| 【Background and Objective】In the brain of Alzhermer’s disease （AD） patients, the levels ofS-adenosylmethionine （SAM）, an endogenous agonist of cystathionine-beta-synthase （CBS）, and hydrogen sulfide （H2S） were decreased; however,the level of homocysteine （Hcy） was increased. Hyperhomocysteinemia（Hhcy） has become an important and independent risk factor for AD. H2S,considerd as a novel neuromodulator, has the neuroprotective effect andregulates synaptic plasticity. Our previous work suggests that H2S has anantagonistic effect on Hcy-induced damage in PC12cells. We thereforehypothesized that H2S has an inhibitory effect on Hcy-caused impairment inthe learning and memory and cognitive function.We used SD rats intracerebroventricularly injected with Hcy as an animalmodel of Hcy neurotoxicity to investigate the effect of Hcy on endogenousH2S generation in brain tissue and the effect of H2S on impairment in thelearning and memory and cognitive function in rats induced by Hcy and theunderling mechanisms.【Methods】SD rats treated with Hcy by intracerebroventricular injection and NaHS by intraperitoneal injection. Learning and memory of rats was assessed by theMorris water maze （MWM）. Cognitive function of rats was evaluated by novelobject recognition test. The H2S generation and the activity of CBS in braintissue were detected by methylene blue spectrophotometric method. Theexpression of BDNF and CBS protein was evaluated by Western blotting.【Results】1. Homocysteine impairs on the learning and memory and the cognitivefunction of SD rats.Results from water maze navigation experiment showed that Hcy （0.6,2.0μmol, for7d） concentration-dependently prolonged the Eclipse period,made the route of rats swimming more tortuous and complex. Spatialresearch training results showed that Hcy （0.6,2.0μmol, for7d）dose-dependently reduced the times of accoss platform and the theproportionality of swimming time of rats. Novel oblect test results showed thatHcy （0.2,0.6,2.0μmol, for7d） decreased the rats preference indexconcentration-dependengly. All of these results suggested that homocysteinedamages the learing and memory and the cognitive function of rats.Methylene blue spectrophotometric experiment results showed that Hcy（0.2,0.62.0μmol, for7d） dose-dependently decreased the formation of H2Sin rats brain and inhibited the activity of CBS, which was a key enzyme ingeneration of H2S in rats brain. Western blot experiment showed that Hcy （0.2,0.62.0μmol, for7d） reduced the level of CBS protein in hippocampus of rats.These data indicated that homosysteine-induced impairment in learing andmemory and cognitive function is involved in the reduction of endogenousH2S.We used western blotting experiment to test the level of BDNF protein inhippocampus of rats and the results showed that Hcy （0.2,0.62.0μmol, for7d）inhibited the expression of BDNF protein concentration-dependently,indicating that homocysteine-induced impairment in the learing and memory and the cognitive function may be associated with the inhibition of BDNFexpression.2. Hydrogen sulfide （H2S） antagonizes homocysteine-inducedimpairment in the learning and memory and the cognitive function of SD ratsRats were intraperitioneally injected with NaHS （a H2S donor） for7d.water maze navigation experiment results showed that NaHS （1.68,3.36mg/kg） restored the Hcy-induced delay of latency period and improved theroute of rats swimming in navigation training and spatial search test showedthat NaHS （1.68,3.36mg/kg） reversed the reduction of times of rate accossplatform and the reduction of proportionality of swimming time in mid-ring.Result from novel object test showed that NaHS （1.68,3.36mg/kg） significantlyimproved rats preference index. These date indicated that H2S antagonizedhomocysteine-induced impairment in the learning and memory and thecognitive function of rats.The result of western blotting showed that NaHS （1.68,3.36mg/kg）significantly attenuatedthe inhibition of expression of BDNF protein in ratshippocampus induced by Hcy （0.6μmol）. These date suggested that theantagonistic role of H2S in Hcy-induced impairment in the learning andmemory and the cognitive function is involed in the increase of BDNF proteinlevel in hippocampus.【Conclusion】1. Homocysteine impairs the learing and memory and the cognitivefunction of rats and the underling mechanisms is involved in the inhibitions ofthe generation of H2S and the downregulation of BDNF expression inhippoampus.2. Hydrogen sulfide has an antagonistic effect on homocysteine-inudceddamage in the learning and memory and the cognitive function and the underling mechanisms is involved in the increase of BDNF protein level inhippocampus. |
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