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

Chao Li, S. Biswas, Xingang Li, Aloke K. Dutta, Weidong Le

Research output: Contribution to journalArticle

39 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)2513-2523
Number of pages11
JournalJournal of Neuroscience Research
Volume88
Issue number11
DOIs
StatePublished - Aug 15 2010

Keywords

  • 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine
  • 5,6-dimethoxy-2-(di-n-propylamino)indan maleate
  • Animal models
  • BDNF
  • Brain-derived neurotrophic factor
  • GDNF
  • Glial cell line-derived factor
  • Lactacystin
  • MPTP
  • Neuroprotection
  • Parkinson's disease
  • U99194

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this