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.
Abstract
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 microg/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 (S...Continue Reading
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