PMID- 18555604 OWN - NLM STAT- MEDLINE DCOM- 20080915 LR - 20181201 IS - 0304-3940 (Print) IS - 0304-3940 (Linking) VI - 440 IP - 2 DP - 2008 Aug 1 TI - Pramipexole has astrocyte-mediated neuroprotective effects against lactacystin toxicity. PG - 97-102 LID - 10.1016/j.neulet.2008.05.067 [doi] AB - Pramipexole, a dopamine D2/D3 receptor agonist used in the treatment of Parkinson's disease, has been reported to have neuroprotective potential. We investigated the effect of pramipexole against cell death induced by a proteasome inhibitor, lactacystin, using primary mecencephalic neuronal cultures and SH-SY5Y cells. In E14 rat primary mesencephalic cultures, the number of surviving tyrosine hydroxylase (TH)-positive neurons and microtubule associated protein 2 (MAP2)-positive neurons was decreased by exposure to 1-5 microM lactacystin in a dose-dependent manner. Pretreatment with 100 microM pramipexole rescued TH-positive neurons and MAP2-positive neurons from the toxicity of lactacystin. The protective effect of pramipexole was not selective for TH-positive dopaminergic neurons. However, the treatment with 100 microM pramipexole did not protect SH-SY5Y cells against lactacystin-induced cell toxicity and proteasome dysfunction. We hypothesized that the protective effect of pramipexole against the lactacystin-toxicity was not direct but a secondary effect mediated by astrocytes. Therefore, we investigated the efficacy of conditioned medium collected from mecencephalic astrocytes treated with pramipexole. The conditioned medium increased the viability of SH-SY5Y cells against the toxicity of lactacystin. Pramipexole increased the levels of brain derived neurotrophic factor (BDNF) in the conditioned medium of astrocyte cultures. These protective effects were not significantly inhibited by dopamine D2 or D3 receptor antagonists. We demonstrated that pramipexole had the protective effect against lactacystin toxicity, mediated by a neurotrophic effect of astrocyte-produced factors including BDNF. FAU - Imamura, Keiko AU - Imamura K AD - Department of Neurology, Institute of Neurological Sciences, Tottori University, Faculty of Medicine, Yonago, Tottori, Japan. imamurakeiko@nifty.com FAU - Takeshima, Takao AU - Takeshima T FAU - Nakaso, Kazuhiro AU - Nakaso K FAU - Ito, Satoru AU - Ito S FAU - Nakashima, Kenji AU - Nakashima K LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20080523 PL - Ireland TA - Neurosci Lett JT - Neuroscience letters JID - 7600130 RN - 0 (Benzothiazoles) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cysteine Proteinase Inhibitors) RN - 0 (Dopamine Agonists) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Receptors, Dopamine D1) RN - 0 (Receptors, Dopamine D2) RN - 133343-34-7 (lactacystin) RN - 83619PEU5T (Pramipexole) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/*analogs & derivatives/toxicity MH - Animals MH - Astrocytes/cytology/*drug effects/metabolism MH - Benzothiazoles/*pharmacology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Death/drug effects MH - Cell Line, Tumor MH - Cells, Cultured MH - Cysteine Proteinase Inhibitors/toxicity MH - Dopamine Agonists/pharmacology MH - Dose-Response Relationship, Drug MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Microtubule-Associated Proteins/metabolism MH - Neurons/cytology/*drug effects/metabolism MH - Pramipexole MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Dopamine D1/agonists MH - Receptors, Dopamine D2/agonists MH - Tyrosine 3-Monooxygenase/metabolism EDAT- 2008/06/17 09:00 MHDA- 2008/09/16 09:00 CRDT- 2008/06/17 09:00 PHST- 2008/02/19 00:00 [received] PHST- 2008/05/03 00:00 [revised] PHST- 2008/05/17 00:00 [accepted] PHST- 2008/06/17 09:00 [pubmed] PHST- 2008/09/16 09:00 [medline] PHST- 2008/06/17 09:00 [entrez] AID - S0304-3940(08)00710-6 [pii] AID - 10.1016/j.neulet.2008.05.067 [doi] PST - ppublish SO - Neurosci Lett. 2008 Aug 1;440(2):97-102. doi: 10.1016/j.neulet.2008.05.067. Epub 2008 May 23.