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 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 (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.
Li
Chao
C
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
Biswas
S
S
Li
Xingang
X
Dutta
A K
AK
Le
Weidong
W
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D052160:Benzothiazoles; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D007150:Immunohistochemistry; D007189:Indans / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents; D010302:Parkinson Disease, Secondary / Q000378:metabolism / Q000517:prevention & control*; D010879:Piperazines / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D001713:Biphenyl Compounds; D019208:Brain-Derived Neurotrophic Factor; D015853:Cysteine Proteinase Inhibitors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007189:Indans; C529806:N(6)-(2-(4-(biphenyl-4-yl)piperazin-1-yl)ethyl)-N(6)-propyl-4,5,6,7-tetrahydrobenzo(d)thiazole-2,6-diamine; D018696:Neuroprotective Agents; D010879:Piperazines; D050637:Receptors, Dopamine D3; D013844:Thiazoles; C067713:lactacystin; C086335:(5,6-dimethoxyindan-2-yl)dipropylamine; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine