Anti-Parkinson effects of a selective alpha2C-adrenoceptor antagonist in the MPTP marmoset model.
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.
Department of Immunobiology, Division Neuropathology, Biomedical Primate Research Centre (BPRC), P.O. Box 3306, 2280 GH Rijswijk, The Netherlands. Electronic address: philippens@bprc.nl.
Ingrid H C H M
IH
Philippens
Department of Diagnosis and Therapy, TNO Defence, Security and Safety, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Marloes J A
MJ
Joosen
Dept. of Neurosciences, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Abdellah
A
Ahnaou
Dept. of Medicinal Chemistry, Division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain.
Ignacio
I
Andres
Dept. of Neurosciences, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Wilhelmus Pim H I M
WP
Drinkenburg
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000284:Administration, Oral; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012720:Severity of Illness Index
D058669:Adrenergic alpha-2 Receptor Antagonists; D000978:Antiparkinson Agents; D018341:Receptors, Adrenergic, alpha-2; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Alpha2C-adrenergic; MPTP; Marmoset monkey; Motor behavior; Non-human primate; Parkinson's disease