The dopaminergic stabilizer, (鈭?-OSU6162, rescues striatal neurons with normal and expanded polyglutamine chains in huntingtin protein from exposure to free radicals and mitochondrial toxins

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• 作者：C. Ruiz^a ; ^b ; M.J. Casarejos^b ; ^c ; I. Rubio^a ; ^b ; S. Gines^b ; ^d ; M. Puigdellivol^b ; ^d ; J. Alberch^b ; ^d ; M.A. Mena^b ; ^c ; J.G. de Yebenes^a ; ^b ; ^{jgyebenes@yahoo.com}
• 关键词：BDNF ; brain derived neurotrophic factor ; CHIP ; carboxy terminus of Hsp70-binding protein ; DIV ; days in vitro ; DMEM ; Dulbecco's Modified Eagle's Medium ; FBS ; fetal bovine serum ; GSH ; glutathione ; HD ; Huntington's disease ; HSP70 ; heat-shock protein 70 
• 刊名：Brain Research
• 出版年：2012
• 期刊代码：8_00068993
• 类别：neu
• 出版时间：12 June, 2012
• 卷：1459
• 期：Complete
• 页码：100-112
• 文件大小：2725 K

摘要

Huntington's disease (HD) is a neurodegenerative disease characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and caused by a polyglutamine expansion in the huntingtin protein. There is so far neither cure nor approved disease-slowing therapy for HD, though recent clinical studies have shown a beneficial long-term effect of pridopidine in patients with HD. The nature of this effect, purely symptomatic or, in addition, neuroprotective, is difficult to elucidate in clinical trials. Pridopidine and (鈭?-OSU6162 are members of a new family of compounds referred to as dopaminergic stabilizers, which normalize abnormal dopamine neurotransmission.

We investigated the effects of (鈭?-OSU6162 on huntingtin knocked-in striatal neurons in culture. Control neurons had normal full-length huntingtin with 7 glutamines while 鈥渕utant鈥?neurons had large expansions (Q = 111). We studied the dose-effect curves of (鈭?-OSU6162 on mitochondrial activity, LDH levels, necrosis and apoptosis in untreated Q7 and Q111 cells. In addition, we investigated the effects of (鈭?-OSU6162 on Q7 and Q111 neurons challenged with different neurotoxins such as sodium glutamate, H₂O₂, rotenone and 3-nitropropionic acid (3NP). As we found prevention of toxicity of some of these neurotoxins, we investigated the putative neuroprotective mechanisms of action of (鈭?-OSU6162 measuring the effects of this dopaminergic stabilizer on expression and release of BDNF, the ratios of Bcl2/Bax proteins and of p-ERK/ERK, the levels of chaperones and GSH, and the effects of (鈭?-OSU6162 on dopamine uptake and release.

We found that (鈭?-OSU6162, 3-150 渭M, produces a dose dependent increase of mitochondrial activity and a reduction of cell death. (鈭?-OSU6162 does not change glutamate toxicity, but it partially prevents that of H₂O₂, rotenone and 3-nitropropionic acid. (鈭?-OSU6162 increases the intracellular levels of BDNF and Bcl2/Bax and decreases those of p-ERK/ERK and CHIP in Q111 cells. (鈭?-OSU6162 increased ³H-dopamine uptake and amphetamine-induced ³H-dopamine release in E13 mouse mid brain neurons.

Our studies demonstrate that (鈭?-OSU6162 improves survival and mitochondrial function in striatal Q111 neurons and the resistance of these cells to several striatal neurotoxins, suggesting that (鈭?-OSU6162 and related compounds should be tested for neuroprotection in animal models and, eventually, in patients with HD.