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, 
H(2)O(2), 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 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 (-)-OSU6162 on dopamine uptake and release. We found that 
(-)-OSU6162, 3-150 μM, 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 H(2)O(2), rotenone and 
3-nitropropionic acid. (-)-OSU6162 increases the intracellular levels of BDNF 
and Bcl2/Bax and decreases those of p-ERK/ERK and CHIP in Q111 cells. 
(-)-OSU6162 increased (3)H-dopamine uptake and amphetamine-induced (3)H-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 striatal neurotoxins, suggesting that 
(-)-OSU6162 and related compounds should be tested for neuroprotection in animal 
models and, eventually, in patients with HD.