Combined minocycline plus pyruvate treatment enhances effects of each agent to inhibit inflammation, oxidative damage, and neuronal loss in an excitotoxic animal model of Huntington's disease.

摘要

The combination effects of minocycline (MC), a second-generation tetracycline compound and pyruvate (PY), a glycolysis end metabolite with antioxidant activity were investigated in the rat striatum following an excitotoxic insult. Striatal injection of quinolinic acid (QUIN) resulted in marked inflammation characterized by microgliosis, astrogliosis and enhanced expressions of pro-inflammatory enzymes inducible nitric oxide synthase and cyclooxygenase-2. Inflammatory responses were attenuated with administration of either MC or PY, however, the combination of both compounds was significantly more effective in reducing inflammation relative to MC or PY applied alone. Immunohistochemical analysis at 7 days post-intrastriatal QUIN injection showed extensive oxidative stress evident as lipid peroxidation, oxidative DNA damage and reactive oxygen species formation which was partially decreased by each agent applied separately but markedly inhibited with the combination of the two compounds. In addition, combination treatments significantly reduced neuronal loss in QUIN-injected striatum compared with the agents applied separately. Furthermore, long-term combination treatment decreased striatal lesions and inflammation after QUIN injection. These results demonstrate that MC and PY confer a considerably enhanced anti-inflammatory and neuroprotective efficacy when applied together and suggest this combinatorial procedure as a novel therapeutic strategy in neurodegenerative disorders such as Huntington's disease which exhibit excitotoxic insults.