br Discussion Herein we demonstrate

Discussion Herein, we demonstrate that mice deficient in L-12/15 LO are more sensitive to 3-NP-induced toxicity although a substantial individual variability in striatal lesion size in response to 3-NP in both genotypes was observed. This variability is not atypical; several studies demonstrate similar results [5], [6], [8]. Despite this, behavioral outcomes did not differ between genotypes. A caveat to this analysis is that mice null for the Alox15 gene demonstrated a 100% increase in behavioral morbidity when compared to their littermate controls, necessitating removal from the study. Additionally, we did not observe any differences in 3-NP-induced weight loss with nearly identical numbers of mice from each genotype [n=6 (+/+) and 7 (−/−)] being removed for excessive weight loss, a phenomenon that also occurs in HD patients [4]. These findings support the idea that this is a consequence of inhibition of peripheral tissue mitochondrial function [3], [18]. Our findings of enhanced striatal sensitivity are in contrast with what has been previously demonstrated in models of stroke and Alzheimer’s disease. Increased L-12/15 LO immunostaining was demonstrated in the peri-infarct area of mice subjected to experimental ischemia [46] as well as in post-mortem PPDA sections from human stroke patients [53]. The finding that Alox15−/− mice or Alox15+/+ mice treated with a novel selective inhibitor of L-12/15-LO had less cerebral ischemic damage when compared to untreated Alox15+/+ mice [53] indicated that this increase contributes to pathology. L-12/15 LO immunoreactivity was also increased in post-mortem AD brains when compared with age-matched controls, in a manner that correlated with the extent of lipid peroxidation [37], [52]. Genetic deletion of L-12/15 LO in the Tg2576 model of AD resulted in a significant reduction in the production and deposition of Aβ in the hippocampus that correlated with improvement of cognitive deficits [51], whereas genetic over-expression of L-12/15 LO in this same mouse strain, led to increased brain Aβ levels and worsened memory impairments [11]. Finally, 3xTg mice receiving systemic administration of a selective inhibitor of L-12/15 LO showed significant reductions in Aβ deposition, phosphorylation of tau, and improvements of memory over those receiving placebo [10]. Together, these data have led to the suggestion that inhibition of L-12/15 LO may be a viable therapeutic strategy for the treatment of stroke [53] and AD [21]. Important differences in the function of the enzyme and/or the susceptibility of the different brain areas studied might explain the differing results found in our study. For instance, the stroke and AD studies focus on cortex and hippocampus, respectively, whereas herein the focus in on the striatum. Given that systemic injection of 3-NP causes similar inhibition of hippocampal, cortical and striatal SDH levels (our unpublished observations), a brain area specific mechanism seems plausible. Disparate cellular effects of L-12/15 LO also have been reported. Whereas its enzymatic products might act as pro-inflammatory factors in some settings [37], [51], [52], [53], studies also point to its role in suppressing inflammation via production of a class of eicosanoids called lipoxins [19], [39], [40]. Thus, loss of L-12/15 LO result in unmitigated inflammation following 3-NP treatment [1], [2]. Enhanced inflammatory gene expression, including increased peripheral expression of interleukin-1β, in L-12/15 LO deficient mice has been reported [23]. We have shown that IL-1β potentiates neuronal cell death under conditions of energy deprivation [16], [17], [20]. Should a similar result occur in brain, it would likely be deleterious. Finally, loss of L-12/15 LO could result in the build-up of arachidonic acid—which itself can be deleterious to brain [31], [48]—or could result in enhanced production of other, perhaps toxic, eicosanoids (e.g., cyclooxygenase [COX] or 5-Lipoxygenase [5-LO] derived metabolites) via substrate diversion [36], [43]. Of note, administration of licofelon, a dual inhibitor of COX/5-LO, significantly reduced 3-NP-induced HD-like symptoms in rats [25], suggesting either one or both enzymes are involved in 3-NP-induced neurotoxicity.