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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.

Experiential learning approaches such as work-integrated learning (WIL) are an important international business (IB) educational tool yet can be challenging to implement. This exploratory research examines the value derived by regional Australian export companies from engagement with such programs. The results suggest that firms perceive considerable benefit from involvement, particularly access to international market research capabilities. Additional benefits such as new market perspectives and extended local and international networks were reported. However, potential recruitment and reputational benefits received limited focus from the participants. The research therefore helps inform IB educators, potentially leading to the development of more accessible, effective and sustainable WIL programs based upon a better understanding of the value of these programs to this key stakeholder group. [Author abstract]

Cystatin C (CYS C, Cst3 ) is an endogenous cysteine protease inhibitor that plays neuroprotective roles in neurodegenerative diseases. We aimed to explore the association of CYS C with Parkinson’s disease (PD) models and investigate its involvement in the role of neurovascular units (NVUs) in PD neuro-pathogenesis. We used A53T α -synuclein (SNCA) transgenic mice and 6-hydroxydopamine-lesioned DAergic PC12 cells as experimental PD models to investigate the mechanisms behind this association. The injections of CYS C were administered to the right substantia nigra (SN) of A53T SNCA transgenic mice to measure the effects of CYS C in transgenic A53T SNCA mice. To explore the angiogenesis in vivo and in vitro , we used the chick embryo chorioallantoic membrane (CAM) assay and tube formation (TF) assay. We found that CYS C has a neuroprotective effect in this in vivo PD model. We observed increased VEGF, NURR1 and autophagy markers LC3B and decreased SNCA and apoptosis marker cleaved CASP3 in different brain regions of CYS C-treated A53T SNCA transgenic mice. In vitro , we observed that CYS C-induced VEGF, a secreted protein, attenuated 6-OHDA-lesioned DAergic PC12 cell degeneration by regulating p-PKC-α/p-ERK1/2-Nurr1 signaling and inducing autophagy. VEGF-mediated angiogenesis was markedly enhanced in the conditioned media of 6-OHDA-lesioned PC12 cells with CYS C-overexpression, whereas blockage of autophagy in CYS C-overexpressing PC12 cells significantly downregulated VEGF expression and the associated angiogenesis. Our data indicate that CYS C displays dual neuronal–vascular functions, promoting PC12 cell survival and angiogenesis via regulating the level of secreted VEGF in NVUs. Our study provides evidence that may aid in the development of an alternative approach for the treatment of PD through modulation of CYS C-mediated neuronal-vascular pathways.

Rationale Istradefylline, an adenosine A 2A receptor antagonist, improves motor function in animal models of Parkinson’s disease (PD) and in patients with PD. In addition, some A 2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests. Objective We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model. Results Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A 1 /A 2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A 1 selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A 2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A 1 specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT 2A/2C receptor antagonist methysergide or the adrenergic α 2 antagonist yohimbine, nor the β-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline. Conclusions Istradefylline exerts antidepressant-like effects via modulation of A 2A receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms.

Dyskinesia is a treatment-limiting side effect of dopaminergic replacement therapies in Parkinson's disease. Here Jenner discusses what we know about the molecular causes of dyskinesia induction and expression, highlighting recent findings that suggest that altered glutamatergic transmission might be important. Key Points Involuntary movements (dyskinesia) develop in the course of Parkinson's disease (PD) and can be treatment-limiting. Two processes seem to be important: the 'priming' of motor systems for the initiation of dyskinesia and the processes that are responsible for its expression. Dyskinesia has been associated with an imbalance in the output of the basal ganglia, but the pathophysiology of the involuntary movements remains unclear. Loss of dopaminergic neurons in the substantia nigra is essential for dyskinesia induction, and the extent of denervation determines the vulnerability to non-physiological replacement of dopamine that occurs in the drug treatment of PD. Attempts to define dyskinesia at the biochemical or molecular level have proved difficult. However, alterations in glutamatergic transmission seem to be key. The basal ganglia are structurally and functionally abnormal in PD as a result of the loss of striatal dopaminergic input. Connectivity with the motor cortex is diminished, and the consequence is the abnormal motor response to drug treatment that comprises dyskinesia. Novel approaches to treatment that alter intracellular signalling cascades and so normalize the integration of sensory and motor inputs to the basal ganglia and result in the restoration of normal movement (without dyskinesia induction or expression) in response to dopamine-replacement therapy might now be possible. L-DOPA ( L -3,4-dihydroxyphenylalanine) remains the most effective drug for the treatment of Parkinson's disease. However, chronic use causes dyskinesia, a complex motor phenomenon that consists of two components: the execution of involuntary movements in response to drug administration, and the 'priming' phenomenon that underlies these movements' establishment and persistence. A reinterpretation of recent data suggests that priming for dyskinesia results from nigral denervation and the loss of striatal dopamine input, which alters glutamatergic synaptic connectivity in the striatum. The subsequent response of the abnormal basal ganglia to dopaminergic drugs determines the manner and timing of dyskinesia expression. The combination of nigral denervation and drug treatment establishes inappropriate signalling between the motor cortex and the striatum, leading to persistent dyskinesia.

Although levodopa provides therapeutic benefit over the entire course of Parkinson’s disease, most patients eventually notice a decline in the duration of benefit from each dose, a phenomenon termed ‘wearing-off’ or ‘end of dose’ deterioration. This is an important indicator that the patient is entering a more complex phase of the disease. Wearing-off has been classically associated with the later stages of Parkinson’s disease, but it is becoming apparent that patients with early disease, presenting as well controlled, may already be experiencing fluctuations in their response to levodopa. However, neither the pathophysiology nor the clinical relevance of the early emergence of wearing-off has been properly explored. We now review the preclinical and clinical evidence that suggests that even patients who are apparently still in the honeymoon phase of drug treatment may have early fluctuations in their motor response to dopaminergic therapy. It is important that early wearing-off is recognized as it has important consequences for the long-term outcome and for the medication regimens to be used.

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.

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by degeneration of dopamine-containing neurons in the midbrain. In cases of familial PD, mutations that lead to failure of the ubiquitin–proteasome system (UPS) have been identified. These genetic abnormalities do not occur in sporadic PD, but we propose that impairment of the UPS could also contribute to neurodegeneration in this disorder. We discuss evidence that failure of the UPS is a common aetiopathogenic factor that underlies the development of familial and sporadic PD, an idea that might help to explain clinical and pathological differences and similarities in these disorders.

Purpose The purpose of this paper is to examine social enterprise sustainability by comparing recent international research with prior findings seeking to identify the important factors that facilitate social enterprise development. Design/methodology/approach The research used a concurrent, convergent mixed methods approach on a sample of 93 social enterprise leaders using surveys and face-to-face interviews. The participants were sourced from a cross-section of social enterprise organisational types from urban and regional locations in Australia and Scotland. Findings The findings support prior research, identifying resourcing, organisational capabilities, collaborative networks and legitimacy as influential in the success of social enterprises. However, the research contributes new knowledge by revealing an overarching growth orientation as the dominant factor in the strategic management for sustainability of these ventures. This growth orientation is generally associated with the intent to achieve profitability. Thus, social enterprise managers view a commercially focused growth orientation as an overarching strategic factor that underpins organisational sustainability. Originality/value The paper delivers new insights into the strategic orientation of social ventures of benefit to policy makers and practitioners alike. The findings are significant for policy makers providing perspectives into how governmental assistance can be targeted to develop sustainable social enterprises, particularly the need to support the growth of these ventures. Similarly, practitioners are alerted to the strategic imperatives of incorporating a commercially focused growth orientation and the latent potential that exists in the networks of social enterprise.

Background: Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily. Objectives: These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation. Methods: Three Phase I studies were conducted, all in healthy adult men aged ≤50 years with a body mass index of 18.5 to 29.9 kg/m 2. In the first study, 7 prototypes of a once-daily ER formulation with various release properties, including rate and pH dependence, were compared with the IR formulation taken 3 times daily to identify the optimal pharmacokinetic resemblance based on predefined criteria derived from plasma AUC 0−24h, C max, and C min. In the second study, a level A in vitro/in vivo correlation (IVIVC) suitable for predicting an entire in vivo bioavailability time course based on in vitro dissolution was established and validated, and the single-dose pharmacokinetics of the optimal ER formulation identified in the first study were analyzed for food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375–4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs). Results: The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC 0−24h,ss of 17.4 ng·h/mL (vs 16.0 ng·h/mL for the IR formulation), C max,ss of 0.967 ng/mL (vs 1.09 ng/mL), and C min,ss of 0.455 ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC 0−30h and 4.87% for C max, and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted values was 119.8 for AUC 0–30h (within the bioequivalence limits of 80%–125%) and 134.1 for C max. At steady state in study 3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state was associated with a linear, dose-proportional increase in pharmacokinetic parameters, including AUC 0–24h,ss and C max,ss. At the highest fasted dose (4.5 mg), the geometric coefficient of variation for interindividual variability at steady state was 30.1% for AUC 0–24h,ss (vs 21.4% for IR pramipexole 1.5 mg TID) and 22.3% for C max,ss (vs 19.0%). At steady state, the upper bounds of the 90% CIs for fed:fasted values with ER 4.5 mg were 122.1 for AUC 0–24h and 126.8 for C max. No serious AEs occurred, and the dropout rate was low. Conclusions: In these studies in healthy male volunteers, an ER pramipexole formulation was identified that resembled the IR formulation in terms of both pharmacokinetics and tolerability. In patients with Parkinson's disease, once-daily use of an ER formulation may improve the convenience of treatment relative to the IR formulation taken 3 times daily and thus increase compliance.