| In recent years, due to abuse of antibiotics, the bacterial multidrug resistance is quickly spread in the world, especially multidrug resistant gram negative bacteria. However, the research and development of new drug against them are few. Because of the the effective treatment of gram-negative bacteria infection, the colistin gets value and is used in clinical. On account of its nephrotoxicity and neurotoxicity, exploring the way to reduce or eliminate the toxicity of colistint is of great significance to guide the clinical medication.Autophagy, also called cellular self-digestion, can degrade the protein and organelle in the cells, which participates in an amount of disease and physiology. Autophagy plays a double-edged role in the cells. It protects the cells against the intracellular damage, for example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing, while high level of autophagy may give rise to cell death. preliminary study showed colistin sulfate-induced autophagy in PC12 cells is protective. because of the complexity of nerve system, model in vivo was studied.Kunming strain female mice, 20~24 g, were divided into the control group and 4 administration groups(intravenously colistin sulfate for 1, 3, 5 and 7 days). The weight, ultrastructure of nerve cells and autophagy related protein(LC3 I/II and p62) were examined, which shows that autophagy occours in 3 days after administration. Based on above, the mice were randomLy divided into the control group, the 3-MA group(600 mg/kg 3-MA), the colistin sulfate group(15 mg/kg colistin sulfate) the colistin sulfate+3-MA group(15 mg/kg colistin sulfate and 600 mg/kg 3-MA). The weight, ultrastructure of nerve cells, neurological behavior in combination test(spontaneous activity, gait score and holding power of the hind legs), oxidation-antioxidation system biochemical indexes tests and autophagy related protein(LC3 I/II and p62) were examined after intravenous injection for 3 days. The result as follow:(1) In the experiment of the colistin sulfate induced neurotoxicity, the number of autophagosome increased in 3 days, and the ratio of LC3 II/LC3 I increased, and the expression of and p62 decreased which were significant difference(p<0.05) after 1 day’s administration and after 3 days’ administration.(2) Compared with the control group, There were higher ratio of LC3 II/LC3 I and lower expression of p62 with highly significant difference(p<0.01) in the colistin group. Compared with the colistin sulfate group, the ratio of LC3 II/LC3 I became lower(p<0.01) and the expression of p62 became higher(p<0.01) in the colistin+3-MA group which indicated that 3-MA can inhibit autophagy in never cells.(3) Compared with the control group, there was no significant difference(p<0.05) in 3-MA group and colistin group, whice indicated the mice has no abnormal behavior because of the autophagy of sciatic nerve. The gait score increased and the spontaneous activity decreased with significant difference(p<0.05), and the holding power of the hind legs decreased with highly significant difference(p<0.01) in in the colistin sulfate + 3-MA group, which demonstrated that autophagy protect never cells against the neurotoxicity induced by colistin sulfate.(4) In the antioxidant tests, MDA increased and CAT decreased with significant difference(p<0.05) and SOD and GSH decreased with highly significant difference(p<0.01) in the colistin sulfate + 3-MA group compared with the control group, which suggested that 3-MA will accelerate unbalance of the oxidation-antioxidation system. So the protection of colistin sulfate-induced autophagy is associated with the oxidative stressIn conclusion, colistin sulfate-induced autophagy protected the sciatic nerve against neurotoxicity, which is related to the oxidative stress. |
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