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Nociceptive behaviour and lumbar spinal NADPH‐d/NOS, p‐ERK AND c‐FOS expression after formalin pain induction in weaned rats
Author(s) -
C. Ruiz,
M. J. Casarejos,
M. A. Mena,
J. G. de Yebenes,
William Hendriks,
Paola Arlotta
Publication year - 2012
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2012.03.289
Subject(s) - nociception , c fos , lumbar , medicine , mapk/erk pathway , acute pain , neuroscience , psychology , anesthesia , chemistry , anatomy , signal transduction , receptor , gene expression , biochemistry , gene
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 (−)-OSU6162 are members of a new family of compounds referred to as dopaminergic stabilizers, which normalize abnormal dopamine neurotransmission. We investigated the effects of (−)-OSU6162 on huntingtin knocked-in striatal neurons in culture. Control neurons had normal full-length huntingtin with 7 glutamines while “mutant” neurons had large expansions (Q = 111). We studied the dose-effect curves of (−)-OSU6162 on mitochondrial activity, LDH levels, necrosis and apoptosis in untreated Q7 and Q111 cells. In addition, we investigated the effects of (−)-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 (−)-OSU6162 measuring the effects of this dopaminergic stabilizer on the ratios of Bcl2/Bax proteins and of p-ERK/ERK, the levels of chaperones and GSH, and the effects of (−)-OSU6162 on dopamine uptake and release. We found that (−)-OSU6162, 3-150 M, produces a dose dependent increase of mitochondrial activity and a reduction of cell death. (−)-OSU6162 does not change glutamate toxicity, but it partially prevents that of H2O2, rotenone and 3-nitropropionic acid. (−)-OSU6162 increases the levels Bcl2/Bax and decreases those of p-ERK/ERK and CHIP in Q111 cells. (−)-OSU6162 increased 3Hdopamine uptake and amphetamine-induced 3H-dopamine release in E13 mouse mid brain neurons. Our studies demonstrate that (−)OSU6162 improves survival and mitochondrial function in striatal Q111 neurons and the resistance of these cells to several neurotoxins that damage striatal neurons, suggesting that (−)-OSU6162 and related compounds should be tested for neuroprotection in animal models and, eventually, in patients with HD.