The adenosine A1 receptor agonist adenosine amine congener exerts a neuroprotective effect against the development of striatal lesions and motor impairments in the 3-nitropropionic acid model of neurotoxicity.
Huntington's disease is a genetic neurodegenerative disorder characterized clinically by both motor and cognitive impairments and striatal lesions. At present, there are no pharmacological treatments able to prevent or slow its development. In the present study, we report the neuroprotective effect of adenosine amine congener (ADAC), a specific A1 receptor agonist known to be devoid of any of the side effects that usually impair the clinical use of such compounds. Remarkably, in a rat model of Huntington's disease generated by subcutaneous infusion of the mitochondrial inhibitor 3-nitropropionic acid (3NP), we have observed that an acute treatment with ADAC (100 microg x kg(-1) x d(-1)) not only strongly reduces the size of the striatal lesion (-40%) and the remaining ongoing striatal degeneration (-30%), but also prevents the development of severe dystonia of hindlimbs. Electrophysiological recording on corticostriatal brain slices demonstrated that ADAC strongly decreases the field EPSP amplitude by 70%, whereas it has no protective effect up to 1 microm against the 3NP-induced neuronal death in primary striatal cultures. This suggests that ADAC protective effects may be mediated presynaptically by the modulation of the energetic impairment-induced striatal excitotoxicity. Altogether, our results indicate that A1 receptor agonists deserve further experimental evaluation in animal models of Huntington's disease.
Blum
David
D
Laboratoire de Neurophysiologie, Université Libre de Bruxelles-Erasme, CP601, 1070 Brussels, Belgium. David.Blum@ulb.ac.be
Gall
David
D
Galas
Marie-Christine
MC
d'Alcantara
Pablo
P
Bantubungi
Kadiombo
K
Schiffmann
Serge N
SN
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004421:Dystonia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics; D006614:Hindlimb / Q000503:physiopathology; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D058906:Purinergic P1 Receptor Agonists; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D015203:Reproducibility of Results; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D016896:Treatment Outcome
D004745:Enkephalins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D058906:Purinergic P1 Receptor Agonists; D012333:RNA, Messenger; C106045:adenosine amine congener; D013385:Succinate Dehydrogenase; D000241:Adenosine; C015392:3-nitropropionic acid