An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models
Introduction
The most common treatment for Parkinson's disease (PD) patients remains to be the dopamine precursor, L-3,4-dihydroxyphenylalanine (l-DOPA) despite the frequent development of severe complications with repeated use, which include on-off fluctuations of therapeutic action (Shoulson et al., 1975), dyskinesia (Ahlskog and Muenter, 2001) and, the unpredictable effects on PD-related cognitive dysfunction, such as attention shifting and working memory (Gotham et al., 1988, Brown and Marsden, 1990, Owen et al., 1992).
Istradefylline (KW-6002), a selective adenosine A2A antagonist, recently approved in Japan for clinical use as an adjunct treatment in PD for the management of l-DOPA-induced motor complications (Dungo and Deeks, 2013, Pinna, 2014), has so far been utilised for extending the therapeutic action of l-DOPA, known as ‘on-time’. With similar efficacy to clinically used dopaminergic metabolising enzyme inhibitors (Rascol et al., 2005, Lees, 2008), istradefylline (20–60 mg/day) when given with optimal doses of l-DOPA increases daily on-time in advanced PD patients by approximately 1 hour (Hauser et al., 2003, Mizuno and Kondo, 2013). However, such treatment regimens commonly exacerbate the expression of certain dyskinesia (Chen et al., 2013, Kondo and Mizuno, 2015), of which may be ‘non-troublesome’ as described by some PD patients (Lewitt et al., 2008, Stacy et al., 2008). Interestingly, preclinical studies have shown that istradefylline also mediates ‘l-DOPA sparing’ effects i.e. maintained anti-parkinsonian response when sub-optimal l-DOPA doses are given (Grondin et al., 1999, Kanda et al., 2000) but further exploration into this treatment regimen is required. This includes characterising the effects of istradefylline with different l-DOPA dose combinations on PD and LID motor symptoms, as well as therapeutic on-time, for elucidating the most effective treatment strategy for clinical application (Bara-Jimenez et al., 2003).
‘Frontal like’ cognitive deficits in PD, on aspects of attention (Flowers and Robertson, 1985, Downes et al., 1989, Sharpe, 1990) and executive function, that is planning and cognitive flexibility (Owen et al., 1993, Brown and Marsden, 1988, Cooper et al., 1991), are also major unmet clinical needs that significantly impact the quality of patient life (Schrag et al., 2000, Chaudhuri et al., 2006). Such deficits can be found present throughout the disease time course (Lees and Smith, 1983, Levin et al., 1989, Owen et al., 1993) and increase in incidence (10–80%) from early to advanced disease stages (Williams-Gray et al., 2007, Hely et al., 2008, Muslimovic et al., 2009). While l-DOPA treatment alleviates parkinsonian motor disabilities by restoring dopamine depletion in regions of the striatum related to motor function, cognitive deficits are often worsened (Gotham et al., 1988, Kulisevsky et al., 1996), possibly from dopamine influx to cortical areas related to cognitive function (Swainson et al., 2000, Cools, 2006). Interestingly, several preclinical studies have suggested that specific blockade of adenosine A2A receptors within the basal ganglia that are localised to enkephalinergic neurons (Schiffmann et al., 1991a, Schiffmann and Vanderhaeghen, 1993), which form specific pathways along corticostriatal-thalamocortical loops (Alexander et al., 1986, Alexander and Crutcher, 1990), may be beneficial for cognitive improvement in PD (Gevaerd et al., 2001, Prediger et al., 2005, Takahashi et al., 2008). In this context, the potential use of istradefylline treatment, for antagonism of A2A receptors, in cognitive dysfunction in PD, remains to be explored.
In this study, we investigated the behavioural effects of istradefylline treatment on motor and cognitive deficits in parkinsonian monkeys, in order to determine efficacious treatment strategies in PD for clinical use. We first evaluated the effects of istradefylline alone, or in combination with optimal and sub-optimal doses of l-DOPA, on therapeutic on-time and motor symptoms in the gold standard MPTP-treated macaque model of PD and LID. Thereafter, the effects of these combinative treatment regimens were evaluated on measurable PD-related cognitive deficits in chronic low dose (CLD) MPTP-treated monkeys.
Section snippets
Methods
Experimental procedures were conducted under the regulations set by the European Communities Council Directive 24 November 1986 (86/609/EEC), approved by the Institute of Laboratory Animal Science Ethical Committee (Chinese Academy of Medical Sciences, Beijing, China), and completed in an AAALAC-accredited facility.
Istradefylline monotherapy mediates specific anti-parkinsonian effects
We first set out to clarify the effects of istradefylline as a monotherapy for PD motor symptoms, given the discrepancies in currently published clinical and preclinical data (Kanda et al., 1998, Grondin et al., 1999, Bara-Jimenez et al., 2003, Pinna et al., 2007, Fernandez et al., 2010). The use of istradefylline in PD for the blockade of adenosine A2A receptors has been suggested to dampen basal ganglia output nuclei activity caused by abnormal hyperactivity of the indirect pathway in PD
Discussion
The main finding from these motor (Table 1) and cognitive (Table 2) behavioural experiments in MPTP-treated macaque models of PD was that istradefylline treatment attenuated l-DOPA-induced cognitive deficits caused by doses of l-DOPA that alleviate parkinsonism. These data support a broader clinical application of istradefylline as an adjunct to l-DOPA for both motor and cognitive symptomatic therapy in PD patients.
Conclusion
We report a series of behavioural experiments in l-DOPA-treated parkinsonian monkeys that demonstrate the use of istradefylline treatment in PD for (i) motor symptoms and (ii) related cognitive deficits. Several separate viable treatment regimens of istradefylline with l-DOPA have been determined for alleviating parkinsonism with less dyskinesia, extending on-time or reducing l-DOPA-induced cognitive dysfunction, supporting its broader clinical applicability in PD patients.
Funding and disclosure
This study was funded in full by Motac Neuroscience Ltd. WKDK, SMC, QL, YJ, SMG, EYP are employees of Motac Neuroscience Ltd. EB is a shareholder of Motac Neuroscience Ltd.
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2022, NeuropharmacologyCitation Excerpt :Addition of istradefylline to levodopa therapy reduces ‘off’ time and potentially increases the quality of “on” time without dyskinesia. It has been suggested that A2A receptor antagonists may also exert effects on cognitive functioning and potentially on other non-motor symptoms such as depression and anxiety (see (Jenner et al., 2020)) However, although some pre-clinical findings in rodent PD models showed promising results on at least some aspects of cognition (Jenner et al., 2020), studies in more relevant non-human primate models were equivocal (Ko et al., 2016). As of this time, there have been no well-designed, controlled clinical trials of A2A receptor antagonists in which objective study of cognitive function in PD was a primary endpoint.