Hydrogen Sulfide And Cysteine ​​propargyl Anti-alzheimer's Disease Research

Objectives:Inflammation plays an important role in neurodegenerative diseases of central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD). Hydrogen sulfide (H2S) is recently recognized as the third'gasotransmitter' alongside nitric oxide and carbon monoxide. The present study was aimed to firstly investigate the effects of sodium hydrosulfide (NaHS), an extrinsic H2S donor, on neuroinflammation induced by bilateral intracerebroventricular (b.i.c.v.) injection of lipopolysaccharide (LPS) in rats, then investigate the effects of S-propargyl-cysteine (SPRC), a noval endogenous H2S donor, on neuroinflammation in the same model, and then investigate the effects of SPRC on beta-amyloid (Aβ) neurotoxity by right lateral intracerebroventricular (r.i.c.v.) injection in rats, as well as explore the possible mechanisms of action.Methods:1. Neuroinflammation was induced by b.i.c.v. injection of LPS in rats, and intragastric administration of ibuprofen (IBU) was used as positive control. Effects of NaHS by intraperitoneal injection (i.p.) on learning and memory functions were evaluated by Morris water maze in rats; After behavioral test, H2S levels of rat hippocampus were measured, and neuronal ultrastructure in CA1 region of hippocampus was observed by transmission electron microscopy (TEM), expressions of tumor necrosis factor (TNF-a) and its receptor 1 (TNF-a receptor 1, TNFR1) mRNA were detected by real time RT-PCR, and expressions of TNF-a and TNFR1 proteins, as well as degradation of IκB-αand thereafter activation of NF-κB in hippocampus were analyzed by Western blot, respectively.2. Neuroinflammation was induced by b.i.c.v. injection of LPS in rats, and intragastric administration of IBU was used as positive control. Effects of SPRC at different doses by i.p. on learning and memory functions were evaluated by Morris water maze in rats; After behavioral test, H2S levels of rat hippocampus were measured, and neuronal ultrastructure in CA1 region of hippocampus was observed by TEM, expressions of TNF-a, TNFR1 and amyloid-βprotein precursor (AβPP) mRNA were detected by real time RT-PCR, and expressions of TNF-a, TNFR1 and AβPP proteins, as well as degradation of IκB-αand thereafter activation of NF-κB in hippocampus were analyzed by Western blot, respectively; 3. AP-neurotoxity model was induced by r.i.c.v. injection in rats, and intragastric administration of donepezil (DON) was used as positive control. Effects of SPRC at different doses by i.p. on learning and memory functions were evaluated by Morris water maze in rats; After behavioral test, neuronal ultrastructure in CA1 region of hippocampus was observed by TEM, expressions of TNF-a, A(3PP and cyclooxygenase-2 (COX-2) mRNA were detected by real time RT-PCR, and expressions of TNF-a, AβPP and COX-2 proteins, as well as degradation of IκB-αand thereafter activation of NF-κB, and phosphorylation of ERK, AKT in hippocampus were analyzed by Western blot, respectively.Results:1. B.i.c.v. injection of LPS into rats caused learning and memory deficits and neuronal ultrastructure damage in hippocampal CA1 regions, decreased the H2S levels in hippocampus. And the expressions of TNF-a, TNFR1, AβPP mRNA and proteins were significantly increased, degradation of IκB-a and thereafter activation of NF-κB p65 in hippocampus were obviously increased; 2. NaHS administration by i.p. significantly attenuated LPS-induced learning and memory deficits and neuronal ultrastructure damage, increased the H2S levels in hippocampus, and inhibited the expressions of TNF-a, TNFR1 mRNA and proteins, as well as repressed the degradation of IκB-a and thereafter activation of NF-κB p65 in hippocampus. However, it did not affect the above indices of sham-operated rats.3. SPRC administration at the doses of 40,80 mg/kg by i.p. significantly attenuated LPS-induced learning and memory deficits and neuronal ultrastructure damage, increased the H2S levels in hippocampus, and inhibited the expressions of TNF-a, TNFR1, AβPP mRNA and proteins, as well as repressed the degradation of IκB-a and thereafter activation of NF-κB p65 in hippocampus.4. R.i.c.v. injection of Aβ25-35 into rats caused learning and memory deficits and neuronal ultrastructure damage in hippocampal CA1 regions, And the expressions of TNF-a, AβPP, COX-2 mRNA and proteins were significantly increased, as well as enhanced the phosphorylation of ERK, degradation of IκB-a and thereafter activation of NF-κB p65, and decreased phosphorylation of Akt in hippocampus. However, SPRC administration at the doses of 40,80 mg/kg by i.p. significantly attenuated Aβ25-35-induced learning and memory deficits and neuronal ultrastructure damage, inhibited the expressions of TNF-a, AβPP, COX-2 mRNA and proteins, inhibited the phosphorylation of ERK, repressed the degradation of IKB-a and thereafter activation of NF-κB p65, and increased phosphorylation of Akt in hippocampus.Conclusion:1. H2S attenuates LPS-induced learning and memory impairment and neuronal ultrastructure damage, at least partly, through reducing the overproduction of pro-inflammatory mediators via inhibition of NF-κB pathway in rats; 2. SPRC attenuates LPS-induced learning and memory impairment and neuronal ultrastructure damage, at least partly, through modulating endogenous H2S releasing and reducing the overproduction of pro-inflammatory mediators and AβPP via inhibition of NF-κB pathway in rats; 3. SPRC attenuates AP25-35-induced learning and memory impairment and neuronal ultrastructure damage, at least partly, through reducing the production of TNF-α,AβPP,COX-2 via inhibition of NF-κB pathway and activation of Akt pathway in rats.