Anti-Parkinson effects of a selective alpha2C-adrenoceptor antagonist in the MPTP marmoset model

•Indirect targeting dopaminergic neurotransmission may provide innovative therapeutic potential in Parkinson's disease.•The alpha2C-adrenoceptor antagonist JNJ27063699 mitigates motor deterioration in MPTP monkey model of Parkinson's disease.•The anti-parkinsonian therapeutic dose of JNJ27063699 is devoid from side effects.•Adrenergic intervention may be successful to improve motor control in Parkinson's disease. Current dopamine replacement therapies, in Parkinson's disease (PD), result in aversive side effects and rapid drug dose escalation over time. Therefore, a non-dopaminergic treatment would be an advantageous supplement to lower the dose of dopamine replacement treatment postponing the occurrence of side effects. The noradrenergic system plays an important role in the facilitation or maintenance of the activity of the nigrostriatal dopamine pathways. Here the putative anti-Parkinson effects of the oral selective alpha2C-adrenoceptor antagonist (JNJ27063699 0.1–10mg/kg p.o.) and of vehicle (fruit syrup) were evaluated in the MPTP-marmoset model. Dose-related anti-Parkinson effects were assessed by means of a behavioural rating scale covering parkinsonian symptoms, body weight and body temperature, and two test systems assessing locomotor activity and complex motor skills of hand–eye coordination for controlled movements in MPTP- or saline-pretreated marmosets. JNJ27063699, at the middle and higher doses, consistently improved locomotor activity and hand–eye coordination capabilities, which indicates an improvement in the coordination of motor control -or movements- in MPTP-pretreated monkeys. No additional effects on the parkinsonian symptoms or side effects were observed on other test systems. Overall, the findings link deficit in motor coordination with dysfunctional adrenergic signalling and it suggest that selective alpha2C adrenergic antagonism may contribute to behavioural improvement in the MPTP-monkey model of PD. In multi-drug medication JNJ27063699 might have potential in the treatment of motor deficit in PD.