The role of the TLR4 signaling pathway in cognitive deficits following surgery in aged rats

Wang,Yi; He,Huijuan; Li,Dan; Zhu,Wenjing; Duan,Kaiming; Le,Yuan; Liao,Yan; Ou,Yangwen

doi:10.3892/mmr.2013.1322

The role of the TLR4 signaling pathway in cognitive deficits following surgery in aged rats

Authors:
- Yi Wang
- Huijuan He
- Dan Li
- Wenjing Zhu
- Kaiming Duan
- Yuan Le
- Yan Liao
- Yangwen Ou
View Affiliations

Affiliations: Department of Anesthesiology, The Third‑Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: February 18, 2013 https://doi.org/10.3892/mmr.2013.1322
Pages: 1137-1142

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Postoperative cognitive dysfunction (POCD), common in elderly patients, refers to a decline in cognitive function following surgery, which may persist or even evolve into Alzheimer's disease (AD). Despite great efforts, the mechanism of POCD remains unclear. In the present study, we tested the hypothesis that Toll‑like receptor 4 (TLR4) on microglia contributes to POCD. Shortly after surgery, aged rats demonstrated significant deficits in memory and learning, accompanied by the activation of microglia, marked upregulation of TLR4 on microglia in the hippocampus, as well as an increased expression of two downstream factors [myeloid differentiation factor 88 (MyD88) and TIR‑domain‑containing adapter‑inducing interferon‑β (TRIF)] and pro‑inflammatory cytokines [including tumor necrosis factor α (TNF‑α) and interleukin 1β (IL‑1β)]. With an increase in time following surgery, the expression of TLR4 and the aforementioned factors and pro‑inflammatory cytokines gradually returned to normal, as did the cognitive function of the aged rats. In conclusion, our study suggests that the activation of TLR4 signaling on microglia may act as an underlying mechanism of POCD.

View Figures

View References

1	Coburn M, Fahlenkamp A, Zoremba N and Schaelte G: Postoperative cognitive dysfunction: Incidence and prophylaxis. Anaesthesist. 59:177–184; quiz 185. 2010. View Article : Google Scholar : PubMed/NCBI
2	Deiner S and Silverstein JH: Postoperative delirium and cognitive dysfunction. Br J Anaesth. 103(Suppl 1): i41–i46. 2009. View Article : Google Scholar : PubMed/NCBI
3	Seitz DP, Shah PS, Herrmann N, Beyene J and Siddiqui N: Exposure to general anesthesia and risk of Alzheimer’s disease: a systematic review and meta-analysis. BMC Geriatr. 11:832011.
4	Hu Z, Ou Y, Duan K and Jiang X: Inflammation: a bridge between postoperative cognitive dysfunction and Alzheimer’s disease. Med Hypotheses. 74:722–724. 2010.PubMed/NCBI
5	Lin D, Cao L, Wang Z, Li J, Washington JM and Zuo Z: Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats. Behav Brain Res. 228:319–327. 2012. View Article : Google Scholar : PubMed/NCBI
6	Cohendy R, Brougere A and Cuvillon P: Anaesthesia in the older patient. Curr Opin Clin Nutr Metab Care. 8:17–21. 2005. View Article : Google Scholar : PubMed/NCBI
7	Rosczyk HA, Sparkman NL and Johnson RW: Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol. 43:840–846. 2008. View Article : Google Scholar : PubMed/NCBI
8	Teeling JL and Perry VH: Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms. Neuroscience. 158:1062–1073. 2009. View Article : Google Scholar : PubMed/NCBI
9	Glezer I, Simard AR and Rivest S: Neuroprotective role of the innate immune system by microglia. Neuroscience. 147:867–883. 2007. View Article : Google Scholar : PubMed/NCBI
10	Crack PJ and Bray PJ: Toll-like receptors in the brain and their potential roles in neuropathology. Immunol Cell Biol. 85:476–480. 2007. View Article : Google Scholar : PubMed/NCBI
11	Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP and Arumugam TV: Toll-like receptors in neurodegeneration. Brain Res Rev. 59:278–292. 2009. View Article : Google Scholar : PubMed/NCBI
12	Haseneder R, Kochs E and Jungwirth B: Postoperative cognitive dysfunction. Possible neuronal mechanisms and practical consequences for clinical routine. Anaesthesist. 61:437–443. 2012.(In German).
13	Shao J, Liu T, Xie QR, et al: Adjudin attenuates lipopolysaccharide (LPS)-and ischemia-induced microglial activation. J Neuroimmunol. 254:83–90. 2012. View Article : Google Scholar : PubMed/NCBI
14	Kamer AR, Galoyan SM, Haile M, et al: Meloxicam improves object recognition memory and modulates glial activation after splenectomy in mice. Eur J Anaesthesiol. 29:332–337. 2012. View Article : Google Scholar : PubMed/NCBI
15	Cai ZY, Yan Y and Chen R: Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model. Neurosci Bull. 26:28–36. 2010. View Article : Google Scholar : PubMed/NCBI
16	Moller JT, Cluitmans P, Rasmussen LS, et al: Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators International Study of Post-Operative Cognitive Dysfunction. Lancet. 351:857–861. 1998. View Article : Google Scholar
17	Zhang Z, Zhang ZY, Wu Y and Schluesener HJ: Immunolocalization of Toll-like receptors 2 and 4 as well as their endogenous ligand, heat shock protein 70, in rat traumatic brain injury. Neuroimmunomodulation. 19:10–19. 2012. View Article : Google Scholar : PubMed/NCBI
18	Krynetskaia NF, Phadke MS, Jadhav SH and Krynetskiy EY: Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage. Mol Cancer Ther. 8:864–872. 2009. View Article : Google Scholar : PubMed/NCBI
19	Zheng Z, Yuan R, Song M, et al: The toll-like receptor 4-mediated signaling pathway is activated following optic nerve injury in mice. Brain Res. Oct 24–2012.(Epub ahead of print). View Article : Google Scholar
20	Brown J, Wang H, Hajishengallis GN and Martin M: TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res. 90:417–427. 2011. View Article : Google Scholar : PubMed/NCBI
21	Li H, Xu H and Sun B: Lipopolysaccharide regulates MMP-9 expression through TLR4/NF-κB signaling in human arterial smooth muscle cells. Mol Med Report. 6:774–778. 2012.PubMed/NCBI
22	Perry VH, Nicoll JA and Holmes C: Microglia in neurodegenerative disease. Nat Rev Neurol. 6:193–201. 2010. View Article : Google Scholar
23	Song M, Jin J, Lim JE, et al: TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation. 8:922011.PubMed/NCBI
24	Hua F, Ma J, Ha T, et al: Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. J Neuroimmunol. 190:101–111. 2007. View Article : Google Scholar : PubMed/NCBI
25	Pascual M, Balino P, Alfonso-Loeches S, Aragon CM and Guerri C: Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage. Brain Behav Immun. 25(Suppl 1): S80–S91. 2011. View Article : Google Scholar : PubMed/NCBI
26	Xie Z and Tanzi RE: Alzheimer’s disease and post-operative cognitive dysfunction. Exp Gerontol. 41:346–359. 2006.
27	Hartholt KA, van der Cammen TJ and Klimek M: Postoperative cognitive dysfunction in geriatric patients. Z Gerontol Geriatr. 45:411–416. 2012. View Article : Google Scholar : PubMed/NCBI