How and why the adenosine A2A receptor became a target for Parkinson's disease therapy.

Dopaminergic therapy for Parkinson's disease has revolutionised the treatment of the motor symptoms of the illness. However, it does not alleviate all components of the motor deficits and has only limited effects on non-motor symptoms. For this reason, alternative non-dopaminergic approaches to treatment have been sought and the adenosine A2A receptor provided a novel target for symptomatic therapy both within the basal ganglia and elsewhere in the brain. Despite an impressive preclinical profile that would indicate a clear role for adenosine A2A antagonists in the treatment of Parkinson's disease, the road to clinical use has been long and full of difficulties. Some aspects of the drugs preclinical profile have not translated into clinical effectiveness and not all the clinical studies undertaken have had a positive outcome. The reasons for this will be explored and suggestions made for the further development of this drug class in the treatment of Parkinson's disease. However, one adenosine A2A antagonist, namely istradefylline has been introduced successfully for the treatment of late-stage Parkinson's disease in two major areas of the world and has become a commercial success through offering the first non-dopaminergic approach to the treatment of unmet need to be introduced in several decades.

Future Directions for Developing Non-dopaminergic Strategies for the Treatment of Parkinson's Disease.

The symptomatic treatment of Parkinson's disease (PD) has been dominated by the use of dopaminergic medication, but significant unmet need remains, much of which is related to non-motor symptoms and the involvement of non-dopaminergic transmitter systems. As such, little has changed in the past decades that has led to milestone advances in therapy and significantly improved treatment paradigms and patient outcomes, particularly in relation to symptoms unresponsive to levodopa. This review has looked at how pharmacological approaches to treatment are likely to develop in the near and distant future and will focus on two areas: 1) novel non-dopaminergic pharmacological strategies to control motor symptoms; and 2) novel non-dopaminergic approaches for the treatment of non-motor symptoms. The overall objective of this review is to use a 'crystal ball' approach to the future of drug discovery in PD and move away from the more traditional dopamine-based treatments. Here, we discuss promising non-dopaminergic and 'dirty drugs' that have the potential to become new key players in the field of Parkinson's disease treatment.

Stalevo® : A pioneering treatment for OFF periods in Parkinsons disease.

Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.

Levodopa Dose Equivalency in Parkinson's Disease: Updated Systematic Review and Proposals.

BACKGROUND: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as 'levodopa equivalent dose' (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. OBJECTIVES: To update LED conversion formulae based on a systematic review. METHODS: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. RESULTS: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. CONCLUSIONS: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gastrointestinal barriers to levodopa transport and absorption in Parkinson's disease.

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.

Why do 'OFF' periods still occur during continuous drug delivery in Parkinson's disease?

Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD.

The Pharmacological Potential of Adenosine A2A Receptor Antagonists for Treating Parkinson's Disease.

The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson's disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.

Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease: Past, Present, and Future.

Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson's disease (PD). MAO-B inhibitor monotherapy has been shown to be effective and safe for the treatment of early-stage PD, while MAO-B inhibitors as adjuvant drugs have been widely applied for the treatment of the advanced stages of the illness. MAO-B inhibitors can effectively improve patients' motor and non-motor symptoms, reduce "OFF" time, and may potentially prevent/delay disease progression. In this review, we discuss the effects of MAO-B inhibitors on motor and non-motor symptoms in PD patients, their mechanism of action, and the future development of MAO-B inhibitor therapy.

Redefining the strategy for the use of COMT inhibitors in Parkinson's disease: the role of opicapone.

INTRODUCTION: Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery. AREAS COVERED: Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment. EXPERT OPINION: This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.

Rotigotine Transdermal Patch for Motor and Non-motor Parkinson's Disease: A Review of 12 Years' Clinical Experience.

Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1-4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.

Istradefylline - a first generation adenosine A2A antagonist for the treatment of Parkinson's disease.

Introduction It is now accepted that Parkinson's disease (PD) is not simply due to dopaminergic dysfunction, and there is interest in developing non-dopaminergic approaches to disease management. Adenosine A2A receptor antagonists represent a new way forward in the symptomatic treatment of PD.Areas covered In this narrative review, we summarize the literature supporting the utility of adenosine A2A antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A2A antagonist currently in clinical use.Expert opinion: At this time, the use of istradefylline in the treatment of PD is limited to the management of motor fluctuations as supported by the results of randomized clinical trials and evaluation by Japanese and USA regulatory authorities. The relatively complicated clinical development of istradefylline was based on classically designed studies conducted in PD patients with motor fluctuations on an optimized regimen of levodopa plus adjunctive dopaminergic medications. In animal models, there is consensus that a more robust effect of istradefylline in improving motor function is produced when combined with low or threshold doses of levodopa rather than with high doses that produce maximal dopaminergic improvement. Exploration of istradefylline as a 'levodopa sparing' strategy in earlier PD would seem warranted.

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate.

The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson's disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.

Can adenosine A2A receptor antagonists modify motor behavior and dyskinesia in experimental models of Parkinson's disease?

Current treatment of the motor symptoms of Parkinson's disease (PD) focuses on dopamine replacement therapies. While these treatments are initially highly effective, with long-term use and disease progression, the therapeutic response is often limited by the development of motor complications, dopaminergic side effects, and residual unresponsive motor and non-motor symptoms. An alternative or additive treatment approach may be to target non-dopaminergic receptors within the motor control pathways, which function to modulate basal ganglia output. Adenosine A2A receptors are one potential non-dopaminergic target as they are selectively localized to the basal ganglia and to the indirect output pathway known to modulate the striato-thalamo-cortical loops critical to the expression of the motor symptoms of PD. This paper reviews the preclinical evidence base for the ability of adenosine A2A receptor blockade to influence motor function and modulate dyskinesia expression. There is consensus that adenosine A2A receptor antagonists - administered either as a monotherapy or in combination with l-DOPA or dopamine agonists - improve motor function in both rodent and primate models of PD, and should be effective for treating the motor symptoms of PD in humans. Importantly, the improvements in motor function were seen in the absence of dyskinesia. The introduction of a non-dopaminergic approach to modifying basal ganglia function provides a useful addition to the range of available therapies for treating PD, and there is a rational basis for a drug that focuses on modifying basal ganglia output.

Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease?

Treatment of non-motor symptoms of Parkinson's disease (PD) is a major unmet need. Targeting adenosine A2A receptors may address some of the neuropsychiatric components of non-motor symptoms - notably cognitive impairment, depression and excessive daytime sleepiness. A2A receptors are located primarily on the indirect gamma-aminobutyric acid (GABA)-ergic striatal output pathway but are also present to some extent in limbic areas of the brain, particularly the nucleus accumbens. Extensive studies show that adenosine antagonists are effective in reversing cognitive deficits in a range of experimental models related to the early executive and visuo-spatial deficits seen in PD. Similarly, A2A receptor antagonists can reverse depressive symptoms in experimental models of PD, including models with high predictive value of effect in humans, and to the same extent as classical antidepressants. Importantly, A2A antagonists are effective in models of the motivational symptoms of depression, which may relate to the apathetic/anhedonic expression of depression that can occur in PD. Adenosine and A2A receptors play a prominent role in regulating the sleep-wake cycle with arousal attributed to A2A receptor antagonism. In rodents, A2A receptor antagonists appear to induce arousal in the active part of the daily cycle only, and not during the inactive phase. This was suggested in small clinical studies in PD where A2A antagonism improved daytime sleepiness without impairing nocturnal sleep. In conclusion, A2A antagonists have potential to affect a range of neuropsychiatric components of PD; this clinical potential requires further investigation in humans.

Improving the Delivery of Levodopa in Parkinson's Disease: A Review of Approved and Emerging Therapies.

Levodopa is the most effective drug for the treatment of Parkinson's disease, but its use as an oral medication is complicated by its erratic absorption, extensive metabolism and short plasma half-life. On long-term use and with disease progression, there is a high incidence of motor and non-motor complications, which remain a major clinical and research challenge. It is widely accepted that levodopa needs to be administered using formulations that result in good and consistent bioavailability and the physiologically relevant and continuous formation of dopamine in the brain to maximise its efficacy while avoiding and reversing 'wearing off' and dyskinesia. However, the physicochemical properties of levodopa along with its pharmacokinetic and pharmacodynamic profile make it difficult to deliver the drug in a manner that fulfils these criteria. In this review, we examine the problems associated with the administration of levodopa in Parkinson's disease and how the use of novel technologies and delivery devices is leading to a more consistent and sustained levodopa delivery with the aim of controlling motor function as well as non-motor symptoms.

'Dopamine agonist Phobia' in Parkinson's disease: when does it matter? Implications for non-motor symptoms and personalized medicine.

INTRODUCTION: Dopamine agonists have been widely used to treat patients with Parkinson's disease, but concerns related to their well-known side effects might prevent their use even when indicated. In this review, the authors describe for the first time the concept of 'Dopamine Agonist Phobia', a pharmacophobia that the authors believe might affect clinicians, and they provide evidence of the benefits of dopamine agonists, focusing on non-motor symptoms. AREAS COVERED: The authors performed an extensive literature research, including studies exploring the use of dopamine agonists for the treatment of non-motor symptoms. The authors indicate the highest level of evidence in each section. EXPERT OPINION: 'Dopamine Agonist Phobia' may preclude valid therapeutic options in selected cases, specifically for the treatment of non-motor symptoms. Thus, the authors propose a personalized approach in Parkinson's disease treatment, and encourage a thoughtful use of dopamine agonists, rather than an overall nihilism.

Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson's Disease-Viewpoint.

To date, there are no clinically effective neuroprotective or disease-modifying treatments that can halt Parkinson's disease (PD) progression. The current clinical approach focuses on symptomatic management. This failure may relate to the complex neurobiology underpinning the development of PD and the absence of true translational animal models. In addition, clinical diagnosis of PD relies on presentation of motor symptoms which occur when the neuropathology is already established. These multiple factors could contribute to the unsuccessful development of neuroprotective treatments for PD. Prodromal symptoms develop years prior to formal diagnosis and may provide an excellent tool for early diagnosis and better trial design. Patients with idiopathic rapid eye movement behavior disorder (iRBD) have the highest risk of developing PD and could represent an excellent group to include in neuroprotective trials for PD. In addition, repurposing drugs with excellent safety profiles is an appealing strategy to accelerate drug discovery. The anti-diabetic drug metformin has been shown to target diverse cellular pathways implicated in PD progression. Multiple studies have, additionally, observed the benefits of metformin to counteract other age-related diseases. The purpose of this viewpoint is to discuss metformin's neuroprotective potential by outlining relevant mechanisms of action and the selection of iRBD patients for future clinical trials in PD.