Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease.
The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation,is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.5or 1 mg/kg/d) and rimonabant (0.1 mg/kg/d) given as monotherapy or combined. The effects of the treatments to counteract dopaminergic cell death and neuroinflammation were assessed by immunohistochemistry for tyrosine hydroxylase and glial cell markers, respectively. Both rimonabant and MSX-3 (1 mg/kg/d) promoted dopaminergic neuron survival in the substantia nigra pars compacta (SNc) when given alone; this effect was weakened when the compounds were combined. Glial activation was not significantly affected by MSX-3 (1 mg/kg/d), whereas rimonabant seemed to increase astrocyte cell density in the SNc. Our findings demonstrate the neuroprotective potential of single treatments and suggest that glial cells might be involved in this protective effect. The results also indicate that the neuroprotective potential of combined therapy may not necessarily reflect or promote single-drug effects and point out that special care should be taken when considering multidrug therapies in PD.
From the Laboratory of Functional Neurochemistry (SC, GL, GA, EM, GFA, FB, MTA), C. Mondino National Neurological Institute, Pavia, Italy; Cell and Molecular Neuropharmacology (RF), Neurosciences Division (JLL), Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain; Department of Biochemistry and Molecular Biology (RF), University of Barcelona, Barcelona, Spain; CIBERNED (JLL), Spain; Pharma Center Bonn (YB, CEM), University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Bonn, Germany; Department of Chemistry (YB), Faculty of Science, Sultan Qaboos University, Muscat, Oman; and National Research Council of Italy (AP), Institute of Neuroscience, Cagliari, Italy.
Silvia
S
Cerri
Giovanna
G
Levandis
Giulia
G
Ambrosi
Elena
E
Montepeloso
Gian Filippo
GF
Antoninetti
Rafael
R
Franco
José Luis
JL
Lanciego
Younis
Y
Baqi
Christa E
CE
Müller
Annalisa
A
Pinna
Fabio
F
Blandini
Marie Therese
MT
Armentero
D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000473:pathology / Q000517:prevention & control*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D014970:Xanthines / Q000494:pharmacology / Q000627:therapeutic use
D058917:Adenosine A2 Receptor Antagonists; D063387:Cannabinoid Receptor Antagonists; C113602:MSX 3 compound; D018696:Neuroprotective Agents; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014970:Xanthines; D000077285:Rimonabant