| [Background and Objective]Hyperhomocysteinemia (Hhcy) is an important and independent riskfactor for Alzheimer’s disease (AD). Hydrogen sulfide (H2S), considered as anew gas neuromodulators besides NO and CO, modulates synapticplasticity and enhances learing and memory. Our previous findings indicatethat H2S has an antagonistic effect on homocystein (Hcy)-causedimpairment in the learning and memory and cognitive function; however,the underlying mechanisms were not inverstigated clearly.BDNF-TrkB (brain-derived neurotrophic factor-Tropomyosin receptorkinase B) pathway and SIRT1(Silent information regulator1) play animportant role in modulation of the learning and memory and cognitivefunction. We have found that H2S could up-regulate the expression of BDNFand SIRT1in neuronal cells. Therefore we hypothesized that the antagonisticeffect of H2S on Hcy-caused impairment in the learning and memory andcognitive function is related to its role in modulation of BDNF-TrkB pathwayand SIRT1.We used SD rats intracerebroventricularly injected with Hcy as an animalmode of AD. The aim of our study is to reveal that BDNF-TrkB pathway andSIRT1mediate the antagonistic effect of H2S on Hcy-caused impairment inthe learning and memory and cognitive function by investigating whetherinhibition of BDNF-TrkB pathway and SIRT1prevent this antagonistic action of H2S using pretreatment with K252a (an inhibitor of TrkB) or Sirtinol (an inhibitorof SIRT1).[Methods]Learning and memory and cognitive function of rats were tested byY-maze, novel object recognition test and the Morris water maze (MWM).Western blotting was use to evaluate the protein expression of SIRT1andBDNF in hippocampus.[Results]1. BDNF-TrkB pathway mediates the antagonistic effect of H2S onHcy-caused impairment in learning and memory and cognitive function.In order to block the BDNF-TrkB pathway in brain, rats pretreated withK252a (1μg/d) intracerebroventricularly and NaHS (a H2S donor,5.6mg/kg/d) intraperitioneally for2days and cotreated with Hcy (0.6μmol/d,in4μL) intracerebroventricularly. We use Y-maze, the novel objectrecognition test and the Morris water maze (MWM) to test the learning andmemory and cognitive function of rats.The results from Y-maze experiment showed that K252a (1μg) reversedthe protective effect of H2S (5.6mg/kg) on Hcy (0.6μmol)-caused decreasein alternative performance. The data from the novel object recognition testindicated that K252a (1μg) reversed the protective effect of H2S (5.6mg/kg)on novel object recognition index of Hcy (0.6μmol)-injected rats.The result from the fourth-day of acquisition phase in MWM test showedthat the latency period of Hcy-injected rats was prolonged and theirswimming route were more tortuous and complex. Pretreatment with NaHS(5.6mg/kg) could reduce the Hcy-induced delay of latency period. K252a(1μg) could reverse H2S protection against Hcy-induced delay of latencyperiod. The spatial search test in MWM showed that the times of rat acrossplatform, the time spended in target quadrant, and the proportionality ofswimming time in mid-ring were reduced in the Hcy-injected rats. NaHS (5.6mg/kg) pretreatment attenuates Hcy-caused reductions in the times of ratacross platform, the time spended in target quadrant, and theproportionality of swimming time in mid-ring; however, K252a (1μg) couldreverse these protective effect of H2S.All the results mentioned above indicated that BDNF-TrkB pathwaymediates the antagonistic effect of H2S on Hcy-induced impairment in thelearning and memory and cognitive function.2. SIRT1mediates the antagonistic effect of H2S on Hcy-caused impairmentin the learning and memory and cognitive function.In order to block SIRT1in brain, rats pretreated with Sirtinol (10nmol/d)intracerebroventricularly and NaHS (a H2S donor,5.6mg/kg/d)intraperitioneally for2days and cotreated with Hcy (0.6μmol/d, in4μL)intracerebroventricularly. We use Y-maze, the novel object recognition testand the Morris water maze (MWM) to test the learning and memory andcognitive function of rats.Western blotting was used to assess SIRT1protein expression inhippocampus. The data showed that H2S could obviously protect SIRT1protein expression from Hcy-caused down-regulation, which indicated thatH2S could up-regulate the expression of SIRT1in the hippocampus of rats.The result from Y-maze experiment showed that Sirtinol (10nmol)reversed the protective effect of H2S (5.6mg/kg) on Hcy (0.6μmol)-causeddecrease in rat alternative performance. The data from the novel objectrecognition test indicated that Sirtinol (10nmol) reversed the role of H2S(NaHS5.6mg/kg) in improving novel object recognition index.The result from the fourth-day water maze navigation experiment showed that Sirtinol (10nmol) could reverse the protection of H2S (NaHS5.6mg/kg) against Hcy-induced delay of latency period. The spatial search testshowed that Sirtinol (10nmol) could reverse the protections of H2S againstHcy-caused reductions in the times of rat across platform, the time spendedin target quadrant, and the proportionality of swimming time in mid-ring.All the results mentioned above indicated that SIRT1mediates theantagonistic effect of H2S on Hcy-induced impairment in the learning andmemory and cognitive function.3. Sirtinol, the specific inhibitor of SIRT1, reverses the protection ofHydrogen sulfide against Hcy-caused down-regulation of BDNFSIRT1was blocked by injecting rats Sirtinol (10nmol/d) in advance andthe BDNF expression was evaluated by western blotting. The resultsdemonstrated that the blocking of SIRT1reversed the protection H2S againstHcy-caused down-regulation of BDNF, which indicated that SIRT1-mediatedthe antagonistic effect of H2S on Hcy-caused impairment in the learningand memory and cognitive function is in an BDNF-TrkB pathway-dependentmanner.[Conclusion]H2S antagonizes Hcy-induced impairment in the learning and memoryand cognitive function by up-regulation of BDNF-TrkB pathway, resultingfrom up-regulation of SIRT1. |
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