To further investigate the role of microglial activation in neurodegeneration, we studied minocycline and naltrexone. Although the exact molecular mechanisms are unknown, minocycline is well characterized as an inhibitor of brain microglial activation [43]. Naltrexone is known to alter neuroinflammatory responses [44,45]. Interestingly, neuroinflammation appears to be linked to addiction [3]. Systemic endotoxin treatment leads to a delayed persistent increase in ethanol drinking by mice [57], whereas transgenic mice lacking proinflammatory genes show reduced ethanol drinking [58] and altered acute ethanol motor and sedative effects [59]. In addition, viral vector siRNA knock-down of TLR4 in amygdala reduces lever pressing for alcohol in alcohol-dependent rats [60]. Naloxone, which is similar to naltrexone, has been reported to block NADPH oxidase [61]. Naltrexone has been recently found to block TLR responses [45]. These studies are consistent with naltrexone having anti-inflammatory effects. Naltrexone is known to reduce drinking in both animals and humans, and is used to treat human alcoholism [62]. Interestingly, minocycline also reduces ethanol drinking in rats [63]. In the present study, we found both minocycline and naltrexone reduced ethanol-poly I:C-elicited microglial activation and increased caspase-3 + IR cells. These findings support the hypothesis that proinflammatory microglial activation contributes to neurodegeneration.
