Dexmedetomidine protects aged rats from postoperative cognitive dysfunction by alleviating hippocampal inflammation

Chen,Nianping; Chen,Xiufang; Xie,Jianping; Wu,Chenglong; Qian,Jiang

doi:10.3892/mmr.2019.10438

Dexmedetomidine protects aged rats from postoperative cognitive dysfunction by alleviating hippocampal inflammation

Authors:
- Nianping Chen
- Xiufang Chen
- Jianping Xie
- Chenglong Wu
- Jiang Qian
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Affiliations: Department of Anesthesiology, Affiliated Hospital of Shaoxing University (Shaoxing Municipal Hospital), Shaoxing, Zhejiang 312000, P.R. China, Department of Neurology, People's Hospital of Shaoxing, Shaoxing, Zhejiang 312000, P.R. China, Department of Anesthesiology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
Published online on: June 27, 2019 https://doi.org/10.3892/mmr.2019.10438
Pages: 2119-2126
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study investigated the effect of dexmedetomidine on hippocampal inflammation and cognitive function in rats with postoperative cognitive dysfunction (POCD). A total of 80 healthy male Sprague Dawley rats were used, 72 of which developed POCD. The rats were randomly divided into four groups: The control, model, low‑dose and high‑dose dexmedetomidine anesthesia groups. A POCD model was established and dexmedetomidine was administered. Cognitive function tests were performed and expression levels of interleukin 1β (IL‑1β), tumor necrosis factor‑α (TNF‑α) and NF‑κB biomarkers were evaluated on the first, third and seventh day following modeling. The cognitive function of rats was measured using a Y‑maze test. The expression levels of IL‑1β and TNF‑α in the hippocampus were determined by ELISA. The protein expression levels of NF‑κB p65 in the hippocampus were determined by western blotting. It was revealed that at 1, 3 and 7 days after surgery, there were no alterations in the exercise ability of rats in the different groups, as reflected by the number of rats passing the alternative arms in the Y‑maze. On the first and third day after surgery, the cognitive dysfunction reflected by the alteration scores of the low‑dose and high‑dose dexmedetomidine anesthesia groups were significantly higher than those of the model group, and the increase in the high‑dose group was more pronounced. Additionally, on the first day after surgery, the expression levels of IL‑1β, TNF‑α and NF‑κB in the hippocampi of rats in the low‑ and high‑dose dexmedetomidine anesthesia groups were significantly lower than those in the model group, and the decrease was more pronounced in the high‑dose group. At 7 days after surgery, the differences in expression levels of IL‑1β, TNF‑α and NF‑κB in the hippocampus among groups were not identified to be statistically significantly different. Taken together, the results of the present study indicated that dexmedetomidine may inhibit hippocampal inflammation induced by surgical trauma, and that dexmedetomidine may effectively improve postoperative cognitive function in rats.

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1	Xu J, Dong H, Qian Q, Zhang X, Wang Y, Jin W and Qian Y: Astrocyte-derived CCL2 participates in surgery-induced cognitive dysfunction and neuroinflammation via evoking microglia activation. Behav Brain Res. 332:145–153. 2017. View Article : Google Scholar : PubMed/NCBI
2	Berger M, Nadler JW, Browndyke J, Terrando N, Ponnusamy V, Cohen HJ, Whitson HE and Mathew JP: Postoperative cognitive dysfunction: Minding the gaps in our knowledge of a common postoperative complication in the elderly. Anesthesiol Clin. 33:517–550. 2015. View Article : Google Scholar : PubMed/NCBI
3	Ballard C, Jones E, Gauge N, Aarsland D, Nilsen OB, Saxby BK, Lowery D, Corbett A, Wesnes K, Katsaiti E, et al: Optimised anaesthesia to reduce post operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomised controlled trial. PLoS One. 7:e374102012. View Article : Google Scholar : PubMed/NCBI
4	Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG and Johnson RW: Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun. 22:301–311. 2008. View Article : Google Scholar : PubMed/NCBI
5	Cao XZ, Ma H, Wang JK, Liu F, Wu BY, Tian AY, Wang LL and Tan WF: Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats. Prog Neuropsychopharmacol Biol Psychiatry. 34:1426–1432. 2010. View Article : Google Scholar : PubMed/NCBI
6	Wuri G, Wang DX, Zhou Y and Zhu SN: Effects of surgical stress on long-term memory function in mice of different ages. Acta Anaesthesiol Scand. 55:474–485. 2011. View Article : Google Scholar : PubMed/NCBI
7	Devasya A and Sarpangala M: Dexmedetomidine: A review of a newer sedative in dentistry. J Clin Pediatr Dent. 39:401–409. 2015. View Article : Google Scholar : PubMed/NCBI
8	Keating GM: Dexmedetomidine: A review of its use for sedation in the intensive care setting. Drugs. 75:1119–1130. 2015. View Article : Google Scholar : PubMed/NCBI
9	Celik F, Göcmez C, Kamaşak K, Tufek A, Guzel A, Tokgoz O, Fırat U and Evliyaoğlu O: The comparison of neuroprotective effects of intrathecal dexmedetomidine and metilprednisolone in spinal cord injury. Int J Surg. 11:414–418. 2013. View Article : Google Scholar : PubMed/NCBI
10	Koca U, Olguner ÇG, Ergür BU, Altekin E, Taşdöğen A, Duru S, Girgin P, Gündüz K, Cilaker Mıcılı S, Güzeldağ S and Akkuş M: The effects of dexmedetomidine on secondary acute lung and kidney injuries in the rat model of intra-abdominal sepsis. ScientificWorldJournal. 2013:2926872013. View Article : Google Scholar : PubMed/NCBI
11	Yeh CH, Hsieh LP, Lin MC, Wei TS, Lin HC, Chang CC and Hsing CH: Dexmedetomidine reduces lipopolysaccharide induced neuroinflammation, sickness behavior, and anhedonia. PLoS One. 13:e01910702018. View Article : Google Scholar : PubMed/NCBI
12	Han C, Fu R and Lei W: Beneficial effects of dexmedetomidine on early postoperative cognitive dysfunction in pediatric patients with tonsillectomy. Exp Ther Med. 16:420–426. 2018.PubMed/NCBI
13	Yang Z, Liu Y, Yuan F, Li Z, Huang S, Shen H and Yuan B: Sinomenine inhibits microglia activation and attenuates brain injury in intracerebral hemorrhage. Mol Immunol. 60:109–114. 2014. View Article : Google Scholar : PubMed/NCBI
14	Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, et al: Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron. 81:1009–1023. 2014. View Article : Google Scholar : PubMed/NCBI
15	Park J, Min JS, Kim B, Chae UB, Yun JW, Choi MS, Kong IK, Chang KT and Lee DS: Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neurosci Lett. 584:191–196. 2015. View Article : Google Scholar : PubMed/NCBI
16	Chen SQ, Wang PJ, Ten GJ, Zhan W, Li MH and Zang FC: Role of myo-inositol by magnetic resonance spectroscopy in early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice. Dement Geriatr Cogn Disord. 28:558–566. 2009. View Article : Google Scholar : PubMed/NCBI
17	Zhu YS, Xiong YF, Luo FQ and Min J: Dexmedetomidine protects rats from postoperative cognitive dysfunction via regulating the GABA_B R-mediated cAMP-PKA-CREB signaling pathway. Neuropathology. 39:30–38. 2019. View Article : Google Scholar : PubMed/NCBI
18	Xu Z, Wang D, Zhou Z, Chen Q, Zhang D, Chen S, Jiang H, Jia C and Liu X: Dexmedetomidine attenuates renal and myocardial Ischemia/Reperfusion injury in a dose-dependent manner by inhibiting inflammatory response. Ann Clin Lab Sci. 49:31–35. 2019.PubMed/NCBI
19	Tucker LB, Fu AH and McCabe JT: Performance of male and female C57BL/6J mice on motor and cognitive tasks commonly used in pre-clinical traumatic brain injury research. J Neurotrauma. 33:880–894. 2016. View Article : Google Scholar : PubMed/NCBI
20	Shoham S, Linial M and Weinstock M: Age-induced spatial memory deficits in rats are correlated with specific brain region alterations in microglial morphology and gene expression. J Neuroimmune Pharmacol. 14:251–262. 2019. View Article : Google Scholar : PubMed/NCBI
21	Hsu WC, Yu CH, Kung WM and Huang KF: Enhancement of matrix metalloproteinases 2 and 9 accompanied with neurogenesis following collagen glycosaminoglycan matrix implantation after surgical brain injury. Neural Regen Res. 13:1007–1012. 2018. View Article : Google Scholar : PubMed/NCBI
22	Lord JM, Midwinter MJ, Chen YF, Belli A, Brohi K, Kovacs EJ, Koenderman L, Kubes P and Lilford RJ: The systemic immune response to trauma: An overview of pathophysiology and treatment. Lancet. 384:1455–1465. 2014. View Article : Google Scholar : PubMed/NCBI
23	Podjaski C, Alvarez JI, Bourbonniere L, Larouche S, Terouz S, Bin JM, Lécuyer MA, Saint-Laurent O, Larochelle C, Darlington PJ, et al: Netrin 1 regulates blood-brain barrier function and neuroinflammation. Brain. 138:1598–1612. 2015. View Article : Google Scholar : PubMed/NCBI
24	Romeo HE, Tio DL and Taylor AN: Effects of glossopharyngeal nerve transection on central and peripheral cytokines and serum corticosterone induced by localized inflammation. J Neuroimmunol. 136:104–111. 2003. View Article : Google Scholar : PubMed/NCBI
25	Le Maitre E, Revathikumar P, Estelius J and Lampa J: Increased recovery time and decreased LPS administration to study the vagus nerve stimulation mechanisms in limited inflammatory responses. J Vis Exp. Mar 29–2017.doi: 10.3791/54890. View Article : Google Scholar : PubMed/NCBI
26	Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA and van de Beek D: Systemic inflammation and microglial activation: Systematic review of animal experiments. J Neuroinflammation. 12:1142015. View Article : Google Scholar : PubMed/NCBI
27	Gyoneva S, Davalos D, Biswas D, Swanger SA, Garnier-Amblard E, Loth F, Akassoglou K and Traynelis SF: Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia. 62:1345–1360. 2014. View Article : Google Scholar : PubMed/NCBI
28	Kang YC, Zhang L, Su Y, Li Y, Ren WL and Wei WS: MicroRNA-26b regulates the microglial inflammatory response in Hypoxia/Ischemia and affects the development of vascular cognitive impairment. Front Cell Neurosci. 12:1542018. View Article : Google Scholar : PubMed/NCBI
29	Fakhoury M: Role of immunity and inflammation in the pathophysiology of neurodegenerative diseases. Neurodegener Dis. 15:63–69. 2015. View Article : Google Scholar : PubMed/NCBI
30	Kim DW, Lee JC, Cho JH, Park JH, Ahn JH, Chen BH, Shin BN, Tae HJ, Seo JY, Cho JH, et al: Neuroprotection of ischemic preconditioning is mediated by Anti-inflammatory, Not Pro-inflammatory, Cytokines in the Gerbil hippocampus induced by a subsequent lethal transient cerebral ischemia. Neurochem Res. 40:1984–1995. 2015. View Article : Google Scholar : PubMed/NCBI
31	Loftis JM, Valerio J, Taylor J, Huang E, Hudson R, Taylor-Young P, Chang M, Ho SB, Dieperink E, Miranda JL and Hauser P: S100B and inflammatory cytokine levels in blood as potential markers of blood-brain barrier damage and psychiatric impairment in comorbid hepatitis C viral infection and alcohol use disorder. Alcohol Clin Exp Res. Jun 28–2018.doi: 10.1111/acer.13796 (Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
32	Farbood Y, Sarkaki A, Dianat M, Khodadadi A, Haddad MK and Mashhadizadeh S: Ellagic acid prevents cognitive and hippocampal long-term potentiation deficits and brain inflammation in rat with traumatic brain injury. Life Sci. 124:120–127. 2015. View Article : Google Scholar : PubMed/NCBI
33	Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D and van Noort JM: Inflammation in neurodegenerative diseases-an update. Immunology. 142:151–166. 2014. View Article : Google Scholar : PubMed/NCBI
34	Ma Y, Yu XY and Wang Y: Dose-related effects of dexmedetomidine on immunomodulation and mortality to septic shock in rats. World J Emerg Med. 9:56–63. 2018. View Article : Google Scholar : PubMed/NCBI
35	Suzumura A: Neuron-microglia interaction in neuroinflammation. Curr Protein Pept Sci. 14:16–20. 2013. View Article : Google Scholar : PubMed/NCBI
36	Bogie JF, Stinissen P and Hendriks JJ: Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol. 128:191–213. 2014. View Article : Google Scholar : PubMed/NCBI
37	Li C, Chen T, Zhou H, Zhang C, Feng Y, Tang F, Hoi MP, He C, Zheng Y and Lee SM: Schisantherin A attenuates neuroinflammation in activated microglia: Role of Nrf2 activation through ERK phosphorylation. Cell Physiol Biochem. 47:1769–1784. 2018. View Article : Google Scholar : PubMed/NCBI
38	Peng J, Zhang P, Zheng H, Ren YQ and Yan H: Dexmedetomidine reduces hippocampal microglia inflammatory response induced by surgical injury through inhibiting NLRP3. Chin J Traumatol. 22:161–165. 2019. View Article : Google Scholar : PubMed/NCBI
39	Li JW, Zong Y, Cao XP and Tan L and Tan L: Microglial priming in Alzheimer's disease. Ann Transl Med. 6:1762018. View Article : Google Scholar : PubMed/NCBI
40	Daskalopoulos EP, Malliou F, Rentesi G, Marselos M, Lang MA and Konstandi M: Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: Role of adrenergic receptor signaling pathways. Am J Physiol Endocrinol Metab. 303:E40–E54. 2012. View Article : Google Scholar : PubMed/NCBI
41	Hoffman WE, Kochs E, Werner C, Thomas C and Albrecht RF: Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole. Anesthesiology. 75:328–332. 1991. View Article : Google Scholar : PubMed/NCBI
42	Fang B, Li XQ, Bi B, Tan WF, Liu G, Zhang Y and Ma H: Dexmedetomidine attenuates blood-spinal cord barrier disruption induced by spinal cord ischemia reperfusion injury in rats. Cell Physiol Biochem. 36:373–383. 2015. View Article : Google Scholar : PubMed/NCBI
43	Yang D and Hong JH: Dexmedetomidine modulates Histamine-induced Ca(2+) Signaling and Pro-inflammatory cytokine expression. Korean J Physiol Pharmacol. 19:413–420. 2015. View Article : Google Scholar : PubMed/NCBI