Pharmacological inhibition of α-synuclein aggregation within liquid condensates.

Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson's disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for drug discovery for Parkinson's disease, which is otherwise still incurable. Here we show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules. We report that the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein aggregation within the condensates both in vitro and in a Caenorhabditis elegans model of Parkinson's disease. By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders.

Tau- and α-synuclein-targeted gold nanoparticles: applications, opportunities, and future outlooks in the diagnosis and therapy of neurodegenerative diseases.

The use of nanomaterials in medicine offers multiple opportunities to address neurodegenerative disorders such as Alzheimer's and Parkinson's disease. These diseases are a significant burden for society and the health system, affecting millions of people worldwide without sensitive and selective diagnostic methodologies or effective treatments to stop their progression. In this sense, the use of gold nanoparticles is a promising tool due to their unique properties at the nanometric level. They can be functionalized with specific molecules to selectively target pathological proteins such as Tau and α-synuclein for Alzheimer's and Parkinson's disease, respectively. Additionally, these proteins are used as diagnostic biomarkers, wherein gold nanoparticles play a key role in enhancing their signal, even at the low concentrations present in biological samples such as blood or cerebrospinal fluid, thus enabling an early and accurate diagnosis. On the other hand, gold nanoparticles act as drug delivery platforms, bringing therapeutic agents directly into the brain, improving treatment efficiency and precision, and reducing side effects in healthy tissues. However, despite the exciting potential of gold nanoparticles, it is crucial to address the challenges and issues associated with their use in the medical field before they can be widely applied in clinical settings. It is critical to ensure the safety and biocompatibility of these nanomaterials in the context of the central nervous system. Therefore, rigorous preclinical and clinical studies are needed to assess the efficacy and feasibility of these strategies in patients. Since there is scarce and sometimes contradictory literature about their use in this context, the main aim of this review is to discuss and analyze the current state-of-the-art of gold nanoparticles in relation to delivery, diagnosis, and therapy for Alzheimer's and Parkinson's disease, as well as recent research about their use in preclinical, clinical, and emerging research areas.

Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients.

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.

Use of antiviral drugs and incidence of Parkinson's disease in Taiwan.

Patients infected with herpes zoster might be at risk for Parkinson's disease (PD). However, antiviral drugs may impede viral deoxyribonucleic acid (DNA) synthesis. This study aimed to determine whether the currently observed association between herpes zoster and PD is consistent with previous findings, and whether antiviral drug use is associated with PD. This retrospective cohort study used the Longitudinal Generation Tracking Database. We included patients aged 40 years and above and applied propensity score matching at 1:1 ratio for study comparability. PD risk was evaluated using Cox proportional hazards regression methods. A total of 234,730 people were analyzed. The adjusted hazard ratio (aHR) for PD in patients with herpes zoster was 1.05. Furthermore, the overall incidence of PD was lower in those treated with antiviral drugs than in the untreated ones (3.17 vs. 3.76 per 1,000 person-years); the aHR was 0.84. After stratifying for sex or age, a similar result was observed. In conclusion, herpes zoster may increase the risk of PD, particularly among females, but receiving antiviral treatment reduces the risk by 16%. Therefore, using antiviral drugs may help prevent PD. However, additional research is required to determine the underlying mechanism(s).

Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation.

BACKGROUND: To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients. METHODS: This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson's Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([18F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson's Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire. DISCUSSION: Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease. TRIAL REGISTRATION: NCT05830396. Registration date: March 20, 2023.

Impaired sequence manipulation in non-demented patients with progressive supranuclear palsy.

PURPOSE: Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or Parkinson's disease (PD) perform poorly in tests that require the flexible arrangement of thoughts or actions. This study investigated whether sequential working memory is differently impaired in patients with PSP versus PD. METHOD: Twenty-nine patients with PSP Richardson's syndrome (PSP-RS), 36 patients with PD, and 36 healthy controls (HC) completed 3 well-established neuropsychological tests, including digit span forward (DST-F), digit span backward (DST-B), and adaptive digit ordering tests (DOT-A). The DST-F required maintaining digit sequences, and the DST-B and DOT-A required maintaining and manipulating digit sequences. FINDING: The PSP-RS group scored lower than the PD and HC groups in the DST-B and DOT-A but not in the DST-F, indicating that the ability to manipulate sequences was impaired, but the maintenance ability was preserved in PSP-RS patients. Moreover, in PSP-RS, the DST-B score negatively correlated with the severity of motor symptoms. The actual levodopa dose positively correlated with the DST-B ordering cost (DST-F score vs. DST-B score). The PSP patients who took a greater dose of levodopa tended to have higher DST-B ordering cost. There was no effect of levodopa on DST-B or DOT-A in PD. CONCLUSION: These results suggested that the ability to manipulate sequence was already reduced in patients with PSP-RS and was worse than in patients with PD.

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson's Disease.

Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.

Function and Mechanism of Abscisic Acid on Microglia-Induced Neuroinflammation in Parkinson's Disease.

Parkinson's disease (PD), as a neurologically implemented disease with complex etiological factors, has a complex and variable pathogenesis. Accompanying further research, neuroinflammation has been found to be one of the possible factors in its pathogenesis. Microglia, as intrinsic immune cells in the brain, play an important role in maintaining microenvironmental homeostasis in the brain. However, over-activation of neurotoxic microglia in PD promotes neuroinflammation, which further increases dopaminergic (DA) neuronal damage and exacerbates the disease process. Therefore, targeting and regulating the functional state of microglia is expected to be a potential avenue for PD treatment. In addition, plant extracts have shown great potential in the treatment of neurodegenerative disorders due to their abundant resources, mild effects, and the presence of multiple active ingredients. However, it is worth noting that some natural products have certain toxic side effects, so it is necessary to pay attention to distinguish medicinal ingredients and usage and dosage when using to avoid aggravating the progression of diseases. In this review, the roles of microglia with different functional states in PD and the related pathways inducing microglia to transform into neuroprotective states are described. At the same time, it is discussed that abscisic acid (ABA) may regulate the polarization of microglia by targeting them, promote their transformation into neuroprotective state, reduce the neuroinflammatory response in PD, and provide a new idea for the treatment of PD and the selection of drugs.

Role of Bioactives in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) affect millions worldwide, with the two most prevalent being Alzheimer's and Parkinson disease [...].

Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson's Disease.

The accumulation of misfolded and aggregated α-synuclein can trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to apoptotic cell death in patients with Parkinson's disease (PD). As the major ER chaperone, glucose-regulated protein 78 (GRP78/BiP/HSPA5) plays a key role in UPR regulation. GRP78 overexpression can modulate the UPR, block apoptosis, and promote the survival of nigral dopamine neurons in a rat model of α-synuclein pathology. Here, we explore the therapeutic potential of intranasal exogenous GRP78 for preventing or slowing PD-like neurodegeneration in a lactacystin-induced rat model. We show that intranasally-administered GRP78 rapidly enters the substantia nigra pars compacta (SNpc) and other afflicted brain regions. It is then internalized by neurons and microglia, preventing the development of the neurodegenerative process in the nigrostriatal system. Lactacystin-induced disturbances, such as the abnormal accumulation of phosphorylated pS129-α-synuclein and activation of the pro-apoptotic GRP78/PERK/eIF2α/CHOP/caspase-3,9 signaling pathway of the UPR, are substantially reversed upon GRP78 administration. Moreover, exogenous GRP78 inhibits both microglia activation and the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in model animals. The neuroprotective and anti-inflammatory potential of exogenous GRP78 may inform the development of effective therapeutic agents for PD and other synucleinopathies.

Ser9p-GSK3ß Modulation Contributes to the Protective Effects of Vitamin C in Neuroinflammation.

BACKGROUND: The prolonged activation of microglia and excessive production of pro-inflammatory cytokines can lead to chronic neuroinflammation, which is an important pathological feature of Parkinson's disease (PD). We have previously reported the protective effect of Vitamin C (Vit C) on a mouse model of PD. However, its effect on microglial functions in neuroinflammation remains to be clarified. Glycogen synthase kinase 3ß (GSK3ß) is a serine/threonine kinase having a role in driving inflammatory responses, making GSK3ß inhibitors a promising target for anti-inflammatory research. METHODS: In this study, we investigated the possible involvement of GSK3ß in Vit C neuroprotective effects by using a well-known 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and a cellular model of neuroinflammation, represented by Lipopolysaccharide (LPS)-activated BV-2 microglial cells. RESULTS: We demonstrated the ability of Vit C to decrease the expression of different mediators involved in the inflammatory responses, such as TLR4, p-IKBα, and the phosphorylated forms of p38 and AKT. In addition, we demonstrated for the first time that Vit C promotes the GSK3ß inhibition by stimulating its phosphorylation at Ser9. CONCLUSION: This study evidenced that Vit C exerts an anti-inflammatory function in microglia, promoting the upregulation of the M2 phenotype through the activation of the Wnt/ß-catenin signaling pathway.

Angiotensin-converting enzyme inhibition prevents l-dopa-induced dyskinesia in a 6-ohda-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.

Functional modification of recombinant brain-derived neurotrophic factor and its protective effect against neurotoxicity.

Brain-derived neurotrophic factor (BDNF) is a neurotrophic protein that promotes neuronal survival, increases neurotransmitter synthesis, and has potential therapeutic effects in neurodegenerative and psychiatric diseases, but its drug development has been limited by the fact that recombinant proteins of BDNF are unstable and do not penetrate the blood-brain barrier (BBB). In this study, we fused a TAT membrane-penetrating peptide with BDNF to express a recombinant protein (TBDNF), which was then PEG-modified to P-TBDNF. Protein characterization showed that P-TBDNF significantly improved the stability of the recombinant protein and possessed the ability to penetrate the BBB, and in cellular experiments, P-TBDNF prevented MPTP-induced nerve cell oxidative stress damage, apoptosis and inflammatory response, and its mechanism of action was closely related to the activation of tyrosine kinase B (TrkB) receptor and inhibition of microglia activation. In animal experiments, P-TBDNF improved motor and cognitive deficits in MPTP mice and inhibited pathological changes in Parkinson's disease (PD). In conclusion, this paper is expected to reveal the mechanism of action of P-TBDNF in inhibiting neurotoxicity, provide a new way for treating PD, and lay the foundation for the future development of recombinant P-TBDNF.

Molecular dynamic investigation for Roco4 kinase inhibitor as treatment options for parkinsonism.

CONTEXT: Parkinson's disease is a neurodegenerative condition characterized by the degeneration of dopaminergic neurons, resulting in motor disabilities such as rigidity, bradykinesia, postural instability, and resting tremors. While the exact cause of Parkinson's remains uncertain, both familial and sporadic forms are often associated with the G2019S mutation found in the kinase domain of LRRK2. Roco4 is an analogue of LRRK2 protein in Dictyostelium discoideum which is an established model organism to investigate LRRK2 inhibitors. In this study, the potential treatment of Parkinson's was explored by inhibiting the activity of the mutated LRRK2 protein using Roco4 as the base protein structure. Mongolicain-A and Bacoside-A exhibited significant selectivity towards the G2019S mutation, displaying a binding affinity of - 12.3 Kcal/mol and - 11.4 Kcal/mol respectively. Mongolicain-A demonstrated increased specificity towards Roco4, while Bacoside-A demonstrated significant binding affinity to all 34 kinases proteins alike. The Molecular Dynamics Studies (MDS) results strongly suggests that Mongolicain-A is a significant inhibitor of Roco4 kinase. ADMET and drugability analysis also suggests that among the two best ligands, Mongolicain-A demonstrates significant physicochemical properties to be suitable for best drug like molecule. Based on the in-silico molecular docking, molecular dynamic simulation, ADMET and drugability analyses, it is strongly suggested that, Mongolicain-A could be a potential candidate for treatment and management of Parkinson's disease via inhibition of LRRK2 protein. Further in-vitro and in-vivo investigations are in demand to validate these findings. METHODS: To identify potential inhibitors, 3069 phytochemicals were screened using molecular docking via AutoDock Vina. Molecular Dynamics Simulation was carried out using GROMACS 2022.2 for a duration of 100ns per complex to study the stability and inhibition potential of the protein ligand complexes. ADMET analysis was carriedout using Molinspiration and preADMET web tool.

Covid-19 in Parkinson's Disease treated by drugs or brain stimulation / COVID-19 en la enfermedad de Parkinson tratada con fármacos o estimulación cerebral

Purpose: Covid-19 has affected all people, especially those with chronic diseases, including Parkinson's Disease (PD). Covid-19 may affect both motor and neuropsychiatric symptoms of PD patients. We intend to evaluate different aspects of Covid-19 impact on PD patients. Methods: 647 PD patients were evaluated in terms of PD-related and Covid-19-related clinical presentations in addition to past medical history during the pandemic through an online questioner. They were compared with an age-matched control group consist of 673 individuals and a sample of the normal population consist of 1215 individuals. Results: The prevalence of Covid-19 in PD patients was 11.28%. The mortality was 1.23% among PD patients. The prevalence of Covid-19 in PD patients who undergone Deep Brain Stimulation (DBS) was 18.18%. No significant association was found between the duration of disease and the prevalence of Covid-19. A statistically significant higher prevalence of Covid-19 in PD patients who had direct contact with SARS-CoV-19 infected individuals was found. No statistically significant association has been found between the worsening of motor symptoms and Covid-19. PD patients and the normal population may differ in the prevalence of some psychological disorders, including anxiety and sleeping disorders, and Covid-19 may affect the psychological status. Conclusion: PD patients possibly follow tighter preventive protocols, which lead to lower prevalence and severity of Covid-19 and its consequences in these patients. Although it seems Covid-19 does not affect motor and psychological aspects of PD as much as it was expected, more accurate evaluations are suggested in order to clarify such effects.(AU)

Objetivo: La COVID-19 ha afectado a toda la población, especialmente a aquellos con enfermedades crónicas, incluyendo a los pacientes con enfermedad de Parkinson (EP). La COVID-19 puede empeorar tanto los signos motores como los síntomas neuropsiquiátricos de los pacientes con EP. El objetivo de este estudio es evaluar diferentes aspectos del impacto de la COVID-19 en los pacientes con EP. Métodos: A través de un cuestionario virtual se evaluó a 647 pacientes con EP de acuerdo con sus presentaciones clínicas relacionadas con la EP y con la COVID-19, además de la historia médica previa durante la pandemia. Se compararon con un grupo de controles sanos de la misma edad que constaba de 673 individuos y una muestra de la población general de 1.215 individuos. Resultados: La prevalencia de la COVID-19 en pacientes con EP fue del 11,28%. La mortalidad fue del 1,23% entre los pacientes con EP. La prevalencia de COVID-19 en pacientes con EP con estimulación cerebral profunda fue del 18,18%. No se encontró una asociación significativa entre la duración de la enfermedad y la prevalencia de COVID-19. Se halló una prevalencia mayor de COVID-19 que fue estadísticamente significativa en pacientes con EP que tuvieron contacto directo con personas infectadas con SARS-CoV-2. No se encontró una asociación estadísticamente significativa entre el empeoramiento de los signos motores y la COVID-19. Los pacientes con EP y la población general podrían diferir en la prevalencia de algunos trastornos psicológicos, incluidos los trastornos de ansiedad y del sueño, y la COVID-19 podría afectar al estado psicológico. Conclusión: Los pacientes con EP posiblemente sigan protocolos preventivos más estrictos, lo que conduce a una menor prevalencia y gravedad de COVID-19 y de sus consecuencias en estos pacientes.(AU)

GLP-1 Receptor Agonists: A New Treatment in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent data highlight similarities between neurodegenerative diseases, including PD and type 2 diabetes mellitus (T2DM), suggesting a crucial interplay between the gut-brain axis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, known for their use in T2DM treatment, are currently extensively studied as novel PD modifying agents. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles and clinical trials regarding GLP-1R agonists and PD published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Many data on animal models and preclinical studies show that GLP1-R agonists can restore dopamine levels, inhibit dopaminergic loss, attenuate neuronal degeneration and alleviate motor and non-motor features of PD. Evidence from clinical studies is also very promising, enhancing the possibility of adding GLP1-R agonists to the current armamentarium of drugs available for PD treatment.

The Gut Microbiota in Parkinson Disease: Interactions with Drugs and Potential for Therapeutic Applications.

The concept of a 'microbiota-gut-brain axis' has recently emerged as an important player in the pathophysiology of Parkinson disease (PD), not least because of the reciprocal interaction between gut bacteria and medications. The gut microbiota can influence levodopa kinetics, and conversely, drugs administered for PD can influence gut microbiota composition. Through a two-step enzymatic pathway, gut microbes can decarboxylate levodopa to dopamine in the small intestine and then dehydroxylate it to m-tyramine, thus reducing availability. Inhibition of bacterial decarboxylation pathways could therefore represent a strategy to increase levodopa absorption. Other bacterial perturbations common in PD, such as small intestinal bacterial overgrowth and Helicobacter pylori infection, can also modulate levodopa metabolism, and eradication therapies may improve levodopa absorption. Interventions targeting the gut microbiota offer a novel opportunity to manage disabling motor complications and dopa-unresponsive symptoms. Mediterranean diet-induced changes in gut microbiota composition might improve a range of non-motor symptoms. Prebiotics can increase levels of short-chain fatty acid-producing bacteria and decrease pro-inflammatory species, with positive effects on clinical symptoms and levodopa kinetics. Different formulations of probiotics showed beneficial outcomes on constipation, with some of them improving dopamine levels; however, the most effective dosage and duration and long-term effects of these treatments remain unknown. Data from faecal microbiota transplantation studies are preliminary, but show encouraging trends towards improvement in both motor and non-motor outcomes.This article summarises the most up-to-date knowledge in pharmacomicrobiomics in PD, and discusses how the manipulation of gut microbiota represents a potential new therapeutic avenue for PD.