RESUMO
Mitochondrial superoxide overproduction is believed to be responsible for the neurotoxicity associated with neurodegeneration. Mitochondria-targeted antioxidants, such as MitoQ, have emerged as potentially effective antioxidant therapies. Methionine sulfoxide reductase A (MsrA) is a key mitochondrial-localized endogenous antioxidative enzyme and it can scavenge oxidizing species by catalyzing the methionine (Met)-centered redox cycle (MCRC). In this study, we observed that the natural L-Met acted as a good scavenger for antimycin A-induced mitochondrial superoxide overproduction in PC12 cells. This antioxidation was largely dependent on the Met oxidase activity of MsrA. S-methyl-L-cysteine (SMLC), a natural analogue of Met that is abundantly found in garlic and cabbage, could activate the Met oxidase activity of MsrA to scavenge free radicals. Furthermore, SMLC protected against antimycin A-induced mitochondrial membrane depolarization and alleviated 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Thus, our data highlighted the possibility for SMLC supplement in the detoxication of mitochondrial damage by activating the Met oxidase activity of MsrA.
Assuntos
Antimicina A/farmacologia , Cisteína/farmacologia , Metionina/metabolismo , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Neurônios/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metionina Sulfóxido Redutases/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/metabolismo , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , RatosRESUMO
BACKGROUND: Sanguis draxonis (SD) is a kind of red resin obtained from the wood of Dracaena cochinchinensis (Lour.) S. C. Chen (D. cochinchinensis). The active components of total flavonoids from SD (SDF) have analgesic effect. AIM: The aim of this study is to evaluate the analgesic effects and potential mechanism of SDF on mechanical hypersensitivity induced by spared nerve injury (SNI) model of neuropathic pain in the rat. METHODS: SNI model in rats was established and then the rats were treated with SDF intragastric administration for 14 days. Paw withdrawal mechanical threshold (PMWT) in response to mechanical stimulation was measured by von Frey filaments on day 1 before operation and days 1, 3, 5, 7, 9, 11, 14 after operation, respectively. After 14 days, we measured the levels of nitric oxide (NO), nitric oxide synthase (NOS), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-10 (IL-10) in the spinal dorsal horn. In addition, the expression of fibroblast growth factor receptor 3 (FGFR3), phosphorylated cyclic AMP response element-binding protein (p-CREB) and glial fibrillary acidic protein (GFAP) of the spinal dorsal horn was evaluated by western blotting and an immunofluorescence histochemical method, respectively. RESULTS: Intragastric administration of SDF (100, 200, 400 mg/kg) alleviated significantly SNI-induced mechanical hypersensitivity, as PMWT increased in a dose-dependent manner. Moreover, SDF not only reduced the level of NO, NOS, TNF-α and IL-1ß, but also upregulated the level of IL-10 in the spinal dorsal horn of SNI rats. At the same time, SDF (100, 200, 400 mg/kg) could inhibit the expression of FGFR3, GFAP and p-CREB in the spinal dorsal horn. CONCLUSION: SDF has potentially reduced mechanical hypersensitivity induced by SNI model of neuropathic pain which may be attributed to inhibition of astrocytic function (like release pro-inflammatory cytokines) and NO release as well as p-CREB activation in the spinal dorsal horn.