Mechanism of repetitively preconditioning 3-nitropropionic acid for protection of dopamine neurons / 中国组织工程研究

ABSTRACT

BACKGROUND: Mainly pathological changes of Parkinson disease (PD)are related to irreversible degeneration and reduction of dopamine neurons of substantia nigra in midbrain; however, oxidative stress reaction plays an important role in onset of PD. 3-nitropropionie acid (3-NP) is an inhibitor of mitochondria compound I, and it can inhibit oxidative phosphorylation so as to restrain energy metabolism. However, professor Riepe from Germany found that small dose of 3-NP can increase the tolerance of neurons to ischemic hypoxia. It is unclear whether it can also strengthen the tolerance of dopamine neurons to neurotoxin.OBJECTIVE: To investigate the possible mechanism and prevention of repetitively preconditioning 3-NP for treating PD.DESIGN: Controlled observational animal study. SETTING: Department of Neurology, Union Hospital affiliated to TongjiMedical College, Huazhong University of Science and Technology. MATERIALS The experiment was carried out at the Neurological Lab oratory, Union Hospital affiliated to Tongji Medical College, Huazhong U niversity of Science and Technology from March to July 2004. A total of48 C57BL mice, weighing 18-20 g, aged 2-3 months, of both genders, were randomly divided into 6 groups with 8 in each group. ① Blank con trol group Mice were not medicated. ② 3-NP single administrationgroup Mice were intraperitoneally injected with 3-NP once. ③ 3-NPrepetitively administrations group Mice were intraperitoneally injectedwith 3-NP every 5 days for 5 times in total. ④ Neurotoxin group Micewere intraperitoneally injected with neurotoxin once every day for 5 timesin total. ⑤ 3-NP single preconditioning group Mice were intraperitoneal ly injected with 3-NP once, and 3 days later, they were intraperitoneallyinjected with neurotoxin once every day for 5 times in total. ⑥ 3-NPrepetitively preconditionings group Mice were intraperitoneally injectedwith 3-NP and repetitively every 5 days for 5 times in total; 3 days later, mice were intraperitoneally injected with neurotoxin once every day for5 times in total. Dosages of 3-NP and neurotoxin were 20 mg/kg and30 mg/kg, respectively. METHODS: Motor coordination of mice was scored with pole test andtraction test before experiment and at 3 days after the last injection ofneurotoxin. Three days after complete injection, mice were sacrificed rapid ly to measure the contents of malondialdehyde (MDA) and reduced glu tathione (GSH) in the substantia nigra of midbrain. MAIN OUTCOME MEASURES: ① Motor and behavior scores; ② con tent of MDA; ③ content of GSH.~ULTS All 48 mice were involved in the final analysis. ① Scores of pole test and traction test were decreased in neurotoxin group as compared with those in control group (P＜0.01); but the scores were increased after 3-NP single/repetitively preconditionings, and there were significant difference (P＜0.05, P＜0.01). Meanwhile, there was also significant differencebetween 3-NP repetitively preconditionings group and 3-NP single preconditioning group (P＜0.05). ② Content of MDA was increased in neurotoxin group as compared with that in control group, and there was significant difference (P＜0.01); content of MDA was decreased after 3-NP single preconditioning as compared with that in neurotoxin group, and there was significant difference (P＜0.05); content of MDA was remarkably decreased after 3-NP repetitively preconditionings as compared with that in neurotoxin group, and there was greatly significant difference (P＜0.01); meanwhile, there was also significant difference between 3-NP repetitively preconditionings group and 3-NP single preconditioning group (P＜0.05). ③As compared with that in blank control group, content GSH in 3-NP single administration group was not changed; content of GSH in 3-NP repetitively administrations group was increased (P＜0.05); content of GSH in neurotoxin group was decreased as compared with that in blank control group (P＜0.01); content of GSH in 3-NP single preconditioning group was not changed as compared with that in neurotoxin group (P＞0.05); content of GSH was increased after 3-NP repetitively preconditionings, and there was significant difference (P＜0.05); meanwhile, there was significant difference between 3-NP repetitively preconditionings group and 3-NP single preconditioning group (P＜0.05).CONCLUSION: 3-NP repetitively preconditionings can activate synthesis of GSH, protect dopamine neurons through decreasing production of MDA.