Dexmedetomidine protects against sepsis‑associated encephalopathy through Hsp90/AKT signaling

Yin,Lijun; Chen,Xuejun; Ji,Hongbo; Gao,Shunli

doi:10.3892/mmr.2019.10718

Dexmedetomidine protects against sepsis‑associated encephalopathy through Hsp90/AKT signaling

Authors:
- Lijun Yin
- Xuejun Chen
- Hongbo Ji
- Shunli Gao
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Affiliations: Department of Anesthesiology, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin 301800, P.R. China
Published online on: October 1, 2019 https://doi.org/10.3892/mmr.2019.10718
Pages: 4731-4740

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Abstract

Sepsis‑associated encephalopathy (SAE) is characterized by neuronal apoptosis and changes in mental status. Accumulating evidence has. indicated that dexmedetomidine is capable of protecting the brain against external stimuli and improving cognitive dysfunctions. The aim of the present study was to investigate the possible neuroprotective effects of dexmedetomidine on SAE and the role of heat‑shock protein (Hsp)90/AKT signaling in an experimental model of sepsis. The SAE model was established by cecal ligation and perforation (CLP) in vivo and lipopolysaccharide (LPS) treated hippocampal neuronal cultures in vitro. It was found that dexmedetomidine inhibited caspase‑3, but increased the expression level ofBcl‑2 in CLP rats. CLP rats also exhibited a decreased level of phosphorylated AKT Thr 308 and Hsp90, and their expression could be reversed by treatment with dexmedetomidine. Additionally, application of dexmedetomidine increased cell survival and decreased neuronal apoptosis in vitro. Furthermore, the neuroprotective effects of dexmedetomidine could be reversed by 17‑AAG (a Hsp90 inhibitor), or wortmannin (a PI3K inhibitor). Analysis of TUNEL staining indicated that dexmedetomidine improved LPS‑induced neuronal apoptosis, which could be eradicated by AKT short hairpin RNA transfection, prazosin or yohimbine. Finally, dexmedetomidine ameliorated both the emotional and spatial cognitive disorders without alteration in locomotor activity. The present findings suggested that dexmedetomidine may protect the brain against SAE, and that the Hsp90/AKT pathway may be involved in this process.

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1	Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D, et al: Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med. 34:344–353. 2006. View Article : Google Scholar : PubMed/NCBI
2	Iacobone E, Bailly-Salin J, Polito A, Friedman D, Stevens RD and Sharshar T: Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med. 37 (10 Suppl):S331–S336. 2009. View Article : Google Scholar : PubMed/NCBI
3	Comim CM, Rezin GT, Scaini G, Di-Pietro PB, Cardoso MR, Petronilho FC, Ritter C, Streck EL, Quevedo J and Dal-Pizzol F: Mitochondrial respiratory chain and creatine kinase activities in rat brain after sepsis induced by cecal ligation and perforation. Mitochondrion. 8:313–318. 2008. View Article : Google Scholar : PubMed/NCBI
4	d'Avila JC, Santiago AP, Amâncio RT, Galina A, Oliveira MF and Bozza FA: Sepsis induces brain mitochondrial dysfunction. Crit Care Med. 36:1925–1932. 2008. View Article : Google Scholar : PubMed/NCBI
5	Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, Berger M, Schäfers M and Heneka MT: NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J Neurosci. 29:14177–14184. 2009. View Article : Google Scholar : PubMed/NCBI
6	Hall JE, Uhrich TD, Barney JA, Arain SR and Ebert TJ: Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg. 90:699–705. 2000. View Article : Google Scholar : PubMed/NCBI
7	Arcangeli A, D'alo C and Gaspari R: Dexmedetomidine use in general anaesthesia. Current Drug Targets. 10:687–695. 2009. View Article : Google Scholar : PubMed/NCBI
8	Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, et al: Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA. 298:2644–2653. 2007. View Article : Google Scholar : PubMed/NCBI
9	Martin E, Ramsay GJ, Mantz J and Sum-Ping ST: The role of the alpha2-adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit. J Intensive Care Med. 18:29–41. 2003. View Article : Google Scholar : PubMed/NCBI
10	Yang CL, Chen CH, Tsai PS, Wang TY and Huang CJ: Protective effects of dexmedetomidine-ketamine combination against ventilator-induced lung injury in endotoxemia rats. J Surg Res. 167:e273–e281. 2011. View Article : Google Scholar : PubMed/NCBI
11	Okada H, Kurita T, Mochizuki T, Morita K and Sato S: The cardioprotective effect of dexmedetomidine on global ischaemia in isolated rat hearts. Resuscitation. 74:538–545. 2007. View Article : Google Scholar : PubMed/NCBI
12	Kocoglu H, Ozturk H, Ozturk H, Yilmaz F and Gulcu N: Effect of dexmedetomidine on ischemia-reperfusion injury in rat kidney: A histopathologic study. Ren Fail. 31:70–74. 2009. View Article : Google Scholar : PubMed/NCBI
13	Engelhard K, Werner C, Eberspacher E, Bachl M, Blobner M, Hildt E, Hutzler P and Kochs E: The effect of the alpha2-agonist dexmedetomidine and the N-methyl-D-aspartate antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg. 96:524–531. 2003. View Article : Google Scholar : PubMed/NCBI
14	Hanci V, Erol B, Bektas S, Mungan G, Yurtlu S, Tokgöz H, Can M and Ozkoçak Turan I: Effect of dexmedetomidine on testicular torsion/detorsion damage in rats. Urol Int. 84:105–111. 2010. View Article : Google Scholar : PubMed/NCBI
15	Downward J: PI 3-kinase, AKT and cell survival. Semin Cell Dev Biol. 15:177–182. 2004. View Article : Google Scholar : PubMed/NCBI
16	Gass P, Schröder H, Prior P and Kiessling M: Constitutive expression of heat shock protein 90 (HSP90) in neurons of the rat brain. Neurosci Lett. 182:188–192. 1194. View Article : Google Scholar
17	Sato S, Fujita N and Tsuruo T: Modulation of AKT kinase activity by binding to Hsp90. Proc Natl Acad Sci USA. 97:10832–10837. 2000. View Article : Google Scholar : PubMed/NCBI
18	Li X, Luo R, Jiang R, Meng X, Wu X, Zhang S and Hua W: The role of the Hsp90/AKT pathway in myocardial calpain-induced caspase-3 activation and apoptosis during sepsis. BMC Cardiovas Dis. 13:82013. View Article : Google Scholar
19	Shen E, Fan J and Peng T: Glycogen synthase kinase-3beta suppresses tumor necrosis factor-alpha expression in cardiomyocytes during lipopolysaccharide stimulation. J Cell Biochem. 104:329–338. 2008. View Article : Google Scholar : PubMed/NCBI
20	Basso AD, Solit DB, Chiosis G, Giri B, Tsichlis P and Rosen N: AKT forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem. 277:39858–39866. 2002. View Article : Google Scholar : PubMed/NCBI
21	Zhang R, Luo D, Miao R, Bai L, Ge Q, Sessa WC and Min W: Hsp90-AKT phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene. 24:3954–3963. 2005. View Article : Google Scholar : PubMed/NCBI
22	Zhu YM, Wang CC, Chen L, Qian LB, Ma LL, Yu J, Zhu MH, Wen CY, Yu LN and Yan M: Both PI3K/AKT and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res. 1494:1–8. 2013. View Article : Google Scholar : PubMed/NCBI
23	McGrath JC, Drummond GB, McLachlan EM, Kilkenny C and Wainwright CL: Guidelines for reporting experiments involving animals: The ARRIVE guidelines. Br J Pharmacol. 160:1573–1576. 2010. View Article : Google Scholar : PubMed/NCBI
24	Bayne K: Revised guide for the care and use of laboratory animals available. American Physiological Society. Physiologist. 39:199, 208–211. 1996.
25	Kaech S and Banker G: Culturing hippocampal neurons. Nat Protoc. 1:2406–2415. 2006. View Article : Google Scholar : PubMed/NCBI
26	Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, Swan R, Kherouf H, Monneret G, Chung CS and Ayala A: PD-1 expression by macrophages serves a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA. 106:6303–6308. 2009. View Article : Google Scholar : PubMed/NCBI
27	Ritter C, Andrades ME, Reinke A, Menna-Barreto S, Moreira JC and Dal-Pizzol F: Treatment with Nacetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis. Crit Care Med. 32:342–249. 2004. View Article : Google Scholar : PubMed/NCBI
28	Vorhees CV and Williams MT: Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nat Protoc. 1:848–858. 2006. View Article : Google Scholar : PubMed/NCBI
29	Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M and Imaki J: Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 110:628–637. 2009. View Article : Google Scholar : PubMed/NCBI
30	Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT and Singer M: Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol. 286:R491–R497. 2004. View Article : Google Scholar : PubMed/NCBI
31	Kamibayashi T and Maze M: Clinical uses of alpha2-adrenergic agonists. Anesthesiology. 93:1345–1349. 2000. View Article : Google Scholar : PubMed/NCBI
32	Siami S, Annane D and Sharshar T: The encephalopathy in sepsis. Crit Care Clin. 24:67–82. 2008. View Article : Google Scholar : PubMed/NCBI
33	Pytel P and Alexander JJ: Pathogenesis of septic encephalopathy. Cur Opin Neurol. 22:283–287. 2009. View Article : Google Scholar
34	Semmler A, Hermann S, Mormann F, Weberpals M, Paxian SA, Okulla T, Schäfers M, Kummer MP, Klockgether T and Heneka MT: Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflam. 5:382008. View Article : Google Scholar
35	Taccone FS, Su F, Pierrakos C, He X, James S, Dewitte O, Vincent JL and De Backer D: Cerebral microcirculation is impaired during sepsis: An experimental study. Crit Care. 14:R1402010. View Article : Google Scholar : PubMed/NCBI
36	Schoeler M, Loetscher PD, Rossaint R, Fahlenkamp AV, Eberhardt G, Rex S, Weis J and Coburn M: Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. BMC Neurol. 12:202012. View Article : Google Scholar : PubMed/NCBI
37	Degos V, Charpentier TL, Chhor V, Brissaud O, Lebon S, Schwendimann L, Bednareck N, Passemard S, Mantz J and Gressens P: Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology. 118:1123–1132. 2013. View Article : Google Scholar : PubMed/NCBI
38	McAdams RM, McPherson RJ, Kapur R, Phillips B, Shen DD and Juul SE: Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats. Pediatr Res. 77:772–778. 2015. View Article : Google Scholar : PubMed/NCBI
39	Park JH, Derry K and Owens R: 896: Dexmedetomidine as adjunctive sedation in mechanically ventilated patients. Crit Care Med. 47:4272019. View Article : Google Scholar
40	Martini M, De Santis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signaling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014. View Article : Google Scholar : PubMed/NCBI
41	Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR and Greenberg ME: Regulation of neuronal survival by the serine-threonine protein kinase AKT. Science. 275:661–665. 1997. View Article : Google Scholar : PubMed/NCBI
42	Li Y, Zeng M, Chen W, Liu C, Wang F, Han X, Zuo Z and Peng S: Dexmedetomidine reduces isofluraneinduced neuroapoptosis partly by preserving PI3K/AKT pathway in the hippocampus of neonatal rats. PLoS One. 9:e936392014. View Article : Google Scholar : PubMed/NCBI
43	Farghaly HS, Mahmoud AM and Abdel-Sater KA: Effect of dexmedetomidine and cold stress in a rat model of neuropathic pain: Role of interleukin-6 and tumor necrosis factor-α. Eur J Pharmacol. 776:139–145. 2016. View Article : Google Scholar : PubMed/NCBI
44	Li J, Chen Q, He X, Alam A, Ning J, Yi B, Lu K and Gu J: Dexmedetomidine attenuates lung apoptosis induced by renal ischemia-reperfusion injury through α₂AR/PI3K/AKT pathway. J Transl Med. 16:782018. View Article : Google Scholar : PubMed/NCBI
45	Ibacache M, Sanchez G, Pedrozo Z, Galvez F, Humeres C, Echevarria G, Duaso J, Hassi M, Garcia L, Díaz-Araya G and Lavandero S: Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart. Biochim Biophys Acta. 1822:537–545. 2012. View Article : Google Scholar : PubMed/NCBI
46	Karkoulias G, Mastrogianni O, Lymperopoulos A, Paris H and Flordellis C: alpha(2)-Adrenergic receptors activate MAPK and AKT through a pathway involving arachidonic acid metabolism by cytochrome P450-dependent epoxygenase, matrix metalloproteinase activation and subtype-specific transactivation of EGFR. Cell Signal. 18:729–739. 2006. View Article : Google Scholar : PubMed/NCBI
47	Cai W, Rudolph JL, Harrison SM, Jin L, Frantz AL, Harrison DA and Andres DA: An evolutionarily conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance. Mol Biol Cell. 22:3231–3241. 2011. View Article : Google Scholar : PubMed/NCBI
48	Koh PO: Nicotinamide attenuates the ischemic brain injury-induced decrease of AKT activation and Bad phosphorylation. Neurosci Lett. 498:105–109. 2011. View Article : Google Scholar : PubMed/NCBI
49	Mendoza MC, Er EE and Blenis J: The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation. Trends Biochem Sci. 36:320–328. 2011. View Article : Google Scholar : PubMed/NCBI
50	Parcellier A, Tintignac LA, Zhuravleva E and Hemmings BA: PKB and the mitochondria: AKTing on apoptosis. Cell Signal. 20:21–30. 2008. View Article : Google Scholar : PubMed/NCBI
51	Franke TF: PI3K/Akt: Getting it right matters. Oncogene. 27:6473–6488. 2008. View Article : Google Scholar : PubMed/NCBI
52	Horwood JM, Dufour F, Laroche S and Davis S: Signalling mechanisms mediated by the phosphoinositide 3-kinase/AKT cascade in synaptic plasticity and memory in the rat. Eur J Neurosci. 23:3375–3384. 2006. View Article : Google Scholar : PubMed/NCBI
53	Björklund M, Siverina I, Heikkinen T, Tanila H, Sallinen J, Scheinin M and Riekkinen P Jr: Spatial working memory improvement by an alpha2-adrenoceptor agonist dexmedetomidine is not mediated through alpha2C-adrenoceptor. Prog Neuropsychopharmacol Biol Psychiatry. 25:1539–1554. 2001. View Article : Google Scholar : PubMed/NCBI
54	Ji MH, Jia M, Zhang MQ, Liu WX, Xie ZC, Wang ZY and Yang JJ: Dexmedetomidine alleviates anxiety-like behaviors and cognitive impairments in a rat model of post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry. 54:284–288. 2014. View Article : Google Scholar : PubMed/NCBI