Structural insights into the human D1 and D2 dopamine receptor signaling complexes.

The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-Gs and D2R-Gi signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.

A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson's disease.

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson's disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Dopamine agonists in the treatment of Parkinson's disease: the show must go on.

Dopamine agonists (DA) have proven very successful in the treatment of Parkinson's disease for a good many years now. In the 1990's they experienced a high level of acceptance particularly in the European countries because their efficacy was in fact established, their tolerability was improved on and, in addition, several preparations were available with longer effect durations. But the discovery of cardiac fibroses led to a substantial setback and even rejection of therapy using ergoline DA. In recent years, impulse control disturbances have been observed increasingly with the result that higher doses have been reduced and the previously popular use of non-ergoline DA was discontinued. In addition, newer data on levodopa were published which clearly relativized the occurrence of late complications under levodopa and led to a differentiated use. Thus the importance of their use has waned over the years. But we should rather avoid repeating the mistakes of the past. DA serve us well and reliably so. The pendulum apparently thrives of the extremes but in the case of DA we should keep from falling back into the other extreme: We can and in fact must further make use of the DA, but with a clear view of specific goals and in a differentiated way. DA constitute the second-most important substance class after levodopa. Their optimized application can only be recommended for the good of our patients.

Sublingual apomorphine in the treatment of Parkinson's disease.

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials.

Fabrication and Characterization of Dissolving Microneedles for Transdermal Drug Delivery of Apomorphine Hydrochloride in Parkinson's Disease.

PURPOSE: We fabricated and characterized polyvinyl alcohol (PVA)-based dissolving microneedles (MNs) for transdermal drug delivery of apomorphine hydrochloride (APO), which is used in treating the wearing-off phenomenon observed in Parkinson's disease. METHODS: We fabricated MN arrays with 11 × 11 needles of four different lengths (300, 600, 900, and 1200 µm) by micromolding. The APO-loaded dissolving MNs were characterized in terms of their physicochemical and functional properties. We also compared the pharmacokinetic parameters after drug administration using MNs with those after subcutaneous injection by analyzing the blood concentration of APO in rats. RESULTS: PVA-based dissolving MNs longer than 600 µm could effectively puncture the stratum corneum of the rat skin with penetrability of approximately one-third of the needle length. Although APO is known to have chemical stability issues in aqueous solutions, the drug content in APO-loaded MNs was retained at 25°C for 12 weeks. The concentration of APO after the administration of APO-loaded 600-µm MNs that dissolved completely in skin within 60 min was 81%. The absorption of 200-µg APO delivered by MNs showed a Tmax of 20 min, Cmax of 76 ng/mL, and AUC0-120 min of 2,829 ng・min/mL, compared with a Tmax of 5 min, Cmax of 126 ng/mL, and AUC0-120 min of 3,224 ng・min/mL for subcutaneous injection. The bioavailability in terms of AUC0-120 min of APO delivered by MNs was 88%. CONCLUSION: APO-loaded dissolving MNs can deliver APO via skin into the systemic circulation with rapid absorption and high bioavailability.

Memory enhancing and neuroprotective effects of apomorphine in a rat model of dementia.

Oxidative stress from generation of increased reactive oxygen species or has been reported to play an important role in dementia. Oxidative stress due to free radicals of oxygen or reactive oxygen species could be precipitating factors in the etiology of dementia. Apomorphine has been reported to have neuroprotective effects. To monitor memory enhancing and neuroprotective effects of apomorphine, we determined the antioxidant enzymes activities, lipid peroxidation, acetylcholine esterase (AChE) activity in brain and plasma, following repetitive administration of apomorphine in rat model of dementia. Biogenic amine levels were also monitored in hippocampus. Repeated administration of scopolamine was taken as an animal model of dementia. Decreased glutathione peroxidase, superoxide dismutase and catalase activities were observed in these animal models of dementia. While increased lipid peroxidation was also observed in the brain and plasma samples. The results showed significant effects of apomorphine. The activities of antioxidant enzymes displayed increased activities in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly higher in brain and plasma of apomorphine treated rats. Superoxide dismutase (SOD) was significantly decreased in plasma of scopolamine injected rats; and a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in scopolamine treated rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM). Short-term memory and long-term memory was impaired significantly in scopolamine treated rats, which was prevented by apomorphine. Moreover, a marked decrease in biogenic amines was also found in the brain of scopolamine treated rats and was reverted in apomorphine treated rats. Results showed that scopolamine-treatment induced memory impairment and induced oxidative stress in rats as compared to saline-treated controls. These impairments were significantly restored by apomorphine administration. In conclusion, our data suggests that apomorphine at the dose of 1 mg/kg could be a potential therapeutic agent to treat dementia and related disorders.

Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

Influence of continuous subcutaneous apomorphine infusion on cognition and behavior in Parkinson's disease: A systematic review.

INTRODUCTION: The efficacy of continuous subcutaneous apomorphine infusion (CSAI) for motor complications of Parkinson's disease (PD) is established. However, its effect on cognition and behavior remains controversial. The main objective of this systematic review was to describe the existing literature on the effects of CSAI on cognition and behavior and to determine the quality for each study. METHODS: PubMed/Medline, Embase, APA PsycInfo®, and Cochrane Library databases were searched, following PRISMA recommendations. Only longitudinal studies evaluating the effect of CSAI on cognition (global cognition, executive functions, visuospatial abilities, language, memory, attention, social cognition) and/or behavior (depression, anxiety, apathy, psychotic symptoms, impulse control disorders, neuropsychiatric fluctuations) in PD were included. The quality of the included studies was also assessed with a questionnaire. RESULTS: Twenty-three longitudinal studies evaluated the effect of CSAI on cognition and/or behavior. Overall, results were suggestive of positive effects, notably on executive functions and emotion recognition. However, there were some reports of cognitive slowing and long-term global cognitive deterioration. At the behavioral level, no study showed significant adverse effect of CSAI. Occasionally, a slight improvement of depression, anxiety, apathy, and neuropsychiatric fluctuations was reported. Nevertheless, only four studies met good quality criteria and controlled study regarding cognition were lacking. CONCLUSION: The results suggest that CSAI has no obvious negative effects on cognition and behavior in PD. This treatment even shows promise in reducing certain symptoms such as neuropsychiatric fluctuations. However, due to methodological limitations in many studies, no robust conclusions can be drawn. Further multicenter controlled trials are needed to confirm these results.

Dopamine differentially affects retinal circuits to shape the retinal code.

Dopamine has long been reported to enhance antagonistic surrounds of retinal ganglion cells (RGCs). Yet, the retina contains many different RGC subtypes and the effects of dopamine can be subtype-specific. Using multielectrode array (MEA) recordings we investigated how dopamine shapes the receptive fields of RGCs in the mouse retina. We found that the non-selective dopamine receptor agonist apomorphine can either increase or decrease RGCs' surround strength, depending on their subtype. We then used two-photon targeted patch-clamp to target a specific RGC subtype, the transient-Off-αRGC. In line with our MEA recordings, apomorphine did not increase the antagonistic surround of transient-Off-αRGCs but enhanced their responses to Off stimuli in the centre receptive field. Both D1 - and D2 -like family receptor (D1 -R and D2 -R) blockers had the opposite effect and reduced centre-mediated responses, but differently affected transient-Off-αRGC's surround. While D2 -R blocker reduced surround antagonism, D1 -R blocker led to surround activation, revealing On responses to large stimuli. Using voltage-clamp recordings we separated excitatory inputs from Off cone bipolar cells and inhibitory inputs from the primary rod pathway. In control conditions, cone inputs displayed strong surround antagonism, while inputs from the primary rod pathway showed no surround. Yet, the surround activation in the D1 -R blockade originated from the primary rod pathway. Our findings demonstrate that dopamine differentially affects RGC subtypes via distinct pathways, suggesting that dopamine has a more complex role in shaping the retinal code than previously reported. KEY POINTS: Receptive fields of retinal ganglion cells (RGCs) have a centre-surround organisation, and previous work has shown that this organisation can be modulated by dopamine in a light-intensity-dependent manner. Dopamine is thought to enhance RGCs' antagonistic surround, but a detailed understanding of how different RGC subtypes are affected is missing. Using a multielectrode array recordings, clustering analysis and pharmacological manipulations, we found that dopamine can either enhance or weaken antagonistic surrounds, and also change response kinetics, of RGCs in a subtype-specific manner. We performed targeted patch-clamp recordings of one RGC subtype, the transient-Off-αRGC, and identified the underlying circuits by which dopamine shapes its receptive field. Our findings demonstrate that dopamine acts in a subtype-specific manner and can have complex effects, which has implications for other retinal computations that rely on receptive field structure.

Home initiation of apomorphine infusion: lessons from the COVID-19 pandemic and implications for current clinical practice.

Starting Parkinson's disease (PD) patients on subcutaneous apomorphine (APO) infusion is generally undertaken on a hospital day-case basis. During the COVID-19 pandemic, day-case facilities were unavailable. To avoid delays in treatment, a new procedure was developed for initiation of APO therapy in the patient's home. A home initiation protocol was developed and followed for each patient in this analysis. The hospital team worked in collaboration with APO nurses provided by the manufacturer of APO therapies to implement initiation and undertake follow-up. In this analysis, 27 PD patients were initiated onto APO infusion and 21 (77.8%) achieved a therapeutic response. Home initiation of APO infusion can be undertaken successfully and has benefits for both patients and healthcare teams. This protocol will now continue as a standard of care at our centre.

Practical use of apomorphine infusion in Parkinson's disease: lessons from the TOLEDO study and clinical experience.

Subcutaneous apomorphine infusion is a device-aided therapy for Parkinson's disease that can be considered when motor fluctuations become persistent and are no longer adequately controlled by oral/transdermal medication. Apomorphine infusion is less invasive than enteral levodopa, deep brain stimulation or focused ultrasound, and is often indicated even when neurosurgical approaches are contraindicated. This article aims to provide practical guidance for doctors and nurses initiating and treating patients with apomorphine infusion, and is based on both trial data and clinical experience from movement disorders specialists. A post hoc analysis of data from the TOLEDO randomized clinical trial of apomorphine infusion was conducted along with an analysis of 'real world' experience from 13 movement disorders specialists using a questionnaire that focused on starting patients on apomorphine infusion. Practical guidelines for starting treatment with apomorphine infusion are provided taking into consideration the regional disparities in healthcare. Apomorphine infusion is straightforward to administer but to be successful it requires concordance from the patient and family, and clinical support from an experienced team of doctors and nurses, particularly in the early months of treatment.

Feasibility and benefits of home initiation of subcutaneous apomorphine infusion for patients with Parkinson's disease: the APOKADO study.

Continuous subcutaneous apomorphine infusion (CSAI) is used to treat patients with Parkinson's disease (PD) who are experiencing motor fluctuations. However, the need to initiate this treatment during a hospital stay may restrict patients' access to it. To assess the feasibility and benefits of initiating CSAI in the patient's own home. A French prospective multicenter longitudinal observational study (APOKADO) among patients with PD who required subcutaneous apomorphine, comparing in-hospital versus home initiation. Clinical status was assessed according to the Hoehn and Yahr score), the Unified Parkinson's Disease Rating Scale Part III, and the Montreal Cognitive Assessment. We assessed patients' quality of life with the 8-item Parkinson's Disease Questionnaire, rated the improvement in their clinical status on the 7-point Clinical Global Impression-Improvement scale, recorded adverse events, and ran a cost-benefit analysis. 145 patients with motor fluctuations were included in 29 centers (office and hospital). Of these, 106 (74%) were initiated onto CSAI at home, and 38 (26%) in hospital. At inclusion, the two groups were comparable for all demographic and PD characteristics. After 6 months, quality of life, adverse events and early dropout rates were similarly rare-across the two groups. Patients in the home group improved more quickly their quality of life and became more autonomous in managing the device than those in the hospital group, and their care costed less. This study shows that home (versus in-hospital) initiation of CSAI is feasible, improves patients' quality of life more quickly, with the same level of tolerance. It is also less expensive. This finding should make it easier for patients to access this treatment in the future.

Non-oral continuous drug delivery based therapies and sleep dysfunction in Parkinson's disease.

Continuous drug delivery (CDD) has emerged as a feasible and pragmatic therapeutic option for dopamine replacement therapy in advanced Parkinson's disease (PD). CDD aims to mimic the physiological tonic dopamine release from striatal dopaminergic neurons and thus reduces the severity and duration of motor and non-motor fluctuations partly related to pulsatile levodopa stimulation. Non-motor symptoms and fluctuations are ubiquitous in PD and include sleep dysfunction, a problem that occurs in over 90% of PD patients across all stages, from prodromal to palliative. In this review, we discuss the currently available and in development non-oral dopaminergic CDD strategies with a focus on their efficacy in the treatment of the burdensome sleep dysfunction in PD.

Adopting the Rumsfeld approach to understanding the action of levodopa and apomorphine in Parkinson's disease.

Dopaminergic therapies dominate the treatment of the motor and non-motor symptoms of Parkinson's disease (PD) but there have been no major advances in therapy in many decades. Two of the oldest drugs used appear more effective than others-levodopa and apomorphine-but the reasons for this are seldom discussed and this may be one cause for a lack of progress. This short review questions current thinking on drug action and looks at whether adopting the philosophy of ex-US Secretary of State Donald Rumsfeld reveals 'unknown' aspects of the actions of levodopa and apomorphine that provide clues for a way forward. It appears that both levodopa and apomorphine have a more complex pharmacology than classical views would suggest. In addition, there are unexpected facets to the mechanisms through which levodopa acts that are either forgotten as 'known unknowns' or ignored as 'unknown unknowns'. The conclusion reached is that we may not know as much as we think about drug action in PD and there is a case for looking beyond the obvious.

Current and novel infusion therapies for patients with Parkinson's disease.

Advanced Parkinson's disease is characterized by periods of poor mobility, dyskinesia and progressive decline in functional independence of the affected person despite the manipulation of levodopa doses and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase-B inhibitors and dopamine agonists. The implementation of drug delivery systems allows to bypass problems related to irregular and often unpredictable intestinal absorption of oral levodopa, which significantly affects its bioavailability and contributes to the development and persistence of motor complications. Subcutaneous apomorphine and levodopa/carbidopa jejunal infusion systems have been available for many years and their efficacy is confirmed by randomized studies and long-term experience in many centers worldwide. Recently, a new formulation of levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone has been introduced to the market. The use of entacapone allows to reduce total daily dose of administered levodopa. Two different soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) have completed clinical development, and both can ensure subcutaneous delivery by a portable pump infusion system. ABBV-951 uses a foslevodopa/foscarbidopa formulation, both prodrugs to improve absorption and tolerability. Both systems provide effective improvement of motor complications and are likely to expand the therapeutic options in advanced patients. Future efforts should focus on the earlier detection of patients who are candidates for device-aided therapies, increasing appropriate referral and broadening the availability of these treatments globally.

Apomorphine for Parkinson's disease: pharmacologic and clinical considerations.

INTRODUCTION: In Parkinson's disease, dopamine depletion in the basal ganglia leads to symptoms including bradykinesia, gait abnormalities, and cognitive impairment. Even with treatment, the disease course leads to decreases in the amount of dopamine produced and released into the synapse. As dopamine production falls and the treatment course is insufficient to match the metabolic supply and demand, acute 'off' periods develop that cause reemergence of symptoms. Apomorphine is used to reverse these 'off' periods and restore function in patients with Parkinson's. This review will provide clinicians a concise article to read to learn more about apomorphine and its appropriate utilization. AREAS COVERED: The research discussed is focused on the history, pharmacokinetics, and mechanism of action of Apomorphine. Its utilization as a treatment for Parkinson's Disease and its comparison to currently utilized drugs is also discussed in this review. We focused on articles published on PubMed and Google Scholar within the last 10 years, but in some instances had to go as far back as 1951 to include early articles published about apomorphine. EXPERT OPINION: The expert opinion section focuses on the ways in which apomorphine could be administered in the future to better promote utilization and increase tolerability.

Frontotemporal Dementia P301L Mutation Potentiates but Is Not Sufficient to Cause the Formation of Cytotoxic Fibrils of Tau.

The P301L mutation in tau protein is a prevalent pathogenic mutation associated with neurodegenerative frontotemporal dementia, FTD. The mechanism by which P301L triggers or facilitates neurodegeneration at the molecular level remains unclear. In this work, we examined the effect of the P301L mutation on the biochemical and biological characteristics of pathologically relevant hyperphosphorylated tau. Hyperphosphorylated P301L tau forms cytotoxic aggregates more efficiently than hyperphosphorylated wildtype tau or unphosphorylated P301L tau in vitro. Mechanistic studies establish that hyperphosphorylated P301L tau exacerbates endoplasmic reticulum (ER) stress-associated gene upregulation in a neuroblastoma cell line when compared to wildtype hyperphosphorylated tau treatment. Furthermore, the microtubule cytoskeleton is severely disrupted following hyperphosphorylated P301L tau treatment. A hyperphosphorylated tau aggregation inhibitor, apomorphine, also inhibits the harmful effects caused by P301L hyperphosphorylated tau. In short, the P301L single mutation within the core repeat domain of tau renders the underlying hyperphosphorylated tau more potent in eliciting ER stress and cytoskeleton damage. However, the P301L mutation alone, without hyperphosphorylation, is not sufficient to cause these phenotypes. Understanding the conditions and mechanisms whereby selective mutations aggravate the pathogenic activities of tau can provide pivotal clues on novel strategies for drug development for frontotemporal dementia and other related neurodegenerative tauopathies, including Alzheimer's disease.

New trends in advanced parkinson disease stage therapy.

The aim of the study was to point out the contribution of new invasive therapeutic procedures in the treatment of advanced stages of Parkinson's disease (PD) in comparison with classical oral pharmacotherapy. Data originated from a group of 43 patients with PD, 39% (17) with classic treatment, 23% (10) with intestinal gel of methyl ester levodopa (Duodopa), 19% (8) of patients were using subcutaneous delivery of apomorphine (APO) and the same quantity of patients had undergone deep brain stimulation (DBS). Majority of patients had advanced stages of PD, stage 4, by standards of Hoehn and Yahr scale (Hoehn and Yahr, 1967). Research observed improvement in majority of patients with novel treatments. A positive effect was also noted in the reduced need for oral therapy, where there was a significant decrease in all new therapies. Benefits were observed in the amount of antiparkinsonic drugs taken per os, where we observed reduction in all new therapies. A positive effect of the new therapeutic approaches in reducing "off" periods in patients has also been noted. In the case of Duodopa and DBS, the "off" period was shortened up to 50% and in the apomorphine pump up to 40%. Patients also reported reduction of some symptoms like rigidity, tremor and bradykinesis while dyskinesis still remains suba challenge. On the basis of the obtained results, it can be concluded that new therapeutic procedures for PCh will make it possible to manage symptoms typical of advanced stages of the disease, which without these procedures would lead to disability, which is the main reason for their indication. However, in early stages, well responding patients or in slow progressing disease oral antiparkinsonics are remaining as golden standard of treatment. This is not just due to good response but also because these classic drug formulations are significantly less expensive. In Slovakia, novel treatments are accessible through healthcare insurance only after secondary revision by insurance company doctors.

A Randomized Trial Assessing the Safety, Pharmacokinetics, and Efficacy During Morning Off of AZ-009.

BACKGROUND: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD). OBJECTIVE: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD. METHODS: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ-009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose. RESULTS: AZ-009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ-009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ-009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ-009 reduced mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg). CONCLUSIONS: AZ-009 appears to be a rapid-acting and reasonably well-tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway.

The chiral molecule, apomorphine, is currently used for the treatment of Parkinson's disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphine has also antioxidant and free radical scavenger activities. Neuroinflammation, oxidative stress, and microglia reactivity have emerged as central players in PD. Thus, modulating microglia activation in PD may be a valid therapeutic strategy. We previously reported that murine microglia are strongly activated upon exposure to A53T mutant α-synuclein. The present study was designed to investigate whether apomorphine enantiomers could modulate this A53T-induced microglial activation. Taken together, the results provided evidence that apomorphine enantiomers decrease A53T-induced microgliosis, through the activation of the NRF2 signalling pathway, leading to a lower pro-inflammatory state and restoring the phagocytic activity. Suppressing NRF2 recruitment (trigonelline exposure) or silencing specifically Nfe2l2 gene (siRNA treatment) abolished or strongly decreased the anti-inflammatory activity of apomorphine. In conclusion, apomorphine, which is already used in PD patients to mimic dopamine activity, may also be suitable to decrease α-synuclein-induced microglial reactivity.