Deletion of galectin-3 was also associated with an increase in microglia, and elevated levels of TNF-α and protein carbonyls, a marker of oxidative injury. Microglial number and phenotype significantly influence the http://www.selleckchem.com/products/mek162.html progression of motor neuron disease. Increases in wild-type (non-SOD1G93A) selleck inhibitor microglia reduced neurodegeneration slowed disease progression and increased survival of SOD1G93A mice, supporting a generally protective role for healthy

microglia against the disease process Inhibitors,research,lifescience,medical (Beers et al. 2006). Alternatively, selective reduction of SOD1 overexpression within diseased microglia increased survival time, particularly at the end stage of disease (Boillee et al. 2006; Wang et al. 2010), suggesting that mSOD1 imparts neurotoxic properties to microglia that contribute to neurodegeneration.

Indeed, SOD1G03A microglia display an inflammatory phenotype characterized by elevations in TNF and other inflammatory molecules (Sargsyan Inhibitors,research,lifescience,medical et al. 2009). Thus, the presence of more SOD1G93A microglial cells in the SOD1G93A/Gal-3−/− cohort may have increased the neurotoxic/pro-inflammatory load on neurons, and accelerated disease progression. Also possible, is that deletion of galectin-3 further enhanced the already neurotoxic properties of the mSOD1G93A microglia. This is indirectly supported by data showing that a 50% reduction in the number of proliferating galectin-3/Mac-2+ mutant (mSOD1) Inhibitors,research,lifescience,medical microglia in CD11b-TKmut−30, SOD1G93A doubly transgenic mice had no effect on neurodegeneration Inhibitors,research,lifescience,medical (Gowing et al. 2008). Increased protein carbonyls correlate with an upregulation

of TNF-α transcripts at an early stage of disease in SOD1G93A mice (Hensley et al. 2006). TNF-α elevation also correlates Inhibitors,research,lifescience,medical with disease progression in the mouse, and TNF-α is increased in serum from ALS patients (Poloni et al. 2000; Hensley et al. 2003). Although the precise role of TNF in disease progression is unclear (Gowing et al. 2006), it has many pro-inflammatory effects, including activation and stimulation of free radical release from microglia, as well as potential synergisms with other pathogenic factors involved in the disease (McGeer and McGeer 2002; Mir et al. 2009). While the present studies do not address any direct Drug_discovery relationship between TNF-α and oxidative injury, the observation that both were increased in SOD1G93A/Gal-3−/− mice supports that neuroinflammation was exacerbated in the absence of galectin-3. Though not always consistent (Doverhag et al. 2010), some evidence suggests a protective role for galectin-3+/Mac-2 expressing microglia, at least in models of acute neurodegeneration (Lalancette-Hebert et al. 2007). Such protection is associated with transition of microglia to a galectin-3 positive alternative activation phenotype (M2) that expresses increased levels of IGF-1 and a type Th2 immune bias (Ohtaki et al. 2008).