Neuroprotective effects of dexmedetomidine on traumatic brain injury: Involvement of neuronal apoptosis and HSP70 expression

Zhang,Man‑He; Zhou,Xiu‑Min; Cui,Jian‑Zhong; Wang,Kai‑Jie; Feng,Yan; Zhang,Hong‑Ao

doi:10.3892/mmr.2018.8898

Neuroprotective effects of dexmedetomidine on traumatic brain injury: Involvement of neuronal apoptosis and HSP70 expression

Authors:
- Man‑He Zhang
- Xiu‑Min Zhou
- Jian‑Zhong Cui
- Kai‑Jie Wang
- Yan Feng
- Hong‑Ao Zhang
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Affiliations: Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Neurosurgery, Tangshan Workers' Hospital, Tangshan, Hebei 063000, P.R. China
Published online on: April 19, 2018 https://doi.org/10.3892/mmr.2018.8898
Pages: 8079-8086
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the protective effect of dexmedetomidine (Dex) on traumatic brain injury (TBI), and further evaluate whether the underlying neuroprotective mechanisms are associated with neurological apoptosis and the expression of 70 kDa heat shock protein (HSP70) in the hippocampus. A total of 90 adult male Sprague‑Dawley rats were randomly assigned into 3 groups (n=30/group): Sham, TBI and Dex groups. The rat models of TBI were established using a modified weight‑drop device and Dex (15 µg/kg) was intravenously administered immediately following TBI. The brain edema and neurological function outcomes of TBI were assessed using wet‑dry weight analysis and the Neurological Severity Score method. The expression levels of B‑cell lymphoma‑2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax) in the rat hippocampus were evaluated using immunohistochemical staining and western blot analysis. The protein levels of HSP70 in the hippocampal region were analyzed using western blot analysis. The results of the present study revealed that administration of Dex post‑TBI improved brain edema and neurological outcomes, due to the attenuation of the TBI‑induced reduction of Bax expression and increase of Bcl‑2 and HSP70 expression. In conclusion, the results of the present study suggested that administration of Dex may serve as a neuroprotective agent against brain injury, at least partially via the inhibition of neuronal apoptosis and upregulation of HSP70 expression in the hippocampus.

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1	Cheng G, Fu L, Zhang HY, Wang YM, Zhang LM and Zhang JN: The role of mitochondrial calcium uniporter in neuroprotection in traumatic brain injury. Med Hypotheses. 80:115–117. 2013. View Article : Google Scholar : PubMed/NCBI
2	Kumar A and Loane DJ: Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention. Brain Behav Immun. 26:1191–1201. 2012. View Article : Google Scholar : PubMed/NCBI
3	Summers CR, Ivins B and Schwab KA: Traumatic brain injury in the United States: An epidemiologic overview. Mt Sinai J Med. 76:105–110. 2009. View Article : Google Scholar : PubMed/NCBI
4	Stein SC, Georgoff P, Meghan S, Mizra K and Sonnad SS: 150 years of treating severe traumatic brain injury: A systematic review of progress in mortality. J Neurotraum. 27:1343–1353. 2010. View Article : Google Scholar
5	Smania N, Avesani R, Roncari L, Ianes P, Girardi P, Varalta V, Gambini MG, Fiaschi A and Gandolfi M: Factors predicting functional and cognitive recovery following severe traumatic, anoxic and cerebrovascular brain damage. J Head Trauma Rehab. 28:131–140. 2013. View Article : Google Scholar
6	Weber JT: Altered calcium signaling following traumatic brain injury. Front Pharmacol. 3:602012. View Article : Google Scholar : PubMed/NCBI
7	Harvey LA and Close JC: Traumatic brain injury in older adults: Characteristics, causes and consequences. Injury. 43:1821–1826. 2012. View Article : Google Scholar : PubMed/NCBI
8	Mangat HS: Severe traumatic brain injury. Continuum (Minneap Minn). 18:532–546. 2012.PubMed/NCBI
9	Zink BJ, Szmydynger-Chodobska J and Chodobski A: Emerging concepts in the pathophysiology of traumatic brain injury. Psychiatr Clin North Am. 33:741–756. 2010. View Article : Google Scholar : PubMed/NCBI
10	Hart T, Brenner L, Clark AN, Bogner JA, Novack TA, Chervoneva I, Nakase-Richardson R and Arango-Lasprilla JC: Major and minor depression after traumatic brain injury. Arch Phys Med Rehabi. 92:1211–1219. 2011. View Article : Google Scholar
11	Bye N, Carron S, Han X, Agyapomaa D, Ng SY, Yan E, Rosenfeld JV and Morganti-Kossmann MC: Neurogenesis and glial proliferation are stimulated following diffuse traumatic brain injury in adult rats. J Neurosci Res. 89:986–1000. 2011. View Article : Google Scholar : PubMed/NCBI
12	Loane DJ and Faden AI: Neuroprotection for traumatic brain injury: Translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci. 31:596–604. 2010. View Article : Google Scholar : PubMed/NCBI
13	Blennow K, Hardy J and Zetterberg H: The neuropathology and neurobiology of traumatic brain injury. Neuron. 76:886–899. 2012. View Article : Google Scholar : PubMed/NCBI
14	Xu X, Jiang R, Gong P, Liu Q, Chen Y, Hou S, Yuan D, Shi J and Lan Q: Up-regulation of FOS-like antigen 1 contributes to neuronal apoptosis in the cortex of rat following traumatic brain injury. Metab Brain Dis. 33:115–125. 2018. View Article : Google Scholar : PubMed/NCBI
15	Sato A: Novel anticancer strategy targeting switch mechanisms in two types of cell death: Necrosis and apoptosis. Yakugaku Zasshi. 1315–1321. 2017. View Article : Google Scholar : PubMed/NCBI
16	Anderson MA, Huang D and Roberts A: Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 51:219–227. 2014. View Article : Google Scholar : PubMed/NCBI
17	Hartings JA, Bullock MR, Okonkwo DO, Murray LS, Murray GD, Fabricius M, Maas AI, Woitzik J, Sakowitz O, Mathern B, et al: Spreading depolarisations and outcome after traumatic brain injury: A prospective observational study. Lancet Neurol. 10:1058–1064. 2011. View Article : Google Scholar : PubMed/NCBI
18	Andriessen TM, Horn J, Franschman G, van der Naalt J, Haitsma I, Jacobs B, Steyerberg EW and Vos PE: Epidemiology, severity classification and outcome of moderate and severe traumatic brain injury: A prospective multicenter study. J Neurotraum. 28:2019–2031. 2011. View Article : Google Scholar
19	Zhang J, Jiang R, Liu L, Watkins T, Zhang F and Dong JF: Traumatic brain injury-associated coagulopathy. J Neurotraum. 29:2597–2605. 2012. View Article : Google Scholar
20	Wang Z, Kou D, Li Z, He Y, Yu W and Du H: Effects of propofol-dexmedetomidine combination on ischemia reperfusion-induced cerebral injury. NeuroRehabilitation. 35:825–834. 2014.PubMed/NCBI
21	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
22	Goyagi T and Tobe Y: Dexmedetomidine improves the histological and neurological outcomes 48 h after transient spinal ischemia in rats. Brain Res. 1566:24–30. 2014. View Article : Google Scholar : PubMed/NCBI
23	Liao Z, Cao D, Han X, Liu C, Peng J, Zuo Z, Wang F and Li Y: Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats. Brain Res Bull. 107:69–78. 2014. View Article : Google Scholar : PubMed/NCBI
24	Cui C, Cui Y, Gao J, Sun L, Wang Y, Wang K, Li R, Tian Y, Song S and Cui J: Neuroprotective effect of ceftriaxone in a rat model of traumatic brain injury. Neurol Sci. 35:695–700. 2014. View Article : Google Scholar : PubMed/NCBI
25	Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H and Demetriadou K: A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J Neurosurg. 80:291–300. 1994. View Article : Google Scholar : PubMed/NCBI
26	Yang NL, Xu DM and Ming GF: Intervention effect of dexmedetomidine on inflammatory response following traumatic brain injury in rats. Pract Prev Med. 17:243–245. 2010.
27	Roof RL, Duvdevani R, Heyburn JW and Stein DG: Progesterone rapidly decreases brain edema: Treatment delayed up to 24 h is still effective. Exp Neurol. 138:246–251. 1996. View Article : Google Scholar : PubMed/NCBI
28	Zhang X, Chen Y, Jenkins LW, Kochanek PM and Clark RS: Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care. 9:66–75. 2005. View Article : Google Scholar : PubMed/NCBI
29	Stoica BA and Faden AI: Cell death mechanisms and modulation in traumatic brain injury. Neurotherapeutics. 7:3–12. 2010. View Article : Google Scholar : PubMed/NCBI
30	Fanselow MS and Dong HW: Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 65:7–19. 2010. View Article : Google Scholar : PubMed/NCBI
31	Shamas-Din A, Brahmbhatt H, Leber B and Andrews DW: BH3-only proteins: Orchestrators of apoptosis. Biochim Biophys Acta. 1813:508–520. 2011. View Article : Google Scholar : PubMed/NCBI
32	Feder ME and Hofmann GE: Heat-shock proteins, molecular chaperones and the stress response: Evolutionary and ecological physiology. Annu Rev Physiol. 61:243–282. 1999. View Article : Google Scholar : PubMed/NCBI
33	Xiong B, Shi QQ and Miao CH: Dexmedetomidine renders a brain protection on hippocampal formation through inhibition of nNOS-NO signalling in endotoxin-induced shock rats. Brain Inj. 28:1003–1008. 2014. View Article : Google Scholar : PubMed/NCBI
34	Wang X, Ji J, Fen L and Wang A: Effects of dexmedetomidine on cerebral blood flow in critically ill patients with or without traumatic brain injury: A prospective controlled trial. Brain Inj. 27:1617–1622. 2013. View Article : Google Scholar : PubMed/NCBI
35	James ML, Olson DM and Graffagnino C: A pilot study of cerebral and haemodynamic physiological changes during sedation with dexmedetomidine or propofol in patients with acute brain injury. Anaesth Intens Care. 40:949–957. 2012.
36	Nasrallah N A, Thomas M, Kuehl S and Diab K: The use of dexmedetomidine for longer than 48 h with evaluation of its secondary outcome in patients with liver disease. Chest. 150:228A2016. View Article : Google Scholar
37	Guler L, Bozkirli F, Bedirli N, Unal Y, Guler A, Oztas Y, Balta S, Cakar M, Demirkol S, Arslan Z and Unlu M: Comparison of the effects of dexmedetomidine vs. ketamine in cardiac ischemia/reperfusion injury in rats-preliminary study. Adv Clin Exp Med. 23:683–689. 2014. View Article : Google Scholar : PubMed/NCBI
38	Si YN, Bao HG, Xu L, Wang XL, Shen Y, Wang JS and Yang XB: Dexmedetomidine protects against ischemia/reperfusion injury in rat kidney. Eur Rev Med Pharmaco Sci. 18:1843–1851. 2014.
39	Jiang L, Li L, Shen J, Qi Z and Guo L: Effect of dexmedetomidine on lung ischemiareperfusion injury. Mol Med Rep. 9:419–426. 2014. View Article : Google Scholar : PubMed/NCBI
40	Cai Y, Xu H, Yan J, Zhang L and Lu Y: Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. Mol Med Rep. 9:1542–1550. 2014. View Article : Google Scholar : PubMed/NCBI
41	Shen M, Wang S, Wen X, Han XR, Wang YJ, Zhou XM, Zhang MH, Wu DM, Lu J and Zheng YL: Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. Biomed Pharmacother. 95:885–893. 2017. View Article : Google Scholar : PubMed/NCBI