Inflammation has been implicated to contribute to PD pathogenesis as revealed by epidemiological and pathological studies as well as experimental modeling but whether these are primary or secondary processes is not well understood ( Hunot and Hirsch, 2003 Tansey et al., 2008 Ouchi et al., 2009 Ton et al., 2012). Fundamental processes thought to underlie ongoing degeneration in PD include oxidative damage, mitochondrial dysfunction, protein clearance abnormalities and protein misfolding ( Imai and Lu, 2011 Plowey and Chu, 2011 Breydo et al., 2012 McCoy and Cookson, 2012). Parkinson's disease (PD) is a progressive CNS disorder characterized behaviorally by motor impairment and neurochemically by a loss of nigrostriatal dopaminergic tone. Taken together, these data provide the first evidence that: (i) LOX isozymes are involved in the maintenance of normal dopaminergic function in the striatum, and (ii) the 5- and 12/15-LOX isozymes contribute differentially to striatal vulnerability in response to neurotoxicant challenge. In na ve null 12/15-LOX mice, no significant change in striatal DA values was observed compared to WT, and following MPTP treatment, the transgenics revealed striatal DA reduction similar to the challenged WT mice. In contrast, null 5-LOX littermates demonstrated no significant striatal DA depletion or astrogliosis (as noted by Western blot analyses for GFAP immunoreactivity). When challenged with the selective dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), WT mice showed marked reduction in DA (31.9%) and robust astrocytic and microglial activation as compared to saline-treated animals.
WT mice (26.2%) however, no changes in levels of DA or TH immunoreactivity were observed in null 12/15-LOX vs. A concomitant decline in striatal tyrosine hydroxylase (TH) enzyme was also revealed in null 5-LOX vs. wildtype (WT)) in striatal dopamine (DA) was detected (n=6-8 per genotype).
In na ve mice deficient in 5-LOX expression, a modest but significant reduction (18.0% reduction vs.
To determine whether the isozymes contribute differently to nigrostriatal vulnerability, the effects of 5- and 12/15-LOX deficiency on dopaminergic tone under na ve and toxicant-challenged conditions were tested. These LOX isozymes are distinct in function, with differential effects on neuroinflammation, and the impact of the distinct isozymes in the pathogenesis of Parkinson's disease (PD) has not as yet been evaluated. The 5- and 12/15- lipoxygenase (LOX) isozymes have been implicated to contribute to disease development in CNS disorders such as Alzheimer's disease.