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Aging and disease    2018, Vol. 9 Issue (3) : 507-522     DOI: 10.14336/AD.2017.0628
Review Article |
Effects of Therapeutic Hypothermia Combined with Other Neuroprotective Strategies on Ischemic Stroke: Review of Evidence
Zhang Zheng1,2, Zhang Linlei3, Ding Yuchuan4, Han Zhao3,*, Ji Xunming1,5,*
1Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
2Department of Neurology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
3Department of Neurology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
4Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA
5China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
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Abstract  

Ischemic stroke is a major cause of death and disability globally, and its incidence is increasing. The only treatment approved by the US Food and Drug Administration for acute ischemic stroke is thrombolytic treatment with recombinant tissue plasminogen activator. As an alternative, therapeutic hypothermia has shown excellent potential in preclinical and small clinical studies, but it has largely failed in large clinical studies. This has led clinicians to explore the combination of therapeutic hypothermia with other neuroprotective strategies. This review examines preclinical and clinical progress towards developing highly effective combination therapy involving hypothermia for stroke patients.

Keywords ischemic stroke      neuroprotection      therapeutic hypothermia      combination therapy     
Corresponding Authors: Han Zhao,Ji Xunming   
About author:

These authors have contributed equally to this work.

Issue Date: 05 June 2018
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Zhang Zheng
Zhang Linlei
Ding Yuchuan
Han Zhao
Ji Xunming
Cite this article:   
Zhang Zheng,Zhang Linlei,Ding Yuchuan, et al. Effects of Therapeutic Hypothermia Combined with Other Neuroprotective Strategies on Ischemic Stroke: Review of Evidence[J]. Aging and disease, 2018, 9(3): 507-522.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0628     OR     http://www.aginganddisease.org/EN/Y2018/V9/I3/507
Main Function of combined strategiesCombined strategiesSpecified treatment
Reduce energy consumptionAnestheticsMethohexital
Thiopentone sodium Xenon Dexmedetomidine
Psychotropic agentsChlorpromazine and promethazine
Suppress calcium overloadNMDA receptor antagonists
Ryanodine receptor inhibitor
Dextromethorphan
MK-801 Delfotel Magnesium with or without tirilazad Dantrolene
Increase blood supplyReperfusion
Vessel dilator Induce arteriogenesis
t-PA
Intra-arterial recanalization Statin Granulocyte colony stimulating factor (G-CSF)
Anti-inflammationAntibioticsTacrolimus
Minocycline
Anti-oxidative stressOxidative stress scavengersEdaravone
Mannitol
Repair damaged cellsBiosynthesis of cell componentCiticoline
Increase oxygen supplyOxygenNormobaric oxygen
Hyperbaric oxygen
Reduce intracranial pressure-Decompressive craniectomy
Anti-apoptosisAnti-apoptosis proteinFNK protein
Gene of anti-apoptosis proteinBcl-2 gene
Multiple protection-Caffeinol (caffeine and ethanol)
Insulin-like growth factor-1 (IGF-1) Brain-derived neurotrophic factor (BDNF) Albumin
Table 1  summary of the second neuroprotective strategies combined with hypothermia in ischemic stroke.
ReferencePermanent(P)/
Transient (T) Ischemia
Temperature degree(°C)Combined TreatmentAim of studyYes/No
Animal
[10]P33Mk-801Enhanced effectNo
[11]T30Mk-801EffectiveYes
[12]T30Mk-801Enhanced effectYes
[18]T34SelfotelEnhanced effectNo
[19]Repetitive34SelfotelEnhanced effectYes
[21]T35.4MagnesiumEnhanced effectYes
[22]P35MagnesiumEnhanced effectYes
[23]T33-34MagnesiumEnhanced effectYes
[24]P35MagnesiumEnhanced effectNo
[27]T33t-PAReduce the side effect of t-PAYes
[28]T34t-PAReduce the side effect of t-PAYes
[29]T32Delayed t-PAEnhanced effectNo
[30]T33t-PAEnhanced effectNo
[42]T35TacrolimusEnhancec/expand time window of tacrolimusYes
[52]T32-33AtorvastatinEnhanced effect/
expand time window of hypothermia
Yes
[57]T35EdaravoneEnhanced effectYes
[65]T34CiticolineEnhanced effectYes
[25]T33MinocyclineEnhanced effectYes
[48]P34MinocyclineEnhanced effectNo
[49]P34-35MinocyclineEnhanced effectNo
[69]T35CaffeinolEnhanced effectYes
[72]T35Chlorpromazine and PromethazineEnhanced effectYes
[77]T33MethohexitalEnhanced effectNo
[84]T36XenonEnhanced effectYes
[88]Incomplete35DexmedetomidineEnhanced effectNo
[98]T33t-PA and Normobaric Oxygen (NBO)Enhanced effectYes
[99]
[105]
T
-
33
31
t-PA And normobaric oxygen (NBO)
Hyperbaric oxygenation (HBO2)
Enhanced effect
Enhanced effect
Yes
Yes
[100]T33t-PA and normobaric oxygen (NBO)reduce the side effect of t-PAYes
[115]T33.5-35Granulocyte-Macrophage Colony-Stimulating Factor (G-CSF)Enhanced effectYes
[120]T32Insulin-Like Growth Factors -1(IGF-1)Enhanced effectYes
[121]T30-33Insulin-Like Growth Factors -1(IGF-1)Enhanced effectNo
[128]P33Brain-Derived Neurotrophic Factor (BDNF)Enhanced effectYes
[133]T33Magnesium and TirilazadEnhanced effectYes
[134]T33Magnesium and TirilazadEffectiveYes
[135]T33Magnesium and TirilazadEnhanced effectYes
[59]P32-34MannitolEnhanced effectNo
[60]T33MannitolEnhanced effectNo
[137]T30-31AlbuminEnhanced effectYes
[141]P32Decompressive CraniectomyEnhanced effectYes
[142]P29-31Decompressive CraniectomyEnhanced effectYes
[147]T35PTD-FNKEnhanced effectYes
[150]T33Gene of Bcl-2Expand time window/Enhanced effectYes
Neuronal culture
[78]-22/32Thiopentone Sodium (TPS)Enhanced effectYes
[93]-33DantroleneEnhanced effectYes
Clinical
[31]T33t-PAEnhanced effectNo
[32]T32-34t-PAEnhanced effectNo
[33]T<35.5t-PAFeasible/improve outcomeYes
[34]T34.5t-PAReduce the side effect of tPAYes
[37]Tdecrease 2
in brain
Intra-Arterial RecanalizationFeasible and safeYes
[69]T33-35Caffeinol and T-PAFeasibleYes
[143]P35Decompressive CraniectomyEnhanced effectYes
Table 2  Summary of outcomes of neuroprotective treatments combined with therapeutic hypothermia in ischemic stroke.
[1] Reith J, Jorgensen HS, Pedersen PM, Nakayama H, Raaschou HO, Jeppesen LL and Olsen TS. (1996). Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet, 8999: 422-5.
[2] Nagel S, Papadakis M, Hoyte L and Buchan AM. (2008). Therapeutic hypothermia in experimental models of focal and global cerebral ischemia and intracerebral hemorrhage. Expert Rev Neurother, 8: 1255-68.
[3] Jong YK, Midori AY. (2015). Hypothermia for treatment of stroke. Brain Circulation, 1: 14-25.
[4] Clark DL, Penner M, Orellana-Jordan IM and Colbourne F. (2008). Comparison of 12, 24 and 48 h of systemic hypothermia on outcome after permanent focal ischemia in rat. Exp Neurol, 2: 386-92.
[5] Krieger DW and Yenari MA. (2004). Therapeutic hypothermia for acute ischemic stroke: what do laboratory studies teach us? Stroke, 6: 1482-9.
[6] Maier CM, Ahern K, Cheng ML, Lee JE, Yenari MA and Steinberg GK. (1998). Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke, 10: 2171-80.
[7] Ridenour TR, Warner DS, Todd MM and McAllister AC. (1992). Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Stroke, 5: 733-8.
[8] Polderman KH and Herold I. (2009). Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods. Crit Care Med, 3: 1101-20.
[9] Bernard SA and Buist M. (2003). Induced hypothermia in critical care medicine: a review. Crit Care Med, 7: 2041-51.
[10] Frazzini VI, Winfree CJ, Choudhri HF, Prestigiacomo CJ and Solomon RA. (1994). Mild hypothermia and MK-801 have similar but not additive degrees of cerebroprotection in the rat permanent focal ischemia model. Neurosurgery, 6: 1040-5; discussion 1045-6.
[11] Green EJ, Pazos AJ, Dietrich WD, McCabe PM, Schneiderman N, Lin B, et al. (1995). Combined postischemic hypothermia and delayed MK-801 treatment attenuates neurobehavioral deficits associated with transient global ischemia in rats. Brain Res, 1-2: 145-52.
[12] Dietrich WD, Lin B, Globus MY, Green EJ, Ginsberg MD and Busto R. (1995). Effect of delayed MK-801 (dizocilpine) treatment with or without immediate postischemic hypothermia on chronic neuronal survival after global forebrain ischemia in rats. J Cereb Blood Flow Metab, 6: 960-8.
[13] Corbett D, Evans S, Thomas C, Wang D and Jonas RA. (1990). MK-801 reduced cerebral ischemic injury by inducing hypothermia. Brain Res, 2: 300-4.
[14] Hattori H and Wasterlain CG. (1991). Hypothermia does not explain MK-801 neuroprotection in a rat model of neonatal hypoxic-ischemic encephalopathy. Neurology, 2 (Pt 1): 330.
[15] Valera E, Sanchez-Martin FJ, Ferrer-Montiel AV, Messeguer A and Merino JM. (2008). NMDA-induced neuroprotection in hippocampal neurons is mediated through the protein kinase A and CREB (cAMP-response element-binding protein) pathway. Neurochem Int, 5: 148-54.
[16] Haberny KA, Paule MG, Scallet AC, Sistare FD, Lester DS, Hanig JP and Slikker WJr., (2002). Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. Toxicol Sci, 1: 9-17.
[17] Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, et al. (1999). Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science, 5398: 70-4.
[18] Shuaib A, Waqar T, Wishart T and Kanthan R. (1995). Post-ischemic therapy with CGS-19755 (alone or in combination with hypothermia) in gerbils. Neurosci Lett, 1-2: 87-90.
[19] Shuaib A, Ijaz S, Mazagri R and Senthilsevlvan A. (1993). CGS-19755 is neuroprotective during repetitive ischemia: this effect is significantly enhanced when combined with hypothermia. Neuroscience, 4: 915-20.
[20] Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, et al. (2010). Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev, 3: 405-96.
[21] Zhu H, Meloni BP, Moore SR, Majda BT and Knuckey NW. (2004). Intravenous administration of magnesium is only neuroprotective following transient global ischemia when present with post-ischemic mild hypothermia. Brain Res, 1-2: 53-60.
[22] Campbell K, Meloni BP and Knuckey NW. (2008). Combined magnesium and mild hypothermia (35 degrees C) treatment reduces infarct volumes after permanent middle cerebral artery occlusion in the rat at 2 and 4, but not 6 h. Brain Res, 258-64.
[23] Song W, Wu YM, Ji Z, Ji YB, Wang SN and Pan SY. (2013). Intra-carotid cold magnesium sulfate infusion induces selective cerebral hypothermia and neuroprotection in rats with transient middle cerebral artery occlusion. Neurol Sci, 4: 479-86.
[24] Meloni BP, Cross JL, Brookes LM, Clark VW, Campbell K and Knuckey NW. (2013). FAST-Mag protocol with or without mild hypothermia (35 degrees C) does not improve outcome after permanent MCAO in rats. Magnes Res, 2: 67-73.
[25] Nagel S, Su Y, Horstmann S, Heiland S, Gardner H, Koziol J, et al. (2008). Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat: effects on BBB breakdown and MMP expression in the acute and subacute phase. Brain Res, 198-206.
[26] Thoresen M, Satas S, Puka-Sundvall M, Whitelaw A, Hallstrom A, Loberg EM, et al. (1997). Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport, 15: 3359-62.
[27] Tang XN, Liu L, Koike MA and Yenari MA. (2013). Mild hypothermia reduces tissue plasminogen activator-related hemorrhage and blood brain barrier disruption after experimental stroke. Ther Hypothermia Temp Manag, 2: 74-83.
[28] Kallmunzer B, Schwab S and Kollmar R. (2012). Mild hypothermia of 34 degrees C reduces side effects of rt-PA treatment after thromboembolic stroke in rats. Exp Transl Stroke Med, 1: 3.
[29] Meden P, Overgaard K, Pedersen H and Boysen G. (1994). Effect of hypothermia and delayed thrombolysis in a rat embolic stroke model. Acta Neurol Scand, 2: 91-8.
[30] Kollmar R, Henninger N, Bardutzky J, Schellinger PD, Schabitz WR and Schwab S. (2004). Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke--an MRI study. Exp Neurol, 1: 204-12.
[31] Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, et al. (2010). Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke, 10: 2265-70.
[32] Bi M, Ma Q, Zhang S, Li J, Zhang Y, Lin L, et al. (2011). Local mild hypothermia with thrombolysis for acute ischemic stroke within a 6-h window. Clin Neurol Neurosurg, 9: 768-73.
[33] Piironen K, Tiainen M, Mustanoja S, Kaukonen KM, Meretoja A, Tatlisumak T and Kaste M. (2014). Mild hypothermia after intravenous thrombolysis in patients with acute stroke: a randomized controlled trial. Stroke, 2: 486-91.
[34] Hong JM, Lee JS, Song HJ, Jeong HS, Choi HA and Lee K. (2014). Therapeutic hypothermia after recanalization in patients with acute ischemic stroke. Stroke, 1: 134-40.
[35] Ji X. (2015). Forward thinking in stroke treatment: Advances in cerebrovascular reperfusion and neurorehabilitation. Brain Circulation, 1: 1-2.
[36] Lapchak PA. (2015). Critical early thrombolytic and endovascular reperfusion therapy for acute ischemic stroke victims: a call for adjunct neuroprotection. Transl Stroke Res, 5: 345-54.
[37] Chen J, Liu L, Zhang H, Geng X, Jiao L, Li G, et al. (2016). Endovascular Hypothermia in Acute Ischemic Stroke: Pilot Study of Selective Intra-Arterial Cold Saline Infusion. Stroke, 7: 1933-5.
[38] Lelekov-Boissard T, Chapuisat G, Boissel JP, Grenier E and Dronne MA. (2009). Exploration of beneficial and deleterious effects of inflammation in stroke: dynamics of inflammation cells. Philos Trans A Math Phys Eng Sci, 1908: 4699-716.
[39] Yenari MA and Han HS. (2006). Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFkappaB). Neurochem Int, 2: 164-9.
[40] Furuichi Y, Katsuta K, Maeda M, Ueyama N, Moriguchi A, Matsuoka N, et al. (2003). Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. Brain Res, 1-2: 137-45.
[41] Noto T, Ishiye M, Furuich Y, Keida Y, Katsuta K, Moriguchi A, et al. (2004). Neuroprotective effect of tacrolimus (FK506) on ischemic brain damage following permanent focal cerebral ischemia in the rat. Brain Res Mol Brain Res, 1: 30-8.
[42] Nito C, Kamiya T, Ueda M, Arii T and Katayama Y. (2004). Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats. Brain Res, 2: 179-85.
[43] Koistinaho M, Malm TM, Kettunen MI, Goldsteins G, Starckx S, Kauppinen RA, et al. (2005). Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J Cereb Blood Flow Metab, 4: 460-7.
[44] Amin AR, Patel RN, Thakker GD, Lowenstein CJ, Attur MG and Abramson SB. (1997). Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines. FEBS Lett, 2-3: 259-64.
[45] Soliman S, Ishrat T, Fouda AY, Patel A, Pillai B and Fagan SC. (2015). Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke. Transl Stroke Res, 4: 309-22.
[46] Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. (2000). Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med, 7: 797-801.
[47] Jordan J, Fernandez-Gomez FJ, Ramos M, Ikuta I, Aguirre N and Galindo MF. (2007). Minocycline and cytoprotection: shedding new light on a shadowy controversy. Curr Drug Deliv, 3: 225-31.
[48] Wang CX, Yang T and Shuaib A. (2003). Effects of minocycline alone and in combination with mild hypothermia in embolic stroke. Brain Res, 1-2: 327-9.
[49] Wang CX, Yang T, Noor R and Shuaib A. (2002). Delayed minocycline but not delayed mild hypothermia protects against embolic stroke. BMC Neurol, 2.
[50] Rosenson RS. (2001). Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. Am J Cardiovasc Drugs, 6: 411-20.
[51] Zhu J, Song W, Li L and Fan X. (2016). Endothelial nitric oxide synthase: a potential therapeutic target for cerebrovascular diseases. Mol Brain, 30.
[52] Lee SH, Kim YH, Kim YJ and Yoon BW. (2008). Atorvastatin enhances hypothermia-induced neuroprotection after stroke. J Neurol Sci, 1-2: 64-8.
[53] Chan PH. (1996). Role of oxidants in ischemic brain damage. Stroke, 6: 1124-9.
[54] Wenjun L, Shaohua Y. (2016). Targeting oxidative stress for the treatment of ischemic stroke: Upstream and downstream therapeutic strategies. Brain Circulation, 4: 153-163.
[55] Takizawa Y, Miyazawa T, Nonoyama S, Goto Y and Itoh M. (2009). Edaravone inhibits DNA peroxidation and neuronal cell death in neonatal hypoxic-ischemic encephalopathy model rat. Pediatr Res, 6: 636-41.
[56] Noor JI, Ueda Y, Ikeda T and Ikenoue T. (2007). Edaravone inhibits lipid peroxidation in neonatal hypoxic-ischemic rats: an in vivo microdialysis study. Neurosci Lett, 1: 5-9.
[57] Nito C, Kamiya T, Amemiya S, Katoh K and Katayama Y. (2003). The neuroprotective effect of a free radical scavenger and mild hypothermia following transient focal ischemia in rats. Acta Neurochir Suppl, 199-203.
[58] Zhang X, Wang X, Zhang J, Huang X, Wei D, Lan W and Hu Z. (2016). Reduction of nitrous oxide emissions from partial nitrification process by using innovative carbon source (mannitol). Bioresour Technol, 789-95.
[59] Kazan S, Karasoy M, Baloglu H and Tuncer R. (1999). The effect of mild hypothermia, mannitol and insulin-induced hypoglycaemia on ischaemic infarct volume in the early period after permanent middle cerebral artery occlusion in the rat. Acta Neurochir (Wien), 9: 979-87.
[60] Karibe H, Zarow GJ and Weinstein PR. (1995). Use of mild intraischemic hypothermia versus mannitol to reduce infarct size after temporary middle cerebral artery occlusion in rats. J Neurosurg, 1: 93-8.
[61] Davalos A and Secades J. (2011). Citicoline preclinical and clinical update 2009-2010. Stroke, 1 Suppl: S36-9.
[62] Secades JJ. (2011). Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol, S1-S62.
[63] Weiss GB. (1995). Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci, 9: 637-60.
[64] Gutierrez-Fernandez M, Rodriguez-Frutos B, Fuentes B, Vallejo-Cremades MT, Alvarez-Grech J, Exposito-Alcaide M and Diez-Tejedor E. (2012). CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke. Neurochem Int, 3: 310-7.
[65] Sahin S, Alkan T, Temel SG, Tureyen K, Tolunay S and Korfali E. (2010). Effects of citicoline used alone and in combination with mild hypothermia on apoptosis induced by focal cerebral ischemia in rats. J Clin Neurosci, 2: 227-31.
[66] Strong R, Grotta JC and Aronowski J. (2000). Combination of low dose ethanol and caffeine protects brain from damage produced by focal ischemia in rats. Neuropharmacology, 3: 515-22.
[67] Chandler LJ, Sumners C and Crews FT. (1993). Ethanol inhibits NMDA receptor-mediated excitotoxicity in rat primary neuronal cultures. Alcohol Clin Exp Res, 1: 54-60.
[68] Aronowski J, Strong R, Shirzadi A and Grotta JC. (2003). Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke, 5: 1246-51.
[69] Martin-Schild S, Hallevi H, Shaltoni H, Barreto AD, Gonzales NR, Aronowski J, et al. (2009). Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia. J Stroke Cerebrovasc Dis, 2: 86-96.
[70] Ford JM, Prozialeck WC and Hait WN. (1989). Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance. Mol Pharmacol, 1: 105-15.
[71] Snyder SH, Banerjee SP, Yamamura HI and Greenberg D. (1974). Drugs, neurotransmitters, and schizophrenia. Science, 4143: 1243-53.
[72] Liu S, Geng X, Forreider B, Xiao Y, Kong Q, Ding Y and Ji X. (2015). Enhanced beneficial effects of mild hypothermia by phenothiazine drugs in stroke therapy. Neurol Res, 5: 454-60.
[73] Patel PM, Drummond JC, Cole DJ, Kelly PJ and Watson M. (1998). Isoflurane and pentobarbital reduce the frequency of transient ischemic depolarizations during focal ischemia in rats. Anesth Analg, 4: 773-80.
[74] Kimbro JR, Kelly PJ, Drummond JC, Cole DJ and Patel PM. (2000). Isoflurane and pentobarbital reduce AMPA toxicity in vivo in the rat cerebral cortex. Anesthesiology, 3: 806-12.
[75] Warner DS, Zhou JG, Ramani R and Todd MM. (1991). Reversible focal ischemia in the rat: effects of halothane, isoflurane, and methohexital anesthesia. J Cereb Blood Flow Metab, 5: 794-802.
[76] Smith DS, Rehncrona S and Siesjo BK. (1980). Barbiturates as protective agents in brain ischemia and as free radical scavengers in vitro. Acta Physiol Scand Suppl, 129-34.
[77] Westermaier T, Zausinger S, Baethmann A, Steiger HJ and Schmid-Elsaesser R. (2000). No additional neuroprotection provided by barbiturate-induced burst suppression under mild hypothermic conditions in rats subjected to reversible focal ischemia. J Neurosurg, 5: 835-44.
[78] Varathan S, Shibuta S, Shimizu T, Varathan V and Mashimo T. (2002). Hypothermia and thiopentone sodium: individual and combined neuroprotective effects on cortical cultures exposed to prolonged hypoxic episodes. J Neurosci Res, 3: 352-62.
[79] David HN, Haelewyn B, Rouillon C, Lecoq M, Chazalviel L, Apiou G, et al. (2008). Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia. FASEB J, 4: 1275-86.
[80] Dickinson R, Peterson BK, Banks P, Simillis C, Martin JC, Valenzuela CA, et al. (2007). Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology, 5: 756-67.
[81] Weber NC, Toma O, Wolter JI, Obal D, Mullenheim J, Preckel B and Schlack W. (2005). The noble gas xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-epsilon and p38 MAPK. Br J Pharmacol, 1: 123-32.
[82] Liu X, Dingley J, Scull-Brown E and Thoresen M. (2015). Adding 5 h delayed xenon to delayed hypothermia treatment improves long-term function in neonatal rats surviving to adulthood. Pediatr Res, 6: 779-83.
[83] Fries M, Brucken A, Cizen A, Westerkamp M, Lower C, Deike-Glindemann J, et al. (2012). Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs. Crit Care Med, 4: 1297-303.
[84] Sheng SP, Lei B, James ML, Lascola CD, Venkatraman TN, Jung JY, et al. (2012). Xenon neuroprotection in experimental stroke: interactions with hypothermia and intracerebral hemorrhage. Anesthesiology, 6: 1262-75.
[85] Hoffman WE, Kochs E, Werner C, Thomas C and Albrecht RF. (1991). Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole. Anesthesiology, 2: 328-32.
[86] Zeng X, Wang H, Xing X, Wang Q and Li W. (2016). Dexmedetomidine Protects against Transient Global Cerebral Ischemia/Reperfusion Induced Oxidative Stress and Inflammation in Diabetic Rats. PLoS One, 3: e0151620.
[87] Luo C, Yuan D, Yao W, Cai J, Zhou S, Zhang Y and Hei Z. (2015). Dexmedetomidine protects against apoptosis induced by hypoxia/reoxygenation through the inhibition of gap junctions in NRK-52E cells. Life Sci, 72-7.
[88] Sato K, Kimura T, Nishikawa T, Tobe Y and Masaki Y. (2010). Neuroprotective effects of a combination of dexmedetomidine and hypothermia after incomplete cerebral ischemia in rats. Acta Anaesthesiol Scand, 3: 377-82.
[89] Wang C, Nguyen HN, Maguire JL and Perry DC. (2002). Role of intracellular calcium stores in cell death from oxygen-glucose deprivation in a neuronal cell line. J Cereb Blood Flow Metab, 2: 206-14.
[90] Li F, Hayashi T, Jin G, Deguchi K, Nagotani S, Nagano I, et al. (2005). The protective effect of dantrolene on ischemic neuronal cell death is associated with reduced expression of endoplasmic reticulum stress markers. Brain Res, 1-2: 59-68.
[91] Hadad E, Cohen-Sivan Y, Heled Y and Epstein Y. (2005). Clinical review: Treatment of heat stroke: should dantrolene be considered? Crit Care, 1: 86-91.
[92] Muehlschlegel S and Sims JR. (2009). Dantrolene: mechanisms of neuroprotection and possible clinical applications in the neurointensive care unit. Neurocrit Care, 1: 103-15.
[93] Xu SY, Hu FY, Ren LJ, Chen L, Zhou ZQ, Zhang XJ and Li WP. (2015). Dantrolene enhances the protective effect of hypothermia on cerebral cortex neurons. Neural Regen Res, 8: 1279-85.
[94] Chen C, Cui H, Li Z, Wang R and Zhou C. (2013). Normobaric oxygen for cerebral ischemic injury. Neural Regen Res, 31: 2885-94.
[95] Tang X, Liu KJ, Ramu J, Chen Q, Li T and Liu W. (2010). Inhibition of gp91(phox) contributes towards normobaric hyperoxia afforded neuroprotection in focal cerebral ischemia. Brain Res, 174-80.
[96] Kim HY, Singhal AB and Lo EH. (2005). Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia. Ann Neurol, 4: 571-5.
[97] Liu W, Sood R, Chen Q, Sakoglu U, Hendren J, Cetin O, et al. (2008). Normobaric hyperoxia inhibits NADPH oxidase-mediated matrix metalloproteinase-9 induction in cerebral microvessels in experimental stroke. J Neurochem, 5: 1196-205.
[98] Cai L, Thibodeau A, Peng C, Ji X, Rastogi R, Xin R, et al. (2016). Combination therapy of normobaric oxygen with hypothermia or ethanol modulates pyruvate dehydrogenase complex in thromboembolic cerebral ischemia. J Neurosci Res, 8: 749-58.
[99] Cai L, Stevenson J, Geng X, Peng C, Ji X, Xin R, et al. (2016). Combining Normobaric Oxygen with Ethanol or Hypothermia Prevents Brain Damage from Thromboembolic Stroke via PKC-Akt-NOX Modulation. Mol Neurobiol
[100] Cai L, Stevenson J, Peng C, Xin R, Rastogi R, Liu K, et al. (2016). Adjuvant therapies using normobaric oxygen with hypothermia or ethanol for reducing hyperglycolysis in thromboembolic cerebral ischemia. Neuroscience, 45-57.
[101] Weinstein PR, Anderson GG and Telles DA. (1987). Results of hyperbaric oxygen therapy during temporary middle cerebral artery occlusion in unanesthetized cats. Neurosurgery, 4: 518-24.
[102] Weinstein PR, Hameroff SR, Johnson PC and Anderson GG. (1986). Effect of hyperbaric oxygen therapy or dimethyl sulfoxide on cerebral ischemia in unanesthetized gerbils. Neurosurgery, 5: 528-32.
[103] Liu W, Khatibi N, Sridharan A and Zhang JH. (2011). Application of medical gases in the field of neurobiology. Medical gas research, 1: 13.
[104] Singhal AB, Ratai E, Benner T, Vangel M, Lee V, Koroshetz WJ, et al. (2007). Magnetic resonance spectroscopy study of oxygen therapy in ischemic stroke. Stroke, 10: 2851-4.
[105] Wada K, Nishi D, Kitamura T, Ono K, Takahara T, Shirotani T and Shimizu A. (2006). Hyperbaric oxygenation therapy enhances the protective effect of moderate hypothermia against forebrain ischemia in the gerbil hippocampus. Undersea Hyperb Med, 6: 399-405.
[106] Minnerup J, Heidrich J, Wellmann J, Rogalewski A, Schneider A and Schabitz WR. (2008). Meta-analysis of the efficacy of granulocyte-colony stimulating factor in animal models of focal cerebral ischemia. Stroke, 6: 1855-61.
[107] Kong T, Choi JK, Park H, Choi BH, Snyder BJ, Bukhari S, et al. (2009). Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte-macrophage colony-stimulating factor in rats. Laboratory investigation. J Neurosurg, 1: 155-63.
[108] Kovacic JC, Muller DW and Graham RM. (2007). Actions and therapeutic potential of G-CSF and GM-CSF in cardiovascular disease. J Mol Cell Cardiol, 1: 19-33.
[109] Buschmann IR, Busch HJ, Mies G and Hossmann KA. (2003). Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation, 5: 610-5.
[110] Schneider UC, Schilling L, Schroeck H, Nebe CT, Vajkoczy P and Woitzik J. (2007). Granulocyte-macrophage colony-stimulating factor-induced vessel growth restores cerebral blood supply after bilateral carotid artery occlusion. Stroke, 4: 1320-8.
[111] Todo K, Kitagawa K, Sasaki T, Omura-Matsuoka E, Terasaki Y, Oyama N, et al. (2008). Granulocyte-macrophage colony-stimulating factor enhances leptomeningeal collateral growth induced by common carotid artery occlusion. Stroke, 6: 1875-82.
[112] Sugiyama Y, Yagita Y, Oyama N, Terasaki Y, Omura-Matsuoka E, Sasaki T and Kitagawa K. (2011). Granulocyte colony-stimulating factor enhances arteriogenesis and ameliorates cerebral damage in a mouse model of ischemic stroke. Stroke, 3: 770-5.
[113] Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, et al. (2006). Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab, 3: 402-13.
[114] Sehara Y, Hayashi T, Deguchi K, Zhang H, Tsuchiya A, Yamashita T, et al. (2007). Decreased focal inflammatory response by G-CSF may improve stroke outcome after transient middle cerebral artery occlusion in rats. J Neurosci Res, 10: 2167-74.
[115] Ghahari L, Safari M, Joghataei MT, Mehdizadeh M and Soleimani M. (2014). Effect of combination therapy using hypothermia and granulocyte colony-stimulating factor in a rat transient middle cerebral artery occlusion model. Iran Biomed J, 4: 239-44.
[116] Jackson R, Tilokee EL, Latham N, Mount S, Rafatian G, Strydhorst J, et al. (2015). Paracrine Engineering of Human Cardiac Stem Cells With Insulin-Like Growth Factor 1 Enhances Myocardial Repair. J Am Heart Assoc, 9: e002104.
[117] Bondanelli M, Ambrosio MR, Onofri A, Bergonzoni A, Lavezzi S, Zatelli MC, et al. (2006). Predictive value of circulating insulin-like growth factor I levels in ischemic stroke outcome. J Clin Endocrinol Metab, 10: 3928-34.
[118] Aberg D, Jood K, Blomstrand C, Jern C, Nilsson M, Isgaard J and Aberg ND. (2011). Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. J Clin Endocrinol Metab, 7: E1055-64.
[119] Lioutas VA, Alfaro-Martinez F, Bedoya F, Chung CC, Pimentel DA and Novak V. (2015). Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke. Transl Stroke Res, 4: 264-75.
[120] Lagina AT3rd, Calo L, Deogracias M, Sanderson T, Kumar R, Wider J and Sullivan JM. (2013). Combination therapy with insulin-like growth factor-1 and hypothermia synergistically improves outcome after transient global brain ischemia in the rat. Acad Emerg Med, 4: 344-51.
[121] George S, Bennet L, Weaver-Mikaere L, Fraser M, Bouwmans J, Mathai S, et al. (2011). White matter protection with insulin-like growth factor 1 and hypothermia is not additive after severe reversible cerebral ischemia in term fetal sheep. Dev Neurosci, 3-4: 280-7.
[122] Geral C, Angelova A and Lesieur S. (2013). From molecular to nanotechnology strategies for delivery of neurotrophins: emphasis on brain-derived neurotrophic factor (BDNF). Pharmaceutics, 1: 127-67.
[123] Tsukahara T, Yonekawa Y, Tanaka K, Ohara O, Wantanabe S, Kimura T, et al. (1994). The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain. Neurosurgery, 2: 323-31; discussion 331.
[124] Yamashita K, Wiessner C, Lindholm D, Thoenen H and Hossmann KA. (1997). Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat. Metab Brain Dis, 4: 271-80.
[125] Schabitz WR, Sommer C, Zoder W, Kiessling M, Schwaninger M and Schwab S. (2000). Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke, 9: 2212-7.
[126] Akaike A, Katsuki H, Kume T and Maeda T. (1999). Reactive oxygen species in NMDA receptor-mediated glutamate neurotoxicity. Parkinsonism Relat Disord, 4: 203-7.
[127] Tremblay R, Hewitt K, Lesiuk H, Mealing G, Morley P and Durkin JP. (1999). Evidence that brain-derived neurotrophic factor neuroprotection is linked to its ability to reverse the NMDA-induced inactivation of protein kinase C in cortical neurons. J Neurochem, 1: 102-11.
[128] Berger C, Schabitz WR, Wolf M, Mueller H, Sommer C and Schwab S. (2004). Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke. Exp Neurol, 2: 305-12.
[129] Sena E, Wheble P, Sandercock P and Macleod M. (2007). Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke, 2: 388-94.
[130] Hellstrom HO, Wanhainen A, Valtysson J, Persson L and Hillered L. (1994). Effect of tirilazad mesylate given after permanent middle cerebral artery occlusion in rat. Acta Neurochir (Wien), 3-4: 188-92.
[131] Beck T and Bielenberg GW. (1990). Failure of the lipid peroxidation inhibitor U74006F to improve neurological outcome after transient forebrain ischemia in the rat. Brain Res, 1-2: 336-8.
[132] Schmid-Elsaesser R, Zausinger S, Hungerhuber E, Baethmann A and Reulen HJ. (1999). Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia. Neurosurgery, 1: 163-71; discussion 171-2.
[133] Schmid-Elsaesser R, Hungerhuber E, Zausinger S, Baethmann A and Reulen HJ. (1999). Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke, 9: 1891-9.
[134] Zausinger S, Westermaier T, Plesnila N, Steiger HJ and Schmid-Elsaesser R. (2003). Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen. Stroke, 6: 1526-32.
[135] Zausinger S, Scholler K, Plesnila N and Schmid-Elsaesser R. (2003). Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Stroke, 9: 2246-51.
[136] Belayev L, Liu Y, Zhao W, Busto R and Ginsberg MD. (2001). Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke, 2: 553-60.
[137] Chen J, Fredrickson V, Ding Y, Cheng H, Wang N, Ling F and Ji X. (2013). Enhanced neuroprotection by local intra-arterial infusion of human albumin solution and local hypothermia. Stroke, 1: 260-2.
[138] Hacke W, Schwab S, Horn M, Spranger M, De Georgia M and von Kummer R. (1996). ’Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol, 4: 309-15.
[139] Wartenberg KE. (2012). Malignant middle cerebral artery infarction. Curr Opin Crit Care, 2: 152-63.
[140] Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C and Mayer SA. (2001). Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke, 9: 2033-5.
[141] Doerfler A, Schwab S, Hoffmann TT, Engelhorn T and Forsting M. (2001). Combination of decompressive craniectomy and mild hypothermia ameliorates infarction volume after permanent focal ischemia in rats. Stroke, 11: 2675-81.
[142] Allahtavakoli M, Kahnouei MH, Rezazadeh H, Roohbakhsh A, Mahmoodi MH, Moghadam-Ahmadi A and Zarisfi M. (2014). Delayed combination therapy of local brain hypothermia and decompressive craniectomy on acute stroke outcome in rat. Iran J Basic Med Sci, 7: 476-82.
[143] Els T, Oehm E, Voigt S, Klisch J, Hetzel A and Kassubek J. (2006). Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis, 1-2: 79-85.
[144] Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, et al. (1998). Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat Med, 12: 1449-52.
[145] Asoh S, Ohsawa I, Mori T, Katsura K, Hiraide T, Katayama Y, et al. (2002). Protection against ischemic brain injury by protein therapeutics. Proc Natl Acad Sci U S A, 26: 17107-12.
[146] Katsura K, Takahashi K, Asoh S, Watanabe M, Sakurazawa M, Ohsawa I, et al. (2008). Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat. J Neurochem, 1: 258-70.
[147] Sakurazawa M, Katsura K, Saito M, Asoh S, Ohta S and Katayama Y. (2012). Mild hypothermia enhanced the protective effect of protein therapy with transductive anti-death FNK protein using a rat focal transient cerebral ischemia model. Brain Res, 86-92.
[148] Yenari MA, Zhao H, Giffard RG, Sobel RA, Sapolsky RM and Steinberg GK. (2003). Gene therapy and hypothermia for stroke treatment. Ann N Y Acad Sci, 54-68; discussion 79-81.
[149] Lawrence MS, McLaughlin JR, Sun GH, Ho DY, McIntosh L, Kunis DM, et al. (1997). Herpes simplex viral vectors expressing Bcl-2 are neuroprotective when delivered after a stroke. J Cereb Blood Flow Metab, 7: 740-4.
[150] Zhao H, Yenari MA, Sapolsky RM and Steinberg GK. (2004). Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome C release. Stroke, 2: 572-7.
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