Dopamine receptor agonists mediate neuroprotection in malonate-induced striatal lesion in the rat.
Mitochondrial bioenergetic defects are involved in neurological disorders associated with neuronal damage in the striatum, such as Huntington's disease and cerebral ischemia. The striatal release of neurotransmitters, in particular dopamine, may contribute to the development of the neuronal damage. Recent studies have shown that dopamine agonists may exert neuroprotective effects via multiple mechanisms, including modulation of dopamine release from nigrostriatal dopaminergic terminals. In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study, we used the malonate model to explore the neuroprotective potential of dopamine agonists. Sprague-Dawley rats were injected systemically with increasing concentrations of D(1), D(2), or mixed D(1)/D(2) dopamine agonists prior to malonate intrastriatal insult. Administration of increasing doses of the D(2)-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D(1)-specific agonist SKF-38393, as well as the mixed D(1)/D(2) agonist apomorphine, conferred higher neuroprotection at lower than at higher concentrations. Our data suggest that malonate-induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D(1) and D(2) agonists showing different profiles of efficacy.
Armentero
Marie-Thérèse
MT
Laboratory of Functional Neurochemistry, IRCCS, C. Mondino, Pavia, Italy.
Fancellu
Roberto
R
Nappi
Giuseppe
G
Blandini
Fabio
F
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D018491:Dopamine Agonists / Q000494:pharmacology*; D008297:Male; D008314:Malonates / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018491:Dopamine Agonists; D008314:Malonates; D018696:Neuroprotective Agents; C030290:malonic acid