title: Dopamine D3 receptor-modulated neuroprotective effects of lisuride.
abstract: Dopamine (DA) contributes to the regulation of voluntary movement, and a deficiency in DAergic neurons leads to movement disorders. The objective of this study was to examine the neuroprotective effect of DA D2-like receptor agonist, lisuride, and the role of DA receptors in this protection. Treatment with lisuride alleviated loss of tyrosine hydroxylase (TH) both direct and intraperitoneal injection in 6-hydroxydopamine (6-OHDA) mouse model. Similar results were obtained in primary neuronal cultures treated with lisuride. Lisuride protected TH expression against 6-OHDA-induced cytotoxicity in a concentration-dependent manner. Then, we evaluated the role of DA D2 and D3 receptor in neuroprotective effect of lisuride. Treatment of neuronal cultures with L-741,626, a DA D2 receptor-selective antagonist, did not alter neuroprotective effect of lisuride. However, protective effect of lisuride on TH expression was abolished when cells were treated with GR103691, a D3 receptor selective antagonist. Furthermore, whether lisuride can alleviate mitochondrial damage of DAergic neurons induced by 6-OHDA, we investigated the expression of the mitochondrial regulatory protein, paraplegin, and changes in mitochondria morphology. Treatment with lisuride countered a 6-OHDA-induced reduction in paraplegin and TH expression, and co-treatment with GR103691 blocked this effect of lisuride. Transmission electron microscopy confirmed the lisuride mitigation of 6-OHDA-induced damage to the mitochondrial membrane and cristae. These results suggest that the DA D3 receptor mediates the neuroprotective effects of lisuride by preventing mitochondrial damage.
authors.affiliation: Department of Veterinary Medicine, Institute of Animal Medicine, Gyeongsang National University, Jinju 660-701, South Korea.
authors.forename: Munki
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Veterinary Medicine, Institute of Animal Medicine, Gyeongsang National University, Jinju 660-701, South Korea.
authors.forename: Sijoon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Veterinary Medicine, Institute of Animal Medicine, Gyeongsang National University, Jinju 660-701, South Korea.
authors.forename: Jeahyeon
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Veterinary Medicine, Institute of Animal Medicine, Gyeongsang National University, Jinju 660-701, South Korea. Electronic address: gonskim@gnu.ac.kr.
authors.forename: Gonsup
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Veterinary Medicine, Institute of Animal Medicine, Gyeongsang National University, Jinju 660-701, South Korea. Electronic address: wonck@gnu.ac.kr.
authors.forename: Chungkil
authors.initials: C
authors.lastname: Won
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000494:pharmacology; D008090:Lisuride / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016627:Oxidopamine / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D061251:Primary Cell Culture; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D018696:Neuroprotective Agents; D010879:Piperazines; D010880:Piperidines; D050637:Receptors, Dopamine D3; C105771:GR 103691; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D016627:Oxidopamine; D008090:Lisuride; D014446:Tyrosine 3-Monooxygenase; D008666:Metalloendopeptidases; C491813:Spg7 protein, mouse; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: 6-hydroxydopamine; D3 receptor; Dopamine; Lisuride; Substantia nigra