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Novel D3 dopamine receptor‐preferring agonist D‐264: Evidence of neuroprotective property in Parkinson's disease animal models induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine and lactacystin

Parkinson's disease (PD), a progressive neurodegenerative movement disorder, is known to be caused by diverse pathological conditions resulting from dysfunction of the ubiquitin‐proteasome system (UPS), mitochondria, and oxidative stress leading to preferential nigral dopamine (DA) neuron degeneration in the substantia nigra. In the present study, we evaluated the novel D3 receptor‐preferring agonist D‐264 in a mouse model of PD to evaluate its neuroprotective properties against both the nigrostriatal dopaminergic toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐ and the proteasome inhibitor lactacystin‐induced dopaminergic degeneration. C57BL/6 male mice either were given MPTP by intraperitoneal injection twice per day for 2 successive days at a dose 20 mg/kg or were microinjected with lactacystin bilaterally (1.25 μg/side) into the medial forebrain bundle (MFB). Pretreatment with D‐264 (1 mg/kg and 5 mg/kg, intraperitoneally, once per day), started 7 days before administration of MPTP or lactacystin. We found that D‐264 significantly improved behavioral performance, attenuated both MPTP‐ and lactacystin‐induced DA neuron loss, and blocked proteasomal inhibition and microglial activation in the substantia nigra (SN). Furthermore, D‐264 treatment was shown to increase the levels of brain‐derived neurotrophic factor (BDNF) and glial cell line‐derived factor (GDNF) in MPTP‐ and lactacystin‐treated mice, possibly indicating, at least in part, the mechanism of neuroprotection by D‐264. Furthermore, pretreatment with the D3 receptor antagonist U99194 significantly altered the effect of neuroprotection conferred by D‐264. Collectively, our study demonstrates that D‐264 can prevent neurodegeneration induced by the selective neurotoxin MPTP and the UPS inhibitor lactacystin. The results indicate that D‐264 could potentially serve as a symptomatic and neuroprotective treatment agent for PD. © 2010 Wiley‐Liss, Inc.