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The Journal of Neuroscience, October 15, 2002, 22(20):9122-9133

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

David Blum, David Gall^*, Marie-Christine Galas^*, Pablo d'Alcantara, Kadiombo Bantubungi, and Serge N. Schiffmann

Laboratoire de Neurophysiologie, Université Libre de Bruxelles-Erasme, CP601, 1070 Brussels, Belgium

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 µg · kg¹ · d¹) 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 µM 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.

Key words: Huntington's disease; 3-nitropropionic acid; adenosine; A₁ receptor; neuroprotection; striatum; cell death

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^* D.G. and M.-C.G. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22209122-12$05.00/0

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