As in AD, the role of inflammation in HD pathogenesis may

similarly involve both peripheral and CNS-resident components of the innate immune system. In patients with HD, increased production of inflammatory cytokines can be detected many years prior to symptom onset, and plasma levels of proinflammatory cytokines correlate with symptom progression (Björkqvist et al., 2008). Circulating monocytes from HD patients are more responsive to a proinflammatory signal than monocytes from control patients, a finding that has been recapitulated in multiple HD mouse models (Björkqvist et al., 2008). This hyperreactivity of monocytes may reflect functional alterations triggered by the presence of mutant huntingtin protein. Whether such functional alterations directly contribute to neurodegeneration in HD remains to be determined. One mechanism whereby peripheral innate immune function Alectinib clinical trial could potentially influence neuron survival or

degeneration in HD involves the tryptophan catabolism pathway, which has been shown to be altered by the expression of mutant huntingtin in yeast (Giorgini et al., 2005). One upstream metabolite in this pathway, L-kynurenine is neuroprotective, while downstream metabolites, 3-hydroxykynurenine and quinolinic acid, are neurotoxic (Zádori et al., 2009). MSNs are preferentially susceptible to the toxicity of quinolinic acid (Roberts et al., click here 1993). A recent study reported that pharmacological inhibition of the rate-limiting enzyme in this pathway, kyneurenine 3-monooxygenase (KMO), markedly slowed disease progression in HD mice (Zwilling et al., 2011). Since the KMO inhibitor employed in this study does not cross the blood-brain-barrier, the authors suggest that inhibition of KMO in the peripheral innate immune system is sufficient to increase levels of neuroprotective metabolites from the tryptophan catabolism pathway in the Chlormezanone CNS. Since KMO expression is promoted by proinflammatory stimuli (Connor et al., 2008), the increased inflammatory responses reported in HD peripheral monocytes may enhance

KMO expression and/or activity and exacerbate neurodegeneration. Interestingly, KMO inhibition also ameliorated pathology in a murine AD model (Zwilling et al., 2011), suggesting that a similar metabolic mechanism may comprise another facet of CNS-innate immunity cross-talk involved in AD neurodegeneration. Both pathological and positron emission tomography (PET) studies have shown that patients with PD exhibit a robust inflammatory response in brain regions undergoing neurodegeneration (Gerhard et al., 2006, McGeer et al., 1988, Ouchi et al., 2009 and Wersinger and Sidhu, 2002). Furthermore, as in AD, epidemiological studies suggest that chronic users of nonsteroidal anti-inflammatory drugs (NSAIDs) may have a decreased risk of PD (Samii et al., 2009).