Notably, early administration of PT320 preserved mitochondrial integrity by regulating the expression of Opa1, which prevents cytochrome c release via cristae remodelling, and Fis1, a key mediator of mitochondrial fission. These molecular effects maintained mitochondrial homeostasis. Other studies have evidenced its protective role by delaying dopaminergic degeneration, improving striatal dopamine release and reuptake, and enhancing spontaneous motor behaviour in a mouse model of early PD [45,46]. MPTP and oxidative stress exposure induce mitochondrial dysfunction, including morphology changes, such as fragmentation, which result in aberrant ultrastructure and apoptosis via caspase activation. This effect is reversed by the administration of incretin agonists, leading to a more uniform and reduced mitochondrial size [9]. These effects collectively suggest that GLP-1 signalling boosts the energetic capacity of neurons and fortifies them against the mitochondrial toxins and oxidative insults that drive PD neurodegeneration.

Oxidative stress, arising from excess reactive oxygen species (ROS) and impaired antioxidant defences, contributes to the degeneration of dopaminergic neurons in PD. GLP-1R agonists have demonstrated potent antioxidative effects in the CNS [3,5,6]. One mechanism is through upregulating endogenous antioxidant enzymes. GLP-1 signalling activates pathways (such as cAMP/PKA and Nrf2) that boost the expression of antioxidant proteins like superoxide dismutase (SOD), catalase, and glutathione peroxidase [47]. In PD model systems, treatment with GLP-1 analogues reduced markers of oxidative damage. For instance, mice receiving semaglutide or liraglutide after chronic MPTP exposure showed significantly lower levels of lipid peroxidation (malondialdehyde) and protein carbonylation in the brain compared to untreated PD controls [36,44,48]. This indicates mitigation of ROS-induced cellular injury.

Another way GLP-1R activation combats oxidative stress is by improving mitochondrial efficiency (as discussed above), thereby reducing the overproduction of ROS from dysfunctional mitochondria. GLP-1RAs also indirectly reduce oxidative stress by attenuating neuroinflammation; activated immune cells produce ROS and nitric oxide, so dampening microglial activation via GLP-1 can decrease this source of oxidative molecules [40,46,49].

Exendin-4 has been shown to reduce oxidative stress, suppress inflammatory mediators, and modulate the activation of MAPK family kinases, including JNK and p38 MAPK [50]. In addition, it increases glutathione and magnesium superoxide dismutase levels and decreases the expression of pro-apoptotic marker, BAX [42,51]. Combined, these actions protect neurons from oxidative damage. Furthermore, in a mouse model of cerebral ischemia-reperfusion, administration of exendin-4 reduced oxidative DNA damage in brain cells, as indicated by decreased 8-hydroxy-2-deoxyguanosine (a biomarker of oxidative DNA damage) and HHE levels (a major product of lipid peroxidation) [52,53,54]. By bolstering antioxidant responses and limiting ROS generation, GLP-1RAs create a more redox-stable environment for vulnerable neurons in PD.

Protecting the survival of dopaminergic neurons in the substantia nigra is a primary goal for disease-modifying PD therapy. GLP-1 receptor stimulation has repeatedly been shown to enhance dopaminergic neuron survival in both toxin and genetic models of PD, partly by maintaining spontaneous firing activity and supporting neuronal function [55]. In a preclinical experimental study, 6 out of 12 neurons were excited by exendin-4, showing a marked rise in firing rate from 2.48 ± 0.29 Hz to 3.61 ± 0.45 Hz [18]. Conversely, when the same neuronal population was exposed simultaneously to exendin, a GLP-1R antagonist, and exendin-4, no significant changes in firing activity were observed. These findings highlight the ability of GLP-1 to increase neuronal excitability in the substantia nigra, contributing to the production of its possible anti-Parkinsonian effects [18]. Furthermore, in rodent studies, systemic administration of GLP-1RAs (exendin-4, liraglutide, etc.) preserved the number of tyrosine hydroxylase (TH)-positive neurons in the SNpc following neurotoxic insults [36]. For example, in a classic 6-hydroxydopamine (6-OHDA) lesioned rat model, exendin-4 treatment attenuated the loss of nigral dopaminergic neurons and maintained striatal dopamine levels, correlating with improved motor function [56]. Similarly, in studies with MPTP-treated mice, once-weekly semaglutide produced greater restoration of nigral TH levels and protection of dopaminergic cell bodies than once-daily liraglutide, demonstrating superior efficacy [5,23]. These interventions also normalized dopamine turnover and receptor expression in the basal ganglia, suggesting preservation of functional dopaminergic transmission.

Mechanistically, GLP-1R activation engages intracellular survival pathways that counteract pro-death signals in neurons. A major pathway is the PI3K/Akt axis, which promotes cell survival; GLP-1RAs strongly activate Akt in dopaminergic neurons, leading to phosphorylation and inactivation of pro-apoptotic factors like glycogen synthase kinase-3β and the Bcl-2-associated death promoter (BAD) [41]. Akt activation also upregulates the expression of anti-apoptotic Bcl-2 family proteins, creating a cell survival bias [57]. Certainly, in models of PD, GLP-1RAs reduced neuronal apoptosis, as evidenced by decreased caspase-3 activation and fewer TUNEL-positive cells in the substantia nigra [13,58]. Another protective mechanism is via neurotrophic support; GLP-1R signalling can induce brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) expression in the brain [59]. Notably, semaglutide increases GDNF levels in the SN and striatum of MPTP mice, which likely contributed to the rescue of dopaminergic neurons [44]. Enhanced trophic support promotes neuronal resilience under stress and may facilitate endogenous repair mechanisms.

Emerging evidence indicates that GLP-1RAs can also stimulate neurogenesis and may support the recruitment of new dopaminergic neurons. Some studies have reported that GLP-1 treatment increases the proliferation of neural progenitors and directs their differentiation towards a dopaminergic lineage [34]. Consistently, a preclinical, in vitro and in vivo experimental study, utilizing SOD1-G93A transgenic ALS mouse model and motor neuron-like cells (NCS-19), respectively, has shown that exendin-4 treatment results in reduced oxidative intracellular stress markers, improved cell survival, and preserved mitochondrial activity, suggesting metabolic stabilization [60]. Likewise, its histological analysis demonstrated that this GLP-1 agonist maintained phenotypic identity and cholinergic function of surviving neurons; preservation of ChAT levels correlates with better neuronal integrity, reduced apoptosis, and decreased glial activity [60].

Conversely, in another preclinical study, also using exendin-4 as a therapeutic alternative for PD, employing an MPTP-induced Parkinson's disease mouse model found that systemic exendin-4 robustly protected striatal dopaminergic terminals, suppressed microglial activations, preventing inflammatory morphological changes, and inhibited both cytokines at the protein and mRNA level [61].

Therefore, exendin-4 has been shown to protect dopaminergic and cholinergic neurons through overlapping mechanisms involving cAMP/PKA, PI3K/Akt, MAPK/ERK, anti-inflammatory signaling, and cellular protection, benefits that could potentially make this treatment an option for becoming a multi-target disease-modifying treatment in neurodegeneration.

Additionally, in a primary rodent neural model, GLP-1R intervention notably enhanced the proliferative potential of murine neural stem cells, suggesting that the PI3K/AKT signalling pathway promotes neuronal differentiation via the regulation of protein structural integrity and the induction of transcription of the proneural factor Achaete-scute homolog 1 (Ascl1) [41]. Ascl1 promotes neuronal differentiation of neural progenitor cells by activating target genes and driving cell cycle exit. In addition, experimental studies have shown that Ascl1 acts as a dominant factor in the transdifferentiation of non-neuronal cells, such as fibroblasts, into neurons [62].

Through these converging mechanisms (anti-apoptotic signalling, metabolic support, anti-inflammatory effects, neurogenesis promotion, and neurotrophic factor induction), GLP-1R agonists provide several pro-survival benefits for dopaminergic neurons. The net result in animal models is reduced dopaminergic cell loss and sustained motor function. These multifaceted neuroprotective effects underpin the potential of GLP-1-based therapies to slow or even halt the progression of PD in patients, particularly if administered early in the neurodegenerative process.

Beyond preserving neurons, GLP-1 signalling may improve synaptic plasticity and function, which is relevant to both motor and cognitive symptoms of PD. GLP-1Rs in the brain are known to modulate synaptic transmission and memory processes. The upregulation of neurotrophic tyrosine kinase receptor type 2 and mTOR genes, both of which play key roles in managing synaptic plasticity, has been identified after administering lixisenatide for 40 days in mice with cognitive impairment [10]. In PD contexts, GLP-1R agonists have been found to protect synapses from degeneration and to promote the formation of new synaptic connections (synaptogenesis) [63]. One underlying mechanism involves the cAMP/PKA pathway; activation of GLP-1Rs increases intracellular cAMP, which in turn activates protein kinase A (PKA). PKA can phosphorylate glutamate AMPA receptor subunits (e.g., GluR1 at Ser⁸⁴⁵), facilitating their insertion into synapses and thereby strengthening synaptic currents and long-term potentiation (LTP) [13,18,63]. Indeed, studies in Alzheimer's models (which are translatable to PD cognitive impairment) showed that GLP-1 analogues prevented oligomeric Aβ-induced loss of synaptic proteins in a PKA-dependent manner, effectively preserving LTP [13,18]. In PD models, exendin-4 has similarly been reported to restore synaptic marker proteins that were reduced by α-synuclein pathology or oxidative stress, suggesting stabilization of synaptic integrity [64].

GLP-1R activation also directly supports neurite outgrowth and synapse formation. In neuronal cultures (PC12 and SH-SY5Y cells), GLP-1 analogues induced robust neurite branching and extension, an effect that requires cytoskeletal reorganization via actin/tubulin polymerization [65,66]. This pro-neuritogenic effect implies that GLP-1 signalling can help re-establish circuit connections or compensate for lost innervation in the brain. Furthermore, by reducing neuroinflammation and oxidative damage, GLP-1RAs create conditions where synapses are less likely to be dismantled [13,67].

Behaviourally, these synaptic benefits translate into improved cognitive outcomes in experimental models. PD patients often have cognitive deficits, and interestingly, the initial open-label exenatide trial reported improved performance on the Mattis Dementia Rating Scale in treated patients compared with controls [5,12]. While that was a small sample, it aligns with preclinical findings that GLP-1R stimulation enhances hippocampal synaptic plasticity and memory [68]. For example, GLP-1R knockout mice have shown impaired LTP and memory formation, whereas GLP-1RAs enhance memory in toxin-induced parkinsonian mice (possibly via effects on the hippocampus and cortex). Overall, GLP-1RAs appear to not only safeguard existing synapses from PD-related insults but also promote adaptive plasticity, which could ameliorate both motor learning and cognitive function [68,69].

Impaired proteostasis, including the accumulation of misfolded α-synuclein, is a hallmark of PD. Autophagy is the cell's waste clearance system that helps remove protein aggregates and damaged organelles [70]. GLP-1 signalling has been implicated in modulating autophagy in beneficial ways for PD. An in vitro experimental study demonstrated that semaglutide exerts neuroprotective effects against 6-OHDA-induced toxicity in human SH-SY5Y neuronal cells by enhancing autophagy, as evidenced by elevated levels of key autophagy markers such as LC3-II/LC3-1, beclin1 and Atg7, along with reduced p62 concentration, a protein that accumulates when autophagy is impaired [48]. GLP-1R activation can enhance autophagic flux to clear toxic proteins while preventing excessive or dysregulated autophagy that might harm cells [9,71]. In a neuronal model of PD, exendin-4 improved autophagy markers and cell survival under rotenone-induced stress, suggesting that GLP-1R stimulation facilitates the clearance of dysfunctional mitochondria and protein aggregates caused by the toxin [43]. Concurrently, by boosting cellular energetic status and mTOR signalling, GLP-1 may avert the maladaptive overactivation of autophagy that can lead to cell death. Indeed, a study reported that a GLP-1 mimetic prevented an "aberrant enhancement of autophagy/mitophagy" in neurons under oxidative stress, thereby protecting axons from degeneration [71]. In vivo evidence reinforces the potential of GLP-1RAs to promote the removal of pathological protein accumulations; in particular, semaglutide-treated MPTP mice have shown reduced α-synuclein accumulation in the brain compared to untreated parkinsonian mice [44]. Similarly, liraglutide decreased the aggregation of toxic proteins in these models [9,36].

These outcomes suggest that GLP-1R activation enhances the efficiency of autophagic clearance of α-synuclein and potentially other cargo, such as dysfunctional mitochondria, in that way reducing the burden of proteinopathy in PD [9,36]. The latter is illustrated in a study that measured the mitochondrial inner membrane (MIM) fusion protein OPA1, which was initially reduced in the MTPT group but was upregulated following GLP-1RA administration. In contrast, the outer membrane (MOM) fusion proteins MFN1 and MFN2 were elevated in the exposed group and decreased after treatment. Although all three proteins contribute to mitochondrial fusion, their differential regulation suggests that complex I inhibition induces an imbalance in the fusion-triggered process, which is partially restored by the GLP-1RA intervention [9,46]. GLP-1RAs might exert these effects via AMPK activation (a known inducer of autophagy) as well as through transcriptional upregulation of autophagy-related genes [72,73]. By fine-tuning the autophagy process, GLP-1RAs can contribute to proteostasis maintenance, which reduces stress on the endoplasmic reticulum and proteasome systems in dopaminergic neurons, ultimately contributing to their survival [74]. Autophagy is a double-edged sword in PD, but GLP-1 seems to tilt it toward neuroprotection rather than neurodegeneration.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the precursor of dopamine and is the most used medication for PD, at the moment [45]. Nevertheless, chronic administration of L-DOPA in PD patients is habitually associated with the presence of involuntary movements (AIMS), also called levodopa-induced dyskinesia. Certainly, early clinical studies showed that about 20–50% of L-DOPA-medicated patients experience dyskinesia within 5 years after initiating its treatment; the severity of the symptoms correlates with the length of its usage [75,76,77]. DA agonists can overstimulate dopamine receptors in both the direct and indirect striatopallidal pathways in the lesioned brain. Consequently, this is thought to lead to reduced neuronal firing in the subthalamic nucleus and internal globus pallidus, resulting in increased involuntary movements [75,76,77].

6-OHDA rat models are widely used to examine AIMs. The injection of 6-hydroxydopamine causes the loss of dopaminergic neurons, resulting in unilateral DA depletion in the striatum. In order to assess dyskinesia, rats are observed over a period at regular intervals following L-DOPA administration [75,76,77]. Three subtypes of AIMs are typically determined: random uncontrollable movement of the forelimb contralateral to the lesion, excessive jaw movements, and dystonic postures or choreiform twisting of the neck and upper body [75,76,77]. The ALO score represents the cumulative dyskinesia severity, typically from 1 (present for less than 30 s) to 4 (present throughout a minute and not suppressible). Favorably, these types of experimental studies have been crucial for testing neuroprotective agents. For instance, 3-week co-administration of PT320, a sustained-release formulation of exendin-4, was shown to notably decrease the AIM scores for ALO (p = 0.031), limb (p = 0.036), and orolingual (p = 0.008) movements [45]. This study represents the general neuroprotective mechanisms of GLP-1RAS, which involve activating the PI3K/Akt pathway, so it modulates PD disruption by enhancing synapse formation and autophagy while inhibiting the accumulation of alpha-synuclein [45]. These mechanisms are relevant since LID may involve disrupted signaling with the basal ganglia circuits.

Exenatide is the synthetic form of exendin-4 derived from Gila monster venom and was the first GLP-1RA tested in PD patients [77]. In rodent PD models (MPTP, 6-OHDA), exenatide demonstrated neuroprotective effects, preserving dopaminergic neurons and improving motor behaviour [98]. A landmark open-label trial in PD patients with moderate disease found that 12 months of exenatide (Byetta^®, twice daily) led to significant improvements in motor and cognitive scores compared to controls, with benefits persisting 3 months post-treatment, suggesting potential disease-modifying effects [99]. A subsequent Phase II randomized controlled trial involving 60 patients, using once-weekly exenatide (Bydureon^®) for 48 weeks, confirmed a relative improvement in off-medication motor scores (MDS-UPDRS part III) in the exenatide group, maintained even 12 weeks after cessation [5,93]. However, a Phase III trial conducted in 2020–2022, with 194 participants subjected to 2 years of treatment (2 mg of exenatide, once weekly), showed that both the placebo and exenatide groups presented worsening MDS-UPDRS part 3 scores at all timepoints [94]. The results of this last trial tempered early optimism, suggesting that exenatide's benefits might be modest or limited to certain subgroups. Nonetheless, exenatide remains the prototypical GLP-1RA in PD research, demonstrating feasibility and some clinical signals of therapeutic effect in animal models. More studies, with larger samples and robust methodology, are required to properly elucidate its therapeutic potential in PD patients.

Liraglutide is a long-acting GLP-1RA (once-daily human GLP-1 analog). It has strong preclinical support, showing protection of dopaminergic neurons and reduced neuroinflammation in MPTP and rotenone rodent models, with evidence of improved motor function and reduced α-synuclein aggregation [36,38]. Liraglutide has also readily improved cognitive function in animals [12,100]. Clinically, a Phase II trial in PD patients has been conducted and registered in clinicaltrials.gov (ID: NCT02953665); however, no official publication has been found and only a pre-print with the results is available (https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4212371↗, accessed on 6 December 2025).

The study utilized three specific primary endpoints to assess motor, non-motor, and cognitive function changes from baseline at 28 and 54 weeks. Most of the outcomes presented did not significantly differ between the liraglutide and placebo groups. There was no therapeutic advantage on either motor or cognitive outcomes. Although the liraglutide group showed a modest 2.6-point improvement in the MDS-UPDRS part III motor scores, this was offset by a larger 5.0-point improvement in the other group, highlighting a more likely pronounced placebo response than any true drug effect. Similarly, MDRS-2 scores were no different between the study groups.

In the same way, many secondary and exploratory measures also failed to show a more visible advantage for liraglutide. Baseline metabolic markers did not predict treatment response, indicating that although liraglutide produced important reductions in BMI and HbA1c, these metabolic improvements did not translate into observable clinical benefits. Differently, there were a few positive findings, like a 6.6-point improvement of NMSS scores in the liraglutide group and a 6.5-point decrease in the placebo group. Despite the lack of clinical studies, liraglutide's ability to improve both metabolic and neurologic parameters makes it an intriguing candidate [5,38]. Further larger trials are needed to confirm its efficacy.

Lixisenatide is a shorter-acting GLP-1RA, administered as a once-daily injection. Preclinical studies have demonstrated its ability to cross the BBB and exert neuroprotective effects [101]. In the Phase II randomized, double-blind "LIXIPARK" trial, 156 patients with early PD (≤3 years from diagnosis) received lixisenatide or placebo for 12 months [83]. Motor progression was measured by the change in the MDS-UPDRS Part III scores, which at baseline were approximately 15 in both groups. The lixisenatide group's motor symptoms essentially stabilized, whereas the placebo group's motor scores worsened; scores had changed by −0.04 points in the Lixisenatide group and +3.04 points in the placebo group, indicating imminent progression [83]. Even after a 2-month washout, patients previously on lixisenatide had better motor function than those who never received it. These results suggest lixisenatide might slow clinical decline in early-stage PD [95]. Lixisenatide also appeared to preserve brain cells, as inferred from stable dopamine imaging in exploratory endpoints. Notably, GI side effects were common, such as nausea in 46% of patients; however, this trial provides a proof of concept that a GLP-1RA can slow PD motor progression and that larger Phase III trials will be needed to verify disease modification and long-term results.

Semaglutide is a potent, long-acting GLP-1RA available as a weekly injection (Ozempic^®) or as an oral formulation. Its higher molecular weight gives it a longer half-life but somewhat lower BBB penetration than exenatide; despite this, semaglutide has shown efficacy in animal models. In a chronic MPTP mouse model, semaglutide not only improved motor performance but also reduced nigral α-synuclein accumulation, lowered oxidative stress markers, and increased dopaminergic neuron survival. In many of these measures, semaglutide performed as well as or better than liraglutide [44]. These findings position semaglutide as a very promising agent for PD. Additional studies report modulation of apoptotic and autophagy-related pathways; semaglutide effectively restored Bcl-2 levels, which were previously reduced by MTPT exposure, and decreased Bax levels [23]. While both drugs, semaglutide and liraglutide, partially lowered the Bax/Bcl2 ratio by increasing Bcl2 and reducing Bax expression significantly (p < 0.001), semaglutide demonstrated to have superior anti-apoptotic efficacy; it could also rescue autophagy impairments seen through a higher expression of beclin1, Atg7, LC3, and P62 in the substantia nigra [23]. Clinically, a Phase II trial (NCT03659682) is enrolling patients to receive weekly semaglutide for up to 2 years, with primary motor outcomes evaluated and possibly exploratory neuroimaging biomarkers [97]. As of 2025, no published clinical results are available yet for semaglutide in PD. However, given its strong glycaemic control profile and neuroprotective preclinical data, semaglutide is anticipated to be a relevant player in upcoming PD trials. One advantage is its convenient dosing schedule (once-weekly injection) and the availability of an oral formulation, which could improve long-term adherence in the PD population.

The dual agonist DA5-CH and NLY01, a pegylated formulation of exenatide, have each shown superior neuroprotective effects in PD models.

Nevertheless, the current development status of DA5-CH remains at the preclinical stage. It has been extensively studied in various animal models, including the MPTP mouse model and the 6-OHDA lesion rat model. Both investigations aimed to evaluate its effects on motor impairments, inflammation, dopamine synthesis, and alpha-synuclein levels [59,102].

In contrast, a Phase II clinical trial determined that by week 36, NLY01 showed no difference from placebo in MDS-UPDRS parts II and III scores: −0.39 (95% CI −2.96 to 2.18, p = 0.77) for 2.5 mg and 0.36 (−2.28 to 3.00, p = 0.79) for 5.0 mg [29].

In a comparative study, one-way ANOVA analysis revealed that DA5-CH managed to recover 79.61% of TH-positive cells, which had been significantly reduced to 39.65% in the MPTP group. In contrast, NLY01 only rescued 48.62% of the cells [59].

Additionally, DA5-CH was shown to inhibit the TLR4/TNF-α-mediated inflammatory pathway more effectively than NLY01. While MPTP elevated the expression of TLR4, NF-kB, and TNF-α, DA5-CH downregulated all three markers, whereas NLY01 only reduced NF-kB and TNF-α, not TLR. In general terms, this demonstrated that the novel dual GLP-1/GIP receptor agonist DA5-CH had a much better performance than NLY01 [59]. Additionally, another dual incretin receptor agonist, tirzepatide, is routinely included in preclinical pharmacokinetic studies to determine its promise as a therapeutic for neurodegenerative diseases. It has been associated with a substantial decrease in the BAX/Bxl-2 ratio, supporting neuronal survival; likewise, histological analysis showed that it protected tyrosine hydroxylase-positive neurons, maintaining the integrity of the nigrostriatal dopaminergic pathway [103]. The treatment not only led to significant behavioral improvements but also attenuated neuroinflammation in a rotenone-induced rat model of Parkinson's disease [104]. Overall, the studies suggest that tirzepatide has disease-modifying potential, although no clinical trials yet confirm these effects. Even so, the study on brain uptake pharmacokinetics showed that tirzepatide has poor BBB penetration, especially in the first hour, implying that it is not efficiently transported into the brain. This limitation may be considered a challenge to its effectiveness in treating central diseases like PD [105].

Other potential agents are dipeptidyl peptidase-4 (DPP-4) inhibitors; DPP-4 is an enzyme that primarily inactivates incretin hormones like GLP-1 and GIP, which are involved in regulating insulin secretion and blood glucose levels. DPP-4 inhibitors boost endogenous GLP-1 and could be another potential treatment avenue, with supporting epidemiological evidence of reducing PD risk [4]. A longitudinal population study included 329 patients diagnosed with PD with a median follow-up of 3.33 years; the incidence of PD was 5 per 10,000 person-years in 36,897 patients using DPP4 inhibitors and 4 per 10,000 person-years in 10,684 using GLP-1 agonists. Interestingly, they reported an important inverse association between use of DPP4 inhibitors and GLP-1 agonists and the onset of PD, with an adjusted incidence rate ratio of 0.64 (95% CI, 0.43–0.88; p < 0.01) for DPP-4 inhibitors [4]. Another preclinical study of DPP4 inhibitors, also known as gliptins (sitagliptin and PF-00734,200), that used the 6-OHDA rat model of PD revealed several beneficial findings, such as dopaminergic cell preservation and DA level protection [106]. Delayed oral treatment with a higher dose of sitagliptin increased dopamine levels in both the lesioned striatum and SNc; similarly, it also augmented neurogenesis and increased BrdU labelling (a marker of cell proliferation/DNA synthesis) in the lesioned striatum [106]. This suggests that they may enhance the migration of NPCs (neuronal progenitor cells) to the lesioned striatum. Despite the remarkable benefits found, the study also highlighted some limitations. For a start, it has been proven that sitagliptin has a low brain access rate (brain/plasma total ratio of 0.07), likely due to it being a substrate for the P-glycoprotein efflux transporter at the cerebral microvasculature. In contrast, PF-00734,200 showed a higher concentration in the rat brain (brain/plasma total ratio of 0.62) [106]. However, there is an efficacy disparity since sitagliptin treatment was more potent than PF-00734,200 in rescuing dopaminergic neurons and protecting against dopamine loss [106]. Another constraint detected is that although gliptins increased BrdU labelling, the newly proliferating cells did not express TH (a marker for dopaminergic neurons), a fact that requires further investigation. Clinical studies need to be performed to properly ascertain their treatment potential.

The dosage and evaluation of the neuroprotective effects of GLP-1RAs in PD are based on extrapolation of the efficacy observed in preclinical models and on standardized dosage guidelines for type 2 diabetes mellitus (T2DM) [107,108]. Exenatide, using a subcutaneous dose of 2 mg, identical to the licensed dose for T2DM, has demonstrated its ability to cross the BBB and be detectable in cerebrospinal fluid at concentrations similar to those associated with beneficial outcomes in preclinical models [5,93,94,99]. In a randomized, double-blind, placebo-controlled trial, weekly exenatide showed a significant advantage in the primary outcome: the adjusted difference in the motor subscale (part III) of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Furthermore, a previous 12-month study also reported an improvement in the MDS-UPDRS of 2.7 points in patients treated with exenatide, compared with a decline of 2.2 points in controls. These findings demonstrate an initial advantage by not requiring a modification of the licensed dose to achieve central access and motor efficacy in PD [5,93,94,99].

The interest in exenatide lies precisely in its favorable pharmacokinetics, as a non-acylated molecule, it has a higher and more efficient rate of penetration of the BBB than its analogues such as semaglutide, evaluated in trials using its licensed doses of 0.5–2 mg weekly (subcutaneous, Ozempic) or 3–14 mg daily (oral, Rybelsus) or liraglutide; both are acylated analogues and their structure gives them a high affinity for albumin and strong plasma protein binding, which significantly restricts their distribution and effective concentration in the central nervous system [109]. Nevertheless, in the randomized, double-blind, placebo-controlled trial of Liraglutide, administered at doses of 1.2 mg or 1.8 mg per day, the primary endpoint was measured by the adjusted difference in the MDS-UPDRS motor scale in the OFF-state, despite the limitations of its central penetration [96,110].

The advantage of exenatide in terms of access to the central nervous system highlights its relevance as a GLP-1RA initially more suitable for PD research. However, the limitations observed with its acylated analogues reinforce the importance of overcoming the pharmacokinetic obstacle for the future of this therapeutic line. For the activation of GLP-1 receptors translatable into the desired effects (improve mitochondrial function, reduce neuroinflammation, and neuronal survival), dosage optimization or molecular modifications are required to allow more efficient passage of the BBB. Thereby, achieving higher concentrations and a direct neuronal effect with the aim of converting neuroprotective promise into tangible clinical benefit in PD.

A consolidated overview of the principal preclinical studies evaluating GLP-1 receptor agonists in Parkinson's disease models, including mechanistic findings, experimental systems, dose considerations, and translational relevance, is provided in Table 2.