Neuroprotection of pramipexole in UPS impairment induced animal model of Parkinson's disease.
Pramipexole (PPX), a dopamine (DA) receptor D3 preferring agonist, has been used as monotherapy or adjunct therapy to treat Parkinson's disease (PD) for many years. Several in vitro and in vivo studies in neurotoxin-induced DA neuron injury models have reported that PPX may possess neuroprotective properties. The present study is to evaluate the neuroprotection of PPX in a sustained DA neuron degeneration model of PD induced by ubiquitin-proteasome system (UPS) impairment. Adult C57BL/6 mice were treated with PPX (low dose 0.1 mg/kg or high dose 0.5 mg/kg, i.p, twice a day) started 7 days before, and continued after microinjection of proteasome inhibitor lactacystin in the medial forebrain bundle for a total 4 weeks. Animal behavior observation, and pathological and biochemical assays were conducted to determine the neuroprotective effects of PPX. We report here that PPX treatment significantly improves rotarod performance, attenuates DA neuron loss and striatal DA reduction, and alleviates proteasomal inhibition and microglial activation in the substantia nigra of lactacystin-lesioned mice. PPX can increase the levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and induce an activation of autophagy. Furthermore, pretreatment with D3 receptor antagonist U99194 can significantly block the PPX-mediated neuroprotection. These results suggest that multiple molecular pathways may be attributed to the neuroprotective effects of PPX in the UPS impairment model of PD.
Li
Chao
C
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Guo
Yuan
Y
Xie
Wenjie
W
Li
Xingang
X
Janokovic
Joseph
J
Le
Weidong
W
D000111:Acetylcysteine / Q000031:analogs & derivatives; D000818:Animals; D001343:Autophagy; D052160:Benzothiazoles / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000627:therapeutic use*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077487:Pramipexole; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism*
D052160:Benzothiazoles; D019208:Brain-Derived Neurotrophic Factor; D018491:Dopamine Agonists; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D061988:Proteasome Inhibitors; D050637:Receptors, Dopamine D3; D025801:Ubiquitin; C067713:lactacystin; D000077487:Pramipexole; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine; D000111:Acetylcysteine