Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in β-amyloid rat model of Alzheimer's disease - PubMed (original) (raw)
Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in β-amyloid rat model of Alzheimer's disease
Aiguo Xuan et al. J Neuroinflammation. 2012.
Abstract
Background: Endogenously produced hydrogen sulfide (H(2)S) may have multiple functions in brain. An increasing number of studies have demonstrated its anti-inflammatory effects. In the present study, we investigated the effect of sodium hydrosulfide (NaHS, a H(2)S donor) on cognitive impairment and neuroinflammatory changes induced by injections of Amyloid-β(1-40) (Aβ(1-40)), and explored possible mechanisms of action.
Methods: We injected Aβ(1-40) into the hippocampus of rats to mimic rat model of Alzheimer's disease (AD). Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia. The expression of interleukin (IL)-1β and tumor necrosis factor (TNF)-α was measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The expression of Aβ(1-40), phospho-p38 mitogen-activated protein kinase (MAPK), phospho-p65 Nuclear factor (NF)-κB, and phospho-c-Jun N-terminal Kinase (JNK) was analyzed by western blot.
Results: We demonstrated that pretreatment with NaHS ameliorated learning and memory deficits in an Aβ(1-40) rat model of AD. NaHS treatment suppressed Aβ(1-40)-induced apoptosis in the CA1 subfield of the hippocampus. Moreover, the over-expression in IL-1β and TNF-α as well as the extensive astrogliosis and microgliosis in the hippocampus induced by Aβ(1-40) were significantly reduced following administration of NaHS. Concomitantly, treatment with NaHS alleviated the levels of p38 MAPK and p65 NF-κB phosphorylation but not JNK phosphorylation that occurred in the Aβ(1-40)-injected hippocampus.
Conclusions: These results indicate that NaHS could significantly ameliorate Aβ(1-40)-induced spatial learning and memory impairment, apoptosis, and neuroinflammation at least in part via the inhibition of p38 MAPK and p65 NF-κB activity, suggesting that administration of NaHS could provide a therapeutic approach for AD.
Figures
Figure 1
Effect of NaHS on Aβ 1-40 -induced cognitive impairment. Aβ1-40 was slowly injected into the hippocampus, and subjected to the Morris water maze test 7 days later. (A) The escape latency in the navigation test. (B) The average swim speed among the groups. (C) The percent of (%) time in the targeted quadrant where the platform had been located in the spatial exploring test. (D) The percent of (%) distance in the targeted quadrant where the platform had been located in the spatial exploring test. Data presented as mean ± S.E.M., n = 10-13. **P < 0.01 vs. sham; #P < 0.05 vs. Aβ1-40.
Figure 2.
Effects of NaHS on DNA fragmentation in the hippocampus of rats injected with Aβ 1-40 . (A, B) No TUNEL-reactive cell was detected in the hippocampus from sham and sham + NaHS rats. (C) The significant number of degenerating pyramidal neurons, labeled with the TUNEL technique was observed in the CA1 subfield of the hippocampus. (D) The number of TUNEL-positive neurons significantly decreased in the hippocampus from Aβ1-40-injected rats receiving NaHS. Scale bar: 40 μm. Arrows point to degenerating pyramidal neurons with their nuclei stained with TUNEL technique. (E) Quantitative analysis of % TUNEL-positive neurons. Data are given as mean ± S.E.M.. **P < 0.01 vs. sham; ##P < 0.01 vs. Aβ1-40.
Figure 3
NaHS pre-treatment reduces Aβ 1-40 levels. Aβ1-40 rats were treated with NaHS (5 mg/kg i.p. once daily). (A) Western blot of Aβ1-40 protein contents. In hippocampal area CA1 the basal levels of Aβ1-40 peptides decreased significantly after NaHS treatment. (B) The relative optical density was normalized to β-Actin. Results are expressed as mean ± S.E.M. with five rats in each group. **P < 0.01 vs. sham; #P < 0.05 vs. Aβ1-40.
Figure 4
Effect of NaHS on Aβ 1–40 -induced the activation of glia in the DG region of rat hippocampus. (A-E, a-d) The distribution and number of GFAP-immunoreactive astrocytes in sham, sham + NaHS, Aβ1-40, and NaHS + Aβ1-40 rats. Scale bar, 500 μm (A-D) and 50 μm (a-d). (F-J) Representative photographs and number of OX-42-immunopositive cells in sham, sham + NaHS, Aβ1-40, and NaHS + Aβ1-40 rats. Scale bar: 250 μm. Six tissue sections per rat were used for the analysis (n = 8-10). Data are presented as the mean ± S.E.M. **P < 0.01 vs. sham; ##P < 0.01, #P < 0.05 vs. Aβ1-40.
Figure 5
Effect of NaHS on the IL-1β, TNF-α production, and mRNA expressions. IL-1β and TNF-α levels in the hippocampus were measured via ELISA. The expressions of IL-1β and TNF-α mRNA in the hippocampus were detected by real time RT-PCR. Aβ1-40 injection into the hippocampus significantly increased the IL-1β, TNF-α production, and mRNA expressions. Treatments with NaHS significantly decreased the levels and mRNA over-expressions of IL-1β and TNF-α. (A) The level of IL-1β. (B) The level of TNF-α. (C) The expressions of IL-1β mRNA. (D) The expressions of TNF-α mRNA. Data are mean ± S.E.M., n = 4. **P < 0.01 vs. sham; ##P < 0.01, #P < 0.05 vs. Aβ1-40.
Figure 6
Western blotting analysis of the relative protein contents. (A, C) Western blot of various protein contents for phospho-p38 MAPK, phospho-p65 NFκB, and phospho-JNK. (B, D) The relative optical density was normalized to β-Actin. Data are mean ± S.E.M., n = 4. **P < 0.01 *P < 0.05 vs. sham(control); #P < 0.05 vs. Aβ1-40.
References
- Mildner A, Schlevogt B, Kierdorf K, Böttcher C, Erny D, Kummer MP, Quinn M, Brück W, Bechmann I, Heneka MT, Priller J, Prinz M. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci. 2011;31:11159–11171. doi: 10.1523/JNEUROSCI.6209-10.2011. - DOI - PMC - PubMed
- Weldon DT, Rogers SD, Ghilard JR, Finke MP, Cleary JP, O’Hare E, Esler WP, Maggio JE, Mantyh PW. Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci. 1998;18:2161–2173. - PMC - PubMed
- Potter PE. Investigational medications for treatment of patients with Alzheimer disease. J Am Osteopath Assoc. 2010;Suppl 8:27–36. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous