Artificial Hibernation by Phenothiazines: A Potential Neuroprotective Therapy Against Cerebral Inflammation in Stroke

Author(s): Longfei Guan, Sichao Guo, James Yip, Kenneth B. Elkin, Fengwu Li, Changya Peng, Xiaokun Geng*, Yuchuan Ding*.

Journal Name: Current Neurovascular Research

Volume 16 , Issue 3 , 2019

Become EABM
Become Reviewer

Abstract:

Background: The inflammatory response to acute cerebral ischemia is a major factor in stroke pathobiology and patient outcome. In the clinical setting, no effective pharmacologic treatments are currently available. Phenothiazine drugs, such as chlorpromazine and promethazine, (C+P) have been widely studied because of their ability to induce neuroprotection through artificial hibernation after stroke. The present study determined their effect on the inflammatory response.

Methods: Sprague-Dawley rats were divided into 4 groups: (1) sham, (2) stroke, (3) stroke treated by C+P without temperature control and (4) stroke treated by C+P with temperature control (n=8 per group). To assess the neuroprotective effect of C+P, brain damage was measured using infarct volume and neurological deficits. The expression of inflammatory response molecules tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) was determined by real-time PCR and Western blotting.

Results: TNF-α, IL-1β, ICAM-1, VCAM-1, and NF-κB mRNA and protein expressions were upregulated, and brain damage and neurological deficits were increased after stroke. These markers of cerebral injury were significantly reduced following C+P administration under drug-induced hypothermia, while C+P administration under normal body temperature reduced them by a lesser degree.

Conclusion: This study showed an inhibitory effect of C+P on brain inflammation, which may be partially dependent on drug-induced hibernation, as well as other mechanisms of action by these drugs. These findings further suggest the great potential of C+P in the clinical treatment of ischemic stroke.

Keywords: Inflammation, ischemia/reperfusion, pharmacological hypothermia, brain metabolism, phenothiazines, stroke.

[1]
Geng X, Ren C, Wang T, et al. Effect of remote ischemic postconditioning on an intracerebral hemorrhage stroke model in rats. Neurol Res 2012; 34(2): 143-8.
[2]
Minnerup J, Sutherland BA, Buchan AM, Kleinschnitz C. Neuroprotection for stroke: Current status and future perspectives. Int J Mol Sci 2012; 13(9): 11753-72.
[3]
Sun MS, Jin H, Sun X, et al. Free radical damage in ischemiareperfusion injury: An obstacle in acute ischemic stroke after revascularization therapy 2018; 2018: 3804979.
[4]
Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 2012; 13(4): 267-78.
[5]
Ma LL, Song L, Yu XD, Yu TX, Liang H, Qiu JX. The clinical study on the treatment for acute cerebral infarction by intra-arterial thrombolysis combined with mild hypothermia. Eur Rev Med Pharmacol Sci 2017; 21(8): 1999-2006.
[6]
Wu D, Zhi X, Duan Y, et al. Inflammatory cytokines are involved in dihydrocapsaicin (DHC) and regional cooling infusion (RCI)-induced neuroprotection in ischemic rat. Brain Res 2019; 1710: 173-80.
[7]
Tahir RA, Pabaney AH. Therapeutic hypothermia and ischemic stroke: A literature review. Surg Neurol Int 2016; 7(Suppl. 14): S381-6.
[8]
Iadecola C, Anrather J. The immunology of stroke: From mechanisms to translation. Nat Med 2011; 17(7): 796-808.
[9]
Widmann C, Gandin C, Petit-Paitel A, Lazdunski M, Heurteaux C. The traditional chinese medicine MLC901 inhibits inflammation processes after focal cerebral ischemia. Sci Rep 2018; 8(1): 18062.
[10]
Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells. J Leukoc Biol 2010; 87(5): 779-89.
[11]
Li WA, Efendizade A, Ding Y. The role of microRNA in neuronal inflammation and survival in the post ischemic brain: A review. Neurol Res 2017; (116): 1-9.
[12]
Aloisi F. Immune function of microglia. Glia 2001; 36(2): 165-79.
[13]
Mankan AK, Lawless MW, Gray SG, Kelleher D, McManus R. NF-kappaB regulation: The nuclear response. J Cell Mol Med 2009; 13(4): 631-43.
[14]
Harari OA, Liao JK. NF-κB and innate immunity in ischemic stroke. Ann N Y Acad Sci 2010; 1207(1): 32-40.
[15]
Coté CJ, Karl HW, Notterman DA, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: analysis of medications used for sedation. Pediatrics 2000; 106(4): 633-44.
[16]
Burn JH. The pharmacology of chlorpromazine and promethazine. Proc R Soc Med 1954; 47(8): 617-21.
[17]
Berntman L, Carlsson C. Influence of “lytic cocktail” on blood flow and oxygen consumption in the rat brain. Acta Anaesthesiol Scand 1978; 22(5): 515-8.
[18]
Geng X, Li F, Yip J, et al. Neuroprotection by Chlorpromazine and Promethazine in severe transient and permanent ischemic stroke. Mol Neurobiol 2017; 54(10): 8140-50.
[19]
Dwyer DS, Lu XH, Bradley RJ. Cytotoxicity of conventional and atypical antipsychotic drugs in relation to glucose metabolism. Brain Res 2003; 971(1): 31-9.
[20]
López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry 2005; 17(3): 113-35.
[21]
Li F, Geng X, Yip J, Ding Y. Therapeutic target and cell-signal communication of Chlorpromazine and Promethazine in attenuating blood-brain barrier disruption after ischemic stroke. Cell Transplant 2019; 28(2): 145-56.
[22]
Liu S, Geng X, Forreider B, et al. Enhanced beneficial effects of mild hypothermia by phenothiazine drugs in stroke therapy. Neurol Res 2015; 37(5): 454-60.
[23]
An H, Duan Y, Wu D, et al. Phenothiazines enhance mild hypothermia-induced neuroprotection via PI3K/Akt regulation in experimental stroke. Sci Rep 2017; 7(1): 7469.
[24]
Geng X, Li F, Yip J, et al. Neuroprotection by Chlorpromazine and Promethazine in severe transient and permanent ischemic stroke. Mol Neurobiol 2017; 54(10): 8140-50.
[25]
Wang F, Luo Y, Ling F, et al. Comparison of neuroprotective effects in ischemic rats with different hypothermia procedures. Neurol Res 2010; 32(4): 378-83.
[26]
Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20(1): 84-91.
[27]
Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD. Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 1996; 27(9): 1616-22.
[28]
Wang F, Wang Y, Geng X, et al. Neuroprotective effect of acute ethanol administration in a rat with transient cerebral ischemia. Stroke 2012; 43(1): 205-10.
[29]
Tessier SN, Wu CW, Storey KB. Molecular control of protein synthesis, glucose metabolism, and apoptosis in the brain of hibernating thirteen-lined ground squirrels. Biochem Cell Biol 2019. [Epub ahead of print].
[30]
Tessier SN, Wu CW, Storey KB. Molecular control of protein synthesis, glucose metabolism, and apoptosis in the brain of hibernating thirteen-lined ground squirrels. Biochem Cell Biol 2019. [Epub ahead of print].
[31]
Balwani S, Chaudhuri R, Nandi D, Jaisankar P, Agrawal A, Ghosh B. Regulation of NF-κB activation through a novel PI-3K-independent and PKA/Akt-dependent pathway in human umbilical vein endothelial cells. PLoS One 2012; 7(10): e46528.
[32]
Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK. Genes Dev 2008; 22(11): 1490-500.
[33]
Forreider B, Pozivilko D, Kawaji Q, Geng X, Ding Y. Hibernation-like neuroprotection in stroke by attenuating brain metabolic dysfunction. Prog Neurobiol 2017; 157: 174-87.
[34]
Liu X, Wu D, Wen S, et al. Mild therapeutic hypothermia protects against cerebral ischemia/reperfusion injury by inhibiting miR-15b expression in rats. Brain Circ 2017; 3(4): 219-26.
[35]
Zhang J, Liu K, Elmadhoun O, et al. Synergistically induced hypothermia and enhanced neuroprotection by pharmacological and physical approaches in stroke. Aging Dis 2018; 9(4): 578-89.
[36]
Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 2009; 37(7): S186-202.
[37]
Wang Q, Li AL, Zhi DS, Huang HL. Effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury. Chin J Traumatol 2007; 10(4): 246-9.
[38]
Zhao QJ, Zhang XG, Wang LX. Mild hypothermia therapy reduces blood glucose and lactate and improves neurologic outcomes in patients with severe traumatic brain injury. J Crit Care 2011; 26(3): 311-5.
[39]
Ren C, Li S, Rajah G, et al. Hypoxia, hibernation and neuroprotection: An experimental study in mice. Aging Dis 2018; 9(4): 761-8.
[40]
Ahmad M, Graham SH. Inflammation after stroke: Mechanisms and therapeutic approaches. Transl Stroke Res 2010; 1(2): 74-84.
[41]
An C, Shi Y, Li P, et al. Molecular dialogs between the ischemic brain and the peripheral immune system: Dualistic roles in injury and repair. Prog Neurobiol 2014; 115: 6-24.
[42]
Zhao H, Steinberg GK, Sapolsky RM. General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. J Cereb Blood Flow Metab 2007; 27(12): 1879-94.
[43]
Ceulemans AG, Zgavc T, Kooijman R, et al. The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. J Neuroinflammation 2010; 7(1): 74.
[44]
Liu L, Liu X, Wang R, et al. Mild focal hypothermia regulates the dynamic polarization of microglia after ischemic stroke in mice 2018 40(6): 508-15.
[45]
Truettner JS, Suzuki T, Dietrich WD. The effect of therapeutic hypothermia on the expression of inflammatory response genes following moderate traumatic brain injury in the rat. Brain Res Mol Brain Res 2005; 138(2): 124-34.
[46]
Zhang H, Zhou M, Zhang J, Mei Y, Sun S, Tong E. Therapeutic effect of post-ischemic hypothermia duration on cerebral ischemic injury. Neurol Res 2008; 30(4): 332-6.
[47]
Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA. Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience 2002; 114(4): 1081-90.
[48]
Deng H, Han HS, Cheng D, Sun GH, Yenari MA. Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation. Stroke 2003; 34(10): 2495-501.
[49]
Ruan Z, Wang HM, Huang XT, et al. A novel caffeoyl triterpene attenuates cerebral ischemic injury with potent anti-inflammatory and hypothermic effects. J Neurochem 2015; 133(1): 93-103.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 3
Year: 2019
Page: [232 - 240]
Pages: 9
DOI: 10.2174/1567202616666190624122727
Price: $58

Article Metrics

PDF: 39
HTML: 2