|Year : 2018 | Volume
| Issue : 1 | Page : 1-13
Hypothermia and brain inflammation after cardiac arrest
Pouya Tahsili-Fahadan1, Salia Farrokh2, Romergryko G Geocadin3
1 Department of Medicine, Virginia Commonwealth University, Falls Church, Virginia; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Department of Pharmacy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3 Department of Neurology; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
|Date of Submission||14-Mar-2018|
|Date of Decision||17-Mar-2018|
|Date of Acceptance||18-Mar-2018|
|Date of Web Publication||18-Apr-2018|
Dr. Romergryko G Geocadin
600 N Wolfe Street, Phipps 455, Baltimore, MD 21287
Source of Support: None, Conflict of Interest: None
The cessation (ischemia) and restoration (reperfusion) of cerebral blood flow after cardiac arrest (CA) induce inflammatory processes that can result in additional brain injury. Therapeutic hypothermia (TH) has been proven as a brain protective strategy after CA. In this article, the underlying pathophysiology of ischemia-reperfusion brain injury with emphasis on the role of inflammatory mechanisms is reviewed. Potential targets for immunomodulatory treatments and relevant effects of TH are also discussed. Further studies are needed to delineate the complex pathophysiology and interactions among different components of immune response after CA and identify appropriate targets for clinical investigations.
Keywords: Brain injury, cardiac arrest, inflammation, therapeutic hypothermia
|How to cite this article:|
Tahsili-Fahadan P, Farrokh S, Geocadin RG. Hypothermia and brain inflammation after cardiac arrest. Brain Circ 2018;4:1-13
| Introduction|| |
Despite major improvements in resuscitation, neurological injury after cardiac arrest (CA) has remained a major cause of morbidity and mortality among survivors., Brain injury occurs not only during the CA (”no-flow” injury) and resuscitation (”partial-flow” injury) but also after reestablishment of brain reperfusion (”reperfusion” injury). Inflammatory processes after ischemia-reperfusion (I/R) induced by CA play a pivotal role in neurological damage. So far, no pharmacological treatment has been approved for neuroprotection after CA. Therapeutic hypothermia (TH) is the only proven treatment to date to decrease the burden of neurological injury. Better understanding of the underlying mechanism for I/R brain injury after CA is essential for the development of new therapeutic targets and neuroprotective strategies. Here, we review the inflammatory processes involved in I/R after CA. We also review the potential neuroprotective effects of TH in regard to brain inflammation.
| Pathophysiology of Brain Injury After Cardiac Arrest|| |
Central nervous system receives almost a third of the cardiac output. Brain injury after CA occurs through several phases. Cerebral blood flow stops with CA (”no-flow” period). Global brain ischemia continues throughout mechanical cardiopulmonary resuscitation that can only provide 25%–40% of baseline cerebral blood flow (”partial-flow” period). Successful return of spontaneous circulation (ROSC) will result in additional processes that may also lead to brain damage (”reperfusion” injury).
Excitotoxicity has been recognized as the main pathological basis of brain injury in the acute phase (minutes to hours after CA). Decreased cerebral blood flow and delivery of oxygen and glucose will enhance anaerobic metabolism within minutes of CA. This will result in lactate production and tissue acidosis. Following ROSC, a transient rise in endogenous and exogenous catecholamines will reduce capillary blood flow that will further enhance lactate acidosis. In addition, depletion of adenosine triphosphate (ATP) and inhibition of Na +/K +-ATPase will result in neuronal depolarization that in turn leads to increased intracellular shift of calcium and hence extracellular glutamate release., Increased glutamate will augment membrane depolarization and further intracellular calcium influx. This will activate a cascade of several calcium-dependent enzymatic pathways such as lipases, proteases, and nucleases that will subsequently lead to disintegration of the cell membrane and tissue necrosis. An increase in the expression of immediate early genes, microRNAs, and heat shock proteins is seen during the acute phase and may contribute to brain injury after CA., Accumulating evidence shows that enhanced release of excitatory amino acids (such as glutamate) will also increase permeability of mitochondrial membrane and thereby mitochondrial swelling and dysfunction.
Brain ischemia and excitotoxicity initiated in the acute phase will induce neuronal loss in the subacute phase (hours to days after CA) by the activation of apoptotic pathways., Activation of cell membrane death receptors (such as FAS receptor by FAS ligand [FASL]) triggers a death-inducing signaling complex that will in turn activate caspases and programmed cell death. Mitochondrial damage will increase the expression of pro-apoptotic BCL-2 family members (such as BCL-2 associated X [BAX]). Cytochrome c released by apoptotic signaling from damaged mitochondria will form an apoptosome that will also activate caspase. In addition, damage to mitochondria activates pro-apoptotic members of protein kinase C (PKC) family such as PKCδ., Damage to mitochondria can also result in apoptosis independent of caspase activation. In addition, reperfusion of ischemic brain will lead to massive generation of free radicals such as reactive oxygen species (ROS)., Ischemia-induced mitochondrial damage and oversaturation of the cellular scavenging systems will decrease clearance of ROS and result in their accumulation.
In the acute phase after CA, early resuscitation and restoration of cerebral blood flow will prevent rapid depletion of brain energy reservoir and hence limit anaerobic metabolism and lactic acidosis. This will ultimately decrease excitotoxicity and the subsequent brain damage. During the subacute phase, inhibition of intrinsic and acquired apoptosis by blocking expression of pro-apoptotic genes, increased expression of anti-apoptotic, and alteration of PKC pathway are the potential therapeutic considerations. Brain ischemia activates several signaling pathways such as members of mitogen-activated protein kinases (MAPKs), nuclear factor-kappa B (NF-κB), and toll-like receptors (TLRs) that can be targets for therapeutic interventions.,,,, Different members of the MAPK pathway play differential roles in brain injury after ischemia. For instance, ERK5 activity seems to be protective while ERK1/2, c-Jun N-terminal kinase (JNK), and p38 may add to brain damage by increasing inflammation.,,,,,, Accordingly, inhibition of ERK1/2, JNK, and p38 has been shown to decrease brain inflammation and improve functional recovery.,,, Stimulation of ERK1/2 pathway, however, may also paradoxically reduce injury by blocking apoptosis and release of trophic factors after global brain ischemia. Activation of NF-κB family members by ischemia leads to gene transcription for several pro-inflammatory as well as some neuroprotective mediators. Therefore, inhibition of NF-κB activity has also resulted in contradictory results., In animal studies, activation of TLRs before induced ischemia decreases brain injury by decreasing release of tissue necrosis factor (TNF)-α; however, it appears that blockage of TLRs is neuroprotective after ischemia., In addition, strategies aimed toward enhanced clearance of ROS and limiting damage to blood–brain barrier (BBB) by blockage of proteases will be important in the prevention of secondary brain damage due to vasogenic edema and elevated intracranial pressure.
| Brain Inflammation and Immunomodulatory Therapies After Cardiac Arrest|| |
Immune response and inflammatory processes start immediately after onset of ischemia and evolve through several phases. Our understanding of inflammation after global brain ischemia is partly derived from the expanding knowledge on inflammation after focal brain ischemia although differences exist. It is very important to mention that the immune response and cerebral inflammation are not merely consisted of deleterious mechanisms that will result in brain damage (maladaptive inflammation) but also include very important processes required for brain repair and recovery (adaptive inflammation)., This needs to be considered in all therapeutic measures designed to modulate the immune response to limit maladaptive processes and enhance beneficial immune response. The balance between these responses will determine the ultimate outcomes. Inflammatory processes involved in I/R brain injury after and corresponding therapeutic considerations are summarized in [Table 1].
|Table 1: Pathophysiology of ischemia-reperfusion injury and effects of therapeutic hypothermia|
Click here to view
Given the pivotal role of inflammatory processes in pathogenesis of I/R brain injury, controlled modulation of immune response provides a wide range of therapeutic opportunities for neuroprotection and neuronal repair and thereby improves clinical outcomes. Accordingly, various immunomodulating strategies have been investigated in different clinical and animal settings with mixed results. Majority of these interventions have been studied in ischemic or hemorrhagic strokes and studies aiming global brain ischemia after CA are mostly lacking. Therefore, in interpretation of animal results and extrapolation of findings to clinical trials, one should consider the brain injury model and possibility of different underlying mechanisms for focal versus global ischemia. In addition, immunomodulating therapies for brain inflammation after I/R need to be approached cautiously and be tailored carefully to enhance the beneficial immune response while limiting the destructive components. This necessitates careful implementation of basic research findings in regard to timing, aggressiveness, and selectivity of immunomodulatory treatments. Temporal course of potential treatments is of the utmost importance to limit damaging processes and enhance those promoting neuronal repair. Ideally, these treatments are provided early and their effects are limited to the pro-inflammatory (acute to early subacute) phase of immune response. Of note, systemic inflammatory response after CA and brain ischemia can result in a temporary immunocompromised state consisted of peripheral lymphopenia. This can be mediated by overactivation of the hypothalamus–pituitary–adrenal gland axis secondary to catecholamine surge and apoptosis of lymphocytes.,, While this state can potentially limit neuronal damage by immune response, it temporarily increases the risk of infections. Although the role of preexisting systemic or nervous system inflammation is less clear and may affect therapeutic options, it is postulated that systemic inflammation exacerbates brain injury. Potential strategies include blockage of pro-inflammatory and promotion of anti-inflammatory mediators. In addition, modulations of immune cells involved in brain inflammation such as inhibition of brain intrinsic microglial activation, prevention of systemic immune cells transmigration into brain parenchyma, and limiting the activity of infiltrated immune cells have been proposed. Of note, no pharmacological treatment has been approved for clinical use till date.
Acute and subacute cerebral inflammation after cardiac arrest
Immune response is not antigen specific and is dominated by nonspecific pro-inflammatory mechanisms during the acute phase (minutes to hours after CA). This involves activation of brain microglia, massive release of pro-inflammatory mediators, and infiltration of peripheral immune cells, leading to brain inflammation. A vicious cycle of inflammation can evolve in the next several hours to days (subacute phase) triggered by additional release of inflammatory mediators from activated intrinsic and extrinsic immune cells. Extensive neuronal death, damage to BBB, and worsening cerebral edema will ensue. Both cellular and humoral components of immune response are involved. Our understanding of the complex interaction among innate and adaptive immune system and the brain is still evolving. Enhanced inflammatory response is thought to help with the removal of cell debris but also contributes to additional injury by both direct cell toxicity and release of pro-inflammatory chemokines and cytokines. For instance, while decreased infiltration of the brain by immune cells is associated with smaller infarct size, it may also lead to higher rates of hemorrhagic transformation of ischemic brain.,
Humoral immune response is mediated by multiple immune mediators after I/R injury. Pro-inflammatory mediators include several cytokines such as interleukin (IL)-1α, IL-1 β, and TNF-α., Exogenous administration of IL-1 β after focal ischemic injury has been shown to increase infarct size in animals. Several pro-inflammatory chemokines are also released after ischemia including CX3CL1, MCP-1, and MIP-1α that will aggravate brain injury by increasing permeability of BBB. Other important pro-inflammatory mediators released after brain ischemia are matrix metalloproteinases (MMPs), especially MMP-9, that disrupt BBB and thereby increase brain edema  and risk of bleeding into infarcted brain tissue., On the other hand, various anti-inflammatory mediators are also released after brain ischemia. Release of IL-10 by T helper 2 (Th2) lymphocytes can inhibit the effects of IL-1 and TNF-α., For instance, knockout IL-10 mice and humans with decreased levels of IL-10 develop larger infarcts after focal ischemia.,,, Transformation growth factor-β (TGF-β),, and insulin-like growth factor 1 (IGF-1), are among other anti-inflammatory mediators that exert neuroprotective properties.
Modulation of humoral immunity
Several studies have investigated humoral immunity and inflammatory mediators as therapeutic targets. Infarct size was reduced in mice knockout for IL-1α/β and their receptor IL1-receptor 1.,,, Administration of IL-1 receptor antagonist, rhlL-1ra, was found to be safe and effective in a phase 2 clinical study of ischemic stroke. Exogenous recombinant IL-6 has been shown to be protective in rats by decreasing inflammation. While experimental blockage of TNF-α limits brain injury, its expression may also be protective against ischemia., The paradoxical effects of TNF-α can be explained by the activation of different downstream receptors that exert toxic versus protective properties by activation of caspases  versus NF-κB pathway, respectively. Inhibition of pro-inflammatory chemokines has been promising in animal models of brain ischemia not only by reducing inflammation and limiting damage to BBB but also by activation of stem cells. Decreased MMP-9 activity has been shown to be protective against acute injury.,,,, However, interventions affecting MMPs need to be approached carefully given that their activity is presumed to be protective during the recovery phase. Anti-inflammatory mediators have also been investigated for treatment of I/R injury. Increased levels of IL-10 have been shown to be protective against focal brain ischemia in animals, but clinical studies are lacking.,,, Increased expression of TGF-β and IGF-1 suppresses activity of Th1 and Th2 lymphocytes and enhances regulatory T-cells (Treg cells) and thereby can be neuroprotective after ischemia in animals.,,,,, However, their role in humans and especially after global I/R injury is yet to be determined.
Cellular immune reactions are mediated by both brain intrinsic microglia and infiltrating peripheral leukocytes. Neuronal loss and injury induced by I/R will activate dormant brain intrinsic microglia within minutes of ischemia by stimulation of their surface TLRs., Enhanced activity of microglia has been shown to last for weeks after the initial insult. During the acute phase, activated microglia convert into a pro-inflammatory (M1) phenotype that obtains macrophage-like properties (such as antigen presentation) and generates several pro-inflammatory mediators (such as IL-1 β, TNF-α, and ROS) and MMPs that can disrupt BBB. Inhibition of microglial activation in experimental models (for instance, by minocycline), has been shown to be neuroprotective, but supportive data in humans are lacking. Ischemia will also activate brain astrocytes that release additional pro-inflammatory mediators such as chemokines, cytokines, nitric oxide, and ROS. Additional immune mediators are released due to systemic inflammatory response induced by systemic ischemia and catecholamine surge after CA. These mediators activate the bone marrow hematopoietic system that is reflected by a decrease in spleen size after brain ischemia and increased release of the immune cells into peripheral bloodstream., Accordingly, splenectomy before brain ischemia in animal studies has been shown to decrease infiltration of immune cells into the brain tissue. Increased expression of several members of selectin family on the surface of endothelium (E-selectin), leukocytes (L-selectin), and platelets (P-selectin) along with increased expression of intracellular and vascular adhesion molecules (ICAM-1 and VCAM-1) facilitates entry of peripheral immune cells into the brain after ischemia through damaged endothelium and BBB.,, Accordingly, levels of P- and E-selectin and ICAM-1 are correlated with severity of stroke.,, Peripheral neutrophils migrate first, followed by macrophages and later natural killer (NK) cells and lymphocytes.,, Neutrophils infiltrate the brain as soon as 30 min after ischemia and release additional pro-inflammatory cytokines and enzymes such elastase, granzyme A, myeloperoxidase, and MMPs that will worsen brain inflammation and further disrupt BBB.,, In addition, nitric oxide production will increase by activation of inducible isoform of nitric oxide synthase.,, Macrophages and peripheral monocytes contribute to both pro- and anti-inflammatory processes after ischemia. Pro-inflammatory monocytes (such as Ly-6Chigh/CCR2+ subpopulation) egress into the brain and some develop macrophage-like features inside the nervous tissue. Infiltrating lymphocytes and their subtypes play a complex role in brain inflammation after ischemia., NK cells and CD4+ and CD8+ T-lymphocytes not only cause neuronal damage by direct cytotoxicity but also exaggerate excitotoxicity by releasing factors such as IL-1 β, IL-17, interferon-γ (IFN-γ), TNF-α, and ROS.,, Release of IFN-γ and granulocyte-macrophage-colony-stimulating factor by NK cells will further activate macrophages, microglia, and astrocytes and leads to a vicious cycle of inflammation in the central nervous system. In addition, increased expression of aquaporin-4 that regulates water transport along with increased activity of MMP and permeability of disrupted BBB and endothelium will lead to vasogenic edema and increased risk of hemorrhage and thereby increased intracranial pressure that can cause additional brain damage.,,,
Modulation of cellular immunity
Various lines of immune cells are involved in brain injury after I/R. Therefore, several animal and human studies have investigated cellular immunity as a therapeutic target. Decreased entry of peripheral immune cells into ischemic brain tissue may result in decreased inflammation and better outcomes. Inhibition of adhesion molecules such as P- and E-selectin and ICAM-1 has been shown to be protective against focal ischemia in animals.,,,, Blocking L-selectin also appears to be protective against I/R injury., However, results of clinical trial in preventing transmigration of peripheral immune cells into the nervous system have been disappointing. Administration of selective monoclonal antibodies against ICAM-1 (enlimomab), CD11b/CD18, and recombinant neutrophil inhibitory factor resulted in no protection and even worsened outcomes., Lack of desirable clinical outcomes has been attributed to the selection of antibody. Role of interventions toward VCAM-1 is unclear, and contradictory results have been reported., Although administration of oral minocycline to modulate early inflammatory response was promising in earlier trials, a phase 4 trial was terminated due to futility., Similarly, despite encouraging results of preliminary studies on the administration of α4-integrin antibody natalizumab after focal ischemia, no significant clinical benefit was found in a recent clinical trial. Fingolimod, an S1P receptor agonist, has been shown to decrease infiltration of lymphocytes into brain and activation of brain microglia. Combination of fingolimod and alteplase in a pilot trial of ischemic stroke has shown improved clinical outcomes.
Chronic cerebral inflammation after cardiac arrest
Inflammatory processes during this phase (days to weeks after CA) stimulate pathways involved in neuronal repair and play an important role in brain recovery. Regulatory mechanism will lead to gradual resolution of the immediate inflammatory response. Microglia assume an anti-inflammatory (M2) phenotype, assist with a clearance of the cell death products,, and secrete anti-inflammatory immune mediators (such as IL-10 and TGF-β) that can subside pro-inflammatory processes and exert neuroprotection., They also promote neuronal repair, prevent premature death of neural stem cells, and enhance neurogenesis and neurite growth by secretion of growth factors such as IGF-1 and glial cell line-derived neurotrophic factor.,,, Activated astrocytes play an anti-inflammatory role as well.,,, Anti-inflammatory monocytes (such as Ly-6Clow/CCR2-subpopulation and Treg cells) also release anti-inflammatory cytokines such as IL-10., Ultimately, neurogenesis, angiogenesis, and synaptogenesis will result in functional recovery.
| Therapeutic Hypothermia and Brain Inflammation After Cardiac Arrest|| |
TH is the only approved treatment to date for neurological injury after CA. Neuroprotective properties of hypothermia have been known for the past three decades; however, clinical application of TH to protect brain after CA was widely adopted after two large prospective clinical trials., Several factors are to be considered in application of TH as a neuroprotective measure. Choosing the optimal temperature is of paramount importance to provide neuroprotection and avoid undesirable adverse effects. It appears that milder reductions in core body and brain temperature can be as effective as lower temperatures. In clinical settings, targeting core temperature of 32°C–34°C was initially recommended for comatose patients with out-of-hospital CAs due to shockable rhythms. However, more recent evidence suggests that targeted temperature management and avoidance of hyperthermia may exert the same clinical benefits. Early application and sufficient maintenance of TH are also important to achieve maximum neuroprotection and improve outcomes. Here, we review the beneficial and neuroprotective effects of TH in regard to cerebral inflammation after CA [Table 1].
Therapeutic hypothermia during acute phase after ischemia-reperfusion injury
In the first several minutes of I/R after CA, early implementation of TH will decrease the metabolic demand and activity of neurons and thereby extends preservation of energy reservoir and prevents shift toward anaerobic metabolism and lactic acidosis. In addition, TH increases expression of glutamate receptor subunit 2 of the AMPA receptor. Upregulation of this subunit reduces influx of calcium after I/R. The subsequent decrease in intracellular calcium level and glutamate release will dampen excitotoxicity., Hypothermia also reduces expression of immediate early genes, stress signals, and microRNAs; however, the significance of these changes in neuroprotection is not clear.,,, Neuroprotection by TH can also be provided by decreased generation of ROS due to blunting cerebral blood flow after reperfusion., In addition, by reducing activity of neuronal and inducible isoforms of nitric oxide synthase, TH decreases production of nitric oxide.,
Therapeutic hypothermia during subacute phase after ischemia-reperfusion injury
The beneficial effects of TH extend beyond the acute phase. As described above, I/R leads to neuronal apoptosis via multiple pathways. TH, on the other hand, can prevent apoptosis via both caspase-dependent and caspase-independent pathways. Hypothermia has been shown to inhibit translocation of apoptosis-inducing factor from mitochondria.,, It also shifts the balance toward stimulation of anti-apoptotic mechanisms (such as BCL-2 and PKCε) and reducing activity of pro-apoptotic processes (such as BAX, PKCδ, and FAS/FASL).,,,, By increasing BCL-2, TH activates the serine/threonine protein kinase AKT that is involved in cell survival and proliferation., Most importantly, TH limits the maladaptive inflammatory response during subacute phase after CA that leads to better outcomes., Hypothermia exerts its anti-inflammatory properties on multiple immune cells and mediators. It decreases activation of microglia and recruitment of immune cells into ischemic brain tissues. It also inhibits NF-κB and MAPK signaling pathways and expression of adhesion molecules involved in ischemia-induced inflammation.,,,,,, Release of various pro-inflammatory cytokines (such as IL-1 β and TNFα) and chemokines (such as MCP-1 and MIP3α) is also reduced by TH.,,,, However, TH will also reduce anti-inflammatory mediators such IL-10 and TGF-β., As discussed above, disruption of BBB by inflammation after I/R injury leads to brain edema and hemorrhagic conversion within infarcted tissues that will eventually cause secondary damage by elevation of intracranial pressure. Hypothermia has been shown to decrease BBB disruption in various brain pathologies. The underlying mechanism for BBB protection by TH is presumed to be decreased proteolytic activity of enzymes such as MMPs and release of MMP inhibitors, as well as preservation of endothelial cells and pericytes.,,,,,, Hypothermia can decrease brain edema by decreased expression of aquaporin-4 after global brain ischemia.,,
Therapeutic hypothermia during chronic phase after ischemia-reperfusion injury
Hypothermia also affects the chronic phase (days to weeks) after I/R brain injury. It has been shown to increase the level of several neurotrophic factors such as brain-derived and glial-derived neurotrophic factors that are involved in neuronal recovery.,, Despite some conflicting reports, it seems that mild hypothermia (as opposed to deep hypothermia with temperatures below 30°C) enhances activity of stem cells and their differentiation into neurons and glial cells after brain ischemia likely by inhibition of apoptosis.,,,,, However, the optimal parameters for hypothermia to promote neurogenesis and whether this effect applies to aged individuals are yet to be determined. Hypothermia limits injury to oligodenrocytes and enhances their proliferation after brain injury., The net effect for increased activity and number of astrocytes by TH after brain injury are not clear. While generation of new astrocytes may be required for brain regeneration, it may also lead to formation of glial scars and interfere with neurogenesis and synaptogenesis. Hypothermia also promotes angiogenesis after brain injury although its clinical benefit has not been proven and can even impair recovery.,, Formation of new neuronal connections (synaptogenesis) is an important part of recovery after extensive brain damage. Hypothermia appears to enhance this process by upregulation of genes required for synapse formation.,,,
| Current Perspectives and Future Directions|| |
Despite astounding evidence for the role of inflammation in pathogenesis of I/R injury and encouraging animal data, TH remains the only proven treatment to date for neuroprotection after CA. Several clinical trials based on animal findings or preliminary clinical data have failed to show benefits and some resulted in worsened outcomes. Complex pathophysiology of I/R injury, in general, and unknown interactions among different components of immune response, in particular, are likely to be responsible for poor translation of bench findings into meaningful bedside trials. In addition, results of animal models from one brain pathology (for instance, brain hemorrhage or focal ischemia) shall be cautiously generalized to another disease (such as global brain ischemia). Even in animal models for global ischemia, it appears that some modifications are required to better reflect the complexity and realities of global brain ischemia in humans. Aging brain, gender-specific factors, and common comorbidities need to be incorporated into animal studies. In regard to immunomodulatory treatments including TH, careful timing of therapeutic interventions is of critical importance. At times, modulation of an immune mediator can result in different outcomes based on timing and activated downstream pathways. As described above, inflammatory processes after brain injury have significant overlap and affecting a single component may not be sufficient to overcome the redundancy. Combination of different therapeutic modalities (such as TH with antibodies against immune cells or mediators) to affect multiple mechanisms simultaneously may be advantageous. While many of the clinical studies targeted blockage of pro-inflammatory mediators and peripheral immune cells, more focus on brain intrinsic microglia and enhancement of anti-inflammatory mediators may result in better outcomes. In addition, application of newer technologies such as molecular imaging and advanced multi-modal MRI in design and interpretation of clinical studies may be helpful.
| Conclusions|| |
Inflammation after CA plays a major role in pathophysiology of brain I/R injury. Modulation of brain inflammation provides a wide range of therapeutic options. TH is the only proven treatment to date that affects multiple aspects of brain inflammation after CA. Further animal and clinical studies are required to identify other treatment options.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bigham BL, Koprowicz K, Rea T, Dorian P, Aufderheide TP, Davis DP, et al.
Cardiac arrest survival did not increase in the resuscitation outcomes consortium after implementation of the 2005 AHA CPR and ECC guidelines. Resuscitation 2011;82:979-83.
Girotra S, Nallamothu BK, Spertus JA, Li Y, Krumholz HM, Chan PS, et al.
Trends in survival after in-hospital cardiac arrest. N
Engl J Med 2012;367:1912-20.
Geocadin RG, Wijdicks E, Armstrong MJ, Damian M, Mayer SA, Ornato JP, et al.
Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2017;88:2141-9.
Maramattom BV, Wijdicks EF. Postresuscitation encephalopathy. Current views, management, and prognostication. Neurologist 2005;11:234-43.
Ristagno G, Tang W, Huang L, Fymat A, Chang YT, Sun S, et al.
Epinephrine reduces cerebral perfusion during cardiopulmonary resuscitation. Crit Care Med 2009;37:1408-15.
Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic–Ischemic brain damage. Ann Neurol 1986;19:105-11.
Vaagenes P, Ginsberg M, Ebmeyer U, Ernster L, Fischer M, Gisvold SE, et al.
Cerebral resuscitation from cardiac arrest: Pathophysiologic mechanisms. Crit Care Med 1996;24:S57-68.
Zipfel GJ, Babcock DJ, Lee JM, Choi DW. Neuronal apoptosis after CNS injury: The roles of glutamate and calcium. J Neurotrauma 2000;17:857-69.
Choi DW. Excitotoxic cell death. J Neurobiol 1992;23:1261-76.
Kamme F, Campbell K, Wieloch T. Biphasic expression of the fos and jun families of transcription factors following transient forebrain ischaemia in the rat. Effect of hypothermia. Eur J Neurosci 1995;7:2007-16.
Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Ann N
Y Acad Sci 2005;1047:248-58.
MacManus JP, Linnik MD. Gene expression induced by cerebral ischemia: An apoptotic perspective. J Cereb Blood Flow Metab 1997;17:815-32.
Jin K, Graham SH, Mao X, Nagayama T, Simon RP, Greenberg DA, et al.
Fas (CD95) may mediate delayed cell death in hippocampal CA1 sector after global cerebral ischemia. J Cereb Blood Flow Metab 2001;21:1411-21.
Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraux QL, et al.
Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci U S A 1999;96:5752-7.
Yenari MA, Iwayama S, Cheng D, Sun GH, Fujimura M, Morita-Fujimura Y, et al.
Mild hypothermia attenuates cytochrome c release but does not alter Bcl-2 expression or caspase activation after experimental stroke. J Cereb Blood Flow Metab 2002;22:29-38.
Dave KR, Bhattacharya SK, Saul I, DeFazio RA, Dezfulian C, Lin HW, et al.
Activation of protein kinase C delta following cerebral ischemia leads to release of cytochrome C from the mitochondria via bad pathway. PLoS One 2011;6:e22057.
Raval AP, Dave KR, Prado R, Katz LM, Busto R, Sick TJ, et al.
Protein kinase C delta cleavage initiates an aberrant signal transduction pathway after cardiac arrest and oxygen glucose deprivation. J Cereb Blood Flow Metab 2005;25:730-41.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al.
Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441-6.
Fraser PA. The role of free radical generation in increasing cerebrovascular permeability. Free Radic Biol Med 2011;51:967-77.
Peters O, Back T, Lindauer U, Busch C, Megow D, Dreier J, et al.
Increased formation of reactive oxygen species after permanent and reversible middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1998;18:196-205.
Piantadosi CA, Zhang J. Mitochondrial generation of reactive oxygen species after brain ischemia in the rat. Stroke 1996;27:327-31.
Aharon AS, Mulloy MR, Drinkwater DC Jr., Lao OB, Johnson MD, Thunder M, et al.
Cerebral activation of mitogen-activated protein kinases after circulatory arrest and low flow cardiopulmonary bypass. Eur J Cardiothorac Surg 2004;26:912-9.
Kellermann K, Gordan ML, Nollert G, Blobner M, Kochs EF, Jungwirth B, et al.
Long-term assessment of NFkappaB expression in the brain and neurologic outcome following deep hypothermic circulatory arrest in rats. Perfusion 2009;24:429-36.
Ueno T, Sawa Y, Kitagawa-Sakakida S, Nishimura M, Morishita R, Kaneda Y, et al.
Nuclear factor-kappa B decoy attenuates neuronal damage after global brain ischemia: A future strategy for brain protection during circulatory arrest. J Thorac Cardiovasc Surg 2001;122:720-7.
Li M, Feng B, Wang L, Guo S, Zhang P, Gong J, et al.
Tollip is a critical mediator of cerebral ischaemia-reperfusion injury. J Pathol 2015;237:249-62.
Downes CE, Crack PJ. Neural injury following stroke: Are toll-like receptors the link between the immune system and the CNS? Br J Pharmacol 2010;160:1872-88.
Wang ZK, Liu FF, Wang Y, Jiang XM, Yu XF. Let-7a gene knockdown protects against cerebral ischemia/reperfusion injury. Neural Regen Res 2016;11:262-9.
] [Full text]
Hu YY, Wang Y, Liang S, Yu XL, Zhang L, Feng LY, et al.
Senkyunolide I attenuates oxygen-glucose deprivation/reoxygenation-induced inflammation in microglial cells. Brain Res 2016;1649:123-31.
Sawe N, Steinberg G, Zhao H. Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 2008;86:1659-69.
Gu N, Ge K, Hao C, Ji Y, Li H, Guo Y, et al.
Neuregulin1β effects on brain tissue via ERK5-dependent MAPK pathway in a rat model of cerebral ischemia-reperfusion injury. J Mol Neurosci 2017;61:607-16.
Wang RM, Yang F, Zhang YX. Preconditioning-induced activation of ERK5 is dependent on moderate Ca2+influx via NMDA receptors and contributes to ischemic tolerance in the hippocampal CA1 region of rats. Life Sci 2006;79:1839-46.
Shackelford DA, Yeh RY. Modulation of ERK and JNK activity by transient forebrain ischemia in rats. J Neurosci Res 2006;83:476-88.
Chen M, Sun HY, Li SJ, Das M, Kong JM, Gao TM, et al.
Nitric oxide as an upstream signal of p38 mediates hypoxia/reoxygenation-induced neuronal death. Neurosignals 2009;17:162-8.
Alessandrini A, Namura S, Moskowitz MA, Bonventre JV. MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci U S A 1999;96:12866-9.
Wang T, Gu J, Wu PF, Wang F, Xiong Z, Yang YJ, et al.
Protection by tetrahydroxystilbene glucoside against cerebral ischemia: Involvement of JNK, SIRT1, and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. Free Radic Biol Med 2009;47:229-40.
Asanuma T, Inanami O, Tabu K, Waki K, Kon Y, Kuwabara M, et al.
Protection against malonate-induced ischemic brain injury in rat by a cell-permeable peptidic c-jun N-terminal kinase inhibitor, (L)-HIV-TAT48-57-PP-JBD20, observed by the apparent diffusion coefficient mapping magnetic resonance imaging method. Neurosci Lett 2004;359:57-60.
Wang X, Wang H, Xu L, Rozanski DJ, Sugawara T, Chan PH, et al.
Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: Exploration of potential mechanism associated with apoptosis. J Pharmacol Exp Ther 2003;304:172-8.
Han BH, Holtzman DM. BDNF protects the neonatal brain from hypoxic-ischemic injuryin vivo
via the ERK pathway. J Neurosci 2000;20:5775-81.
Ridder DA, Schwaninger M. NF-kappaB signaling in cerebral ischemia. Neuroscience 2009;158:995-1006.
Kim E, Kim HC, Lee S, Ryu HG, Park YH, Kim JH, et al.
Dexmedetomidine confers neuroprotection against transient global cerebral ischemia/reperfusion injury in rats by inhibiting inflammation through inactivation of the TLR-4/NF-κB pathway. Neurosci Lett 2017;649:20-7.
Pradillo JM, Fernández-López D, García-Yébenes I, Sobrado M, Hurtado O, Moro MA, et al
. Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning. J Neurochem 2009;109:287-94.
Kriz J. Inflammation in ischemic brain injury: Timing is important. Crit Rev Neurobiol 2006;18:145-57.
Chamorro Á, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R, et al.
The immunology of acute stroke. Nat Rev Neurol 2012;8:401-10.
Chamorro A, Hallenbeck J. The harms and benefits of inflammatory and immune responses in vascular disease. Stroke 2006;37:291-3.
Petcu EB, Kocher T, Kuhr A, Buga AM, Klöting I, Herndon JG, et al.
Mild systemic inflammation has a neuroprotective effect after stroke in rats. Curr Neurovasc Res 2008;5:214-23.
Fu Y, Liu Q, Anrather J, Shi FD. Immune interventions in stroke. Nat Rev Neurol 2015;11:524-35.
Liesz A, Roth S, Zorn M, Sun L, Hofmann K, Veltkamp R, et al.
Acquired immunoglobulin G deficiency in stroke patients and experimental brain ischemia. Exp Neurol 2015;271:46-52.
Esmaeili A, Dadkhahfar S, Fadakar K, Rezaei N. Post-stroke immunodeficiency: Effects of sensitization and tolerization to brain antigens. Int Rev Immunol 2012;31:396-409.
Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, et al.
Stroke-induced immunodepression: Experimental evidence and clinical relevance. Stroke 2007;38:770-3.
Kamel H, Iadecola C. Brain-immune interactions and ischemic stroke: Clinical implications. Arch Neurol 2012;69:576-81.
Eltzschig HK, Eckle T. Ischemia and reperfusion–from mechanism to translation. Nat Med 2011;17:1391-401.
Wang X, Yue TL, Barone FC, White RF, Gagnon RC, Feuerstein GZ, et al.
Concomitant cortical expression of TNF-alpha and IL-1 beta mRNAs follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol 1994;23:103-14.
Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ, et al.
Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 2001;21:5528-34.
Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K, et al.
Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke 1995;26:676-80.
Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV. Inflammation and brain edema: New insights into the role of chemokines and their receptors. Acta Neurochir Suppl 2006;96:444-50.
Yang Y, Rosenberg GA. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res 2015;1623:30-8.
Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR. Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci Lett 1997;238:53-6.
Lu A, Clark JF, Broderick JP, Pyne-Geithman GJ, Wagner KR, Ran R, et al.
Reperfusion activates metalloproteinases that contribute to neurovascular injury. Exp Neurol 2008;210:549-59.
Lu A, Suofu Y, Guan F, Broderick JP, Wagner KR, Clark JF, et al.
Matrix metalloproteinase-2 deletions protect against hemorrhagic transformation after 1 h of cerebral ischemia and 23 h of reperfusion. Neuroscience 2013;253:361-7.
Castellanos M, Leira R, Serena J, Pumar JM, Lizasoain I, Castillo J, et al.
Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke 2003;34:40-6.
Tarkowski E, Rosengren L, Blomstrand C, Jensen C, Ekholm S, Tarkowski A, et al.
Intrathecal expression of proteins regulating apoptosis in acute stroke. Stroke 1999;30:321-7.
Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, et al.
Interleukin-10 in the brain. Crit Rev Immunol 2001;21:427-49.
Pelidou SH, Kostulas N, Matusevicius D, Kivisäkk P, Kostulas V, Link H, et al.
High levels of IL-10 secreting cells are present in blood in cerebrovascular diseases. Eur J Neurol 1999;6:437-42.
Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, et al.
Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci 2000;12:2265-72.
Ooboshi H, Ibayashi S, Shichita T, Kumai Y, Takada J, Ago T, et al.
Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation 2005;111:913-9.
Perini F, Morra M, Alecci M, Galloni E, Marchi M, Toso V, et al.
Temporal profile of serum anti-inflammatory and pro-inflammatory interleukins in acute ischemic stroke patients. Neurol Sci 2001;22:289-96.
Kumar P, Yadav AK, Misra S, Kumar A, Chakravarty K, Prasad K, et al.
Role of interleukin-10 (-1082A/G) gene polymorphism with the risk of ischemic stroke: A meta-analysis. Neurol Res 2016;38:823-30.
Pang L, Ye W, Che XM, Roessler BJ, Betz AL, Yang GY, et al.
Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ss1 expression. Stroke 2001;32:544-52.
Cekanaviciute E, Fathali N, Doyle KP, Williams AM, Han J, Buckwalter MS, et al.
Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. Glia 2014;62:1227-40.
Boche D, Cunningham C, Gauldie J, Perry VH. Transforming growth factor-beta 1-mediated neuroprotection against excitotoxic injury in vivo
. J Cereb Blood Flow Metab 2003;23:1174-82.
Guan J. Insulin-like growth factor-1 (IGF-1) derived neuropeptides, a novel strategy for the development of pharmaceuticals for managing ischemic brain injury. CNS Neurosci Ther 2011;17:250-5.
Kooijman R, Sarre S, Michotte Y, De Keyser J. Insulin-like growth factor I: A potential neuroprotective compound for the treatment of acute ischemic stroke? Stroke 2009;40:e83-8.
Choi JS, Kim SJ, Shin JA, Lee KE, Park EM. Effects of estrogen on temporal expressions of IL-1beta and IL-1ra in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation. Neurosci Lett 2008;438:233-7.
Lazovic J, Basu A, Lin HW, Rothstein RP, Krady JK, Smith MB, et al.
Neuroinflammation and both cytotoxic and vasogenic edema are reduced in interleukin-1 type 1 receptor-deficient mice conferring neuroprotection. Stroke 2005;36:2226-31.
Stroemer RP, Rothwell NJ. Cortical protection by localized striatal injection of IL-1ra following cerebral ischemia in the rat. J Cereb Blood Flow Metab 1997;17:597-604.
Relton JK, Martin D, Thompson RC, Russell DA. Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol 1996;138:206-13.
Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, et al.
Arandomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005;76:1366-72.
Loddick SA, Turnbull AV, Rothwell NJ. Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1998;18:176-9.
Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, et al.
Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 1997;28:1233-44.
Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Fenger C, Nielsen HH, et al.
Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci 2009;29:1319-30.
Ginis I, Jaiswal R, Klimanis D, Liu J, Greenspon J, Hallenbeck JM, et al.
TNF-alpha-induced tolerance to ischemic injury involves differential control of NF-kappaB transactivation: The role of NF-kappaB association with p300 adaptor. J Cereb Blood Flow Metab 2002;22:142-52.
Alikhani M, Alikhani Z, Raptis M, Graves DT. TNF-alphain vivo
stimulates apoptosis in fibroblasts through caspase-8 activation and modulates the expression of pro-apoptotic genes. J Cell Physio 2004;201:341-8.
Huang L, Wong S, Snyder EY, Hamblin MH, Lee JP. Human neural stem cells rapidly ameliorate symptomatic inflammation in early-stage ischemic-reperfusion cerebral injury. Stem Cell Res Ther 2014;5:129.
Khan IS, Odom M, Ehtesham M, Colvin D, Quarles CC, McLaughlin B, et al
. Intraarterial administration of norcantharidin attenuates ischemic stroke damage in rodents when given at the time of reperfusion: Novel uses of endovascular capabilities. J Neurosurg 2016;125:152-9.
Lee JH, Cui HS, Shin SK, Kim JM, Kim SY, Lee JE, et al.
Effect of propofol post-treatment on blood-brain barrier integrity and cerebral edema after transient cerebral ischemia in rats. Neurochem Res 2013;38:2276-86.
Pandey AK, Bhattacharya P, Shukla SC, Paul S, Patnaik R. Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: A molecular docking study exploring possible neuroprotection. Neural Regen Res 2015;10:568-75.
] [Full text]
Varano GP, Parisi V, Adornetto A, Cavaliere F, Amantea D, Nucci C, et al.
Post-ischemic treatment with azithromycin protects ganglion cells against retinal ischemia/reperfusion injury in the rat. Mol Vis 2017;23:911-21.
Wang R, Wu X, Liang J, Qi Z, Liu X, Min L, et al.
Intra-artery infusion of recombinant human erythropoietin reduces blood-brain barrier disruption in rats following cerebral ischemia and reperfusion. Int J Neurosci 2015;125:693-702.
Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, et al.
Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 2006;12:441-5.
Fouda AY, Pillai B, Dhandapani KM, Ergul A, Fagan SC. Role of interleukin-10 in the neuroprotective effect of the angiotensin type 2 receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol 2017;799:128-34.
Nakajima M, Nito C, Sowa K, Suda S, Nishiyama Y, Nakamura-Takahashi A, et al.
Mesenchymal stem cells overexpressing interleukin-10 promote neuroprotection in experimental acute ischemic stroke. Mol Ther Methods Clin Dev 2017;6:102-11.
Yang H, Zhang A, Zhang Y, Ma S, Wang C. Resveratrol pretreatment protected against cerebral ischemia/reperfusion injury in rats via expansion of T regulatory cells. J Stroke Cerebrovasc Dis 2016;25:1914-21.
Zhang R, Liu C, Liu X, Guo Y. Protective effect of spatholobus suberectus on brain tissues in cerebral ischemia. Am J Transl Res 2016;8:3963-9.
Wang S, Yin J, Ge M, Dai Z, Li Y, Si J, et al.
Transforming growth-beta 1 contributes to isoflurane postconditioning against cerebral ischemia-reperfusion injury by regulating the c-jun N-terminal kinase signaling pathway. Biomed Pharmacother 2016;78:280-90.
Xiong D, Deng Y, Huang B, Yin C, Liu B, Shi J, et al.
Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB, PPARα and PPARγ in rats. Int Immunopharmacol 2016;30:157-62.
Ruocco A, Nicole O, Docagne F, Ali C, Chazalviel L, Komesli S, et al.
Atransforming growth factor-beta antagonist unmasks the neuroprotective role of this endogenous cytokine in excitotoxic and ischemic brain injury. J Cereb Blood Flow Metab 1999;19:1345-53.
Yamauchi T, Sakurai M, Abe K, Takano H, Sawa Y. Neuroprotective effects of activated protein C through induction of insulin-like growth factor-1 (IGF-1), IGF-1 receptor, and its downstream signal phosphorylated serine-threonine kinase after spinal cord ischemia in rabbits. Stroke 2006;37:1081-6.
Famakin B, Mou Y, Spatz M, Lawal M, Hallenbeck J. Downstream toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia. J Neuroinflammation 2012;9:174.
McDonough A, Lee RV, Noor S, Lee C, Le T, Iorga M, et al.
Ischemia/reperfusion induces interferon-stimulated gene expression in microglia. J Neurosci 2017;37:8292-308.
Keilhoff G, Schweizer H, John R, Langnaese K, Ebmeyer U. Minocycline neuroprotection in a rat model of asphyxial cardiac arrest is limited. Resuscitation 2011;82:341-9.
Kaur C, Ling EA. Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res 2008;5:71-81.
Wang W, Lu R, Feng DY, Liang LR, Liu B, Zhang H, et al.
Inhibition of microglial activation contributes to propofol-induced protection against post-cardiac arrest brain injury in rats. J Neurochem 2015;134:892-903.
Wang QY, Sun P, Zhang Q, Yao SL. Minocycline attenuates microglial response and reduces neuronal death after cardiac arrest and cardiopulmonary resuscitation in mice. J Huazhong Univ Sci Technolog Med Sci 2015;35:225-9.
Fagan SC, Cronic LE, Hess DC. Minocycline development for acute ischemic stroke. Transl Stroke Res 2011;2:202-8.
Akdemir G, Ratelade J, Asavapanumas N, Verkman AS. Neuroprotective effect of aquaporin-4 deficiency in a mouse model of severe global cerebral ischemia produced by transient 4-vessel occlusion. Neurosci Lett 2014;574:70-5.
Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM, et al.
An early and sustained peripheral inflammatory response in acute ischaemic stroke: Relationships with infection and atherosclerosis. J Neuroimmunol 2003;139:93-101.
Seifert HA, Hall AA, Chapman CB, Collier LA, Willing AE, Pennypacker KR. A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation. J Neuroimmune Pharmacol 2012;7:1017-24.
Ajmo CT Jr., Vernon DO, Collier L, Hall AA, Garbuzova-Davis S, Willing A, et al.
The spleen contributes to stroke-induced neurodegeneration. J Neurosci Res 2008;86:2227-34.
Love S, Barber R. Expression of P-selectin and intercellular adhesion molecule-1 in human brain after focal infarction or cardiac arrest. Neuropathol Appl Neurobiol 2001;27:465-73.
Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G. Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab 1995;15:42-51.
del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ, et al.
Inflammation and stroke: Putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 2000;10:95-112.
Cha JK, Jeong MH, Kim EK, Lim YJ, Ha BR, Kim SH, et al.
Surface expression of P-selectin on platelets is related with clinical worsening in acute ischemic stroke. J Korean Med Sci 2002;17:811-6.
Zhao DX, Feng J, Cong SY, Zhang W. Association of E-selectin gene polymorphisms with ischemic stroke in a chinese han population. J Neurosci Res 2012;90:1782-7.
Shyu KG, Chang H, Lin CC. Serum levels of intercellular adhesion molecule-1 and E-selectin in patients with acute ischaemic stroke. J Neurol 1997;244:90-3.
Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R. Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: A study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 2003;183:25-33.
Gan Y, Liu Q, Wu W, Yin JX, Bai XF, Shen R, et al.
Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc Natl Acad Sci U S A 2014;111:2704-9.
Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, et al.
Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 2009;40:1849-57.
Clark RS, Kochanek PM, Schwarz MA, Schiding JK, Turner DS, Chen M, et al.
Inducible nitric oxide synthase expression in cerebrovascular smooth muscle and neutrophils after traumatic brain injury in immature rats. Pediatr Res 1996;39:784-90.
Iadecola C, Zhang F, Xu S, Casey R, Ross ME. Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 1995;15:378-84.
Nogawa S, Forster C, Zhang F, Nagayama M, Ross ME, Iadecola C. Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia. Proc Natl Acad Sci U S A 1998;95:10966-71.
Hammond MD, Taylor RA, Mullen MT, Ai Y, Aguila HL, Mack M, et al.
CCR2+ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci 2014;34:3901-9.
Schroeter M, Jander S. T-cell cytokines in injury-induced neural damage and repair. Neuromolecular Med 2005;7:183-95.
Deng G, Carter J, Traystman RJ, Wagner DH, Herson PS. Pro-inflammatory T-lymphocytes rapidly infiltrate into the brain and contribute to neuronal injury following cardiac arrest and cardiopulmonary resuscitation. J Neuroimmunol 2014;274:132-40.
Lehmann J, Härtig W, Seidel A, Füldner C, Hobohm C, Grosche J, et al.
Inflammatory cell recruitment after experimental thromboembolic stroke in rats. Neuroscience 2014;279:139-54.
Wang ZK, Xue L, Wang T, Wang XJ, Su ZQ. Infiltration of invariant natural killer T cells occur and accelerate brain infarction in permanent ischemic stroke in mice. Neurosci Lett 2016;633:62-8.
Katada R, Akdemir G, Asavapanumas N, Ratelade J, Zhang H, Verkman AS, et al.
Greatly improved survival and neuroprotection in aquaporin-4-knockout mice following global cerebral ischemia. FASEB J 2014;28:705-14.
Xiao F. Bench to bedside: Brain edema and cerebral resuscitation: The present and future. Acad Emerg Med 2002;9:933-46.
Xiao F, Arnold TC, Zhang S, Brown C, Alexander JS, Carden DL, et al.
Cerebral cortical aquaporin-4 expression in brain edema following cardiac arrest in rats. Acad Emerg Med 2004;11:1001-7.
Mocco J, Choudhri T, Huang J, Harfeldt E, Efros L, Klingbeil C, et al.
HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res 2002;91:907-14.
Lehmberg J, Beck J, Baethmann A, Uhl E. Effect of P-selectin inhibition on leukocyte-endothelium interaction and survival after global cerebral ischemia. J Neurol 2006;253:357-63.
Kanemoto Y, Nakase H, Akita N, Sakaki T. Effects of anti-intercellular adhesion molecule-1 antibody on reperfusion injury induced by late reperfusion in the rat middle cerebral artery occlusion model. Neurosurgery 2002;51:1034-41.
Kitagawa K, Matsumoto M, Mabuchi T, Yagita Y, Ohtsuki T, Hori M, et al.
Deficiency of intercellular adhesion molecule 1 attenuates microcirculatory disturbance and infarction size in focal cerebral ischemia. J Cereb Blood Flow Metab 1998;18:1336-45.
Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 2004;35:179-84.
Cheng Y, Zhang HT, Sun L, Guo S, Ouyang S, Zhang Y, et al.
Involvement of cell adhesion molecules in polydatin protection of brain tissues from ischemia-reperfusion injury. Brain Res 2006;1110:193-200.
Uhm CS, Kim KB, Lim JH, Pee DH, Kim YH, Kim H, et al.
Effective treatment with fucoidin for perinatal hypoxic-ischemic encephalopathy in rats. Neurosci Lett 2003;353:21-4.
Becker KJ. Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and enlimomab (R6.5) in acute stroke. Curr Med Res Opin 2002;18 Suppl 2:s18-22.
Zhang LH, Wei EQ. Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on transient global cerebral ischemia in rats. Acta Pharmacol Sin 2003;24:1241-7.
Justicia C, Martín A, Rojas S, Gironella M, Cervera A, Panés J, et al.
Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. J Cereb Blood Flow Metab 2006;26:421-32.
Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, et al.
Minocycline treatment in acute stroke: An open-label, evaluator-blinded study. Neurology 2007;69:1404-10.
Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, et al.
Minocycline to improve neurologic outcome in stroke (MINOS): A dose-finding study. Stroke 2010;41:2283-7.
Elkins J, Veltkamp R, Montaner J, Johnston SC, Singhal AB, Becker K, et al.
Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): A randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol 2017;16:217-26.
Li W, Xu H, Testai FD. Mechanism of action and clinical potential of fingolimod for the treatment of stroke. Front Neurol 2016;7:139.
Zhu Z, Fu Y, Tian D, Sun N, Han W, Chang G, et al.
Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: A Pilot trial. Circulation 2015;132:1104-12.
Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, Kauppinen RA, et al.
Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 2007;27:1941-53.
Szalay G, Martinecz B, Lénárt N, Környei Z, Orsolits B, Judák L, et al.
Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun 2016;7:11499.
Amantea D, Micieli G, Tassorelli C, Cuartero MI, Ballesteros I, Certo M, et al.
Rational modulation of the innate immune system for neuroprotection in ischemic stroke. Front Neurosci 2015;9:147.
Xia CY, Zhang S, Gao Y, Wang ZZ, Chen NH. Selective modulation of microglia polarization to M2 phenotype for stroke treatment. Int Immunopharmacol 2015;25:377-82.
Bohacek I, Cordeau P, Lalancette-Hebert M, Gorup D, Weng YC, Gajovic S, et al
. Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury. J Neuroinflammation 2012;9:191.
Selvamani A, Sathyan P, Miranda RC, Sohrabji F. An antagomir to microRNA let7f promotes neuroprotection in an ischemic stroke model. PLoS One 2012;7:e32662.
Lai AY, Todd KG. Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines. Glia 2006;53:809-16.
Narantuya D, Nagai A, Sheikh AM, Masuda J, Kobayashi S, Yamaguchi S, et al.
Human microglia transplanted in rat focal ischemia brain induce neuroprotection and behavioral improvement. PLoS One 2010;5:e11746.
Narayanan SV, Perez-Pinzon MA. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Cond Med 2017;1:2-8.
Sharma HS, Miclescu A, Wiklund L. Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: A light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. J Neural Transm (Vienna) 2011;118:87-114.
Xu L, Emery JF, Ouyang YB, Voloboueva LA, Giffard RG. Astrocyte targeted overexpression of hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia. Glia 2010;58:1042-9.
Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 2016;144:103-20.
Biswas A, Bruder D, Wolf SA, Jeron A, Mack M, Heimesaat MM, et al.
Ly6C(high) monocytes control cerebral toxoplasmosis. J Immunol 2015;194:3223-35.
Ramakrishna C, Newo AN, Shen YW, Cantin E. Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis. PLoS Pathog 2011;7:e1002071.
Zhang ZG, Chopp M. Promoting brain remodeling to aid in stroke recovery. Trends Mol Med 2015;21:543-8.
Busto R, Dietrich WD, Globus MY, Valdés I, Scheinberg P, Ginsberg MD, et al.
Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987;7:729-38.
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al.
Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N
Engl J Med 2002;346:557-63.
Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N
Engl J Med 2002;346:549-56.
Ceulemans AG, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y, et al.
The dual role of the neuroinflammatory response after ischemic stroke: Modulatory effects of hypothermia. J Neuroinflammation 2010;7:74.
van der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR. Hypothermia in animal models of acute ischaemic stroke: A systematic review and meta-analysis. Brain 2007;130:3063-74.
Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al.
Targeted temperature management at 33°C versus 36°C after cardiac arrest. N
Engl J Med 2013;369:2197-206.
Kaibara T, Sutherland GR, Colbourne F, Tyson RL. Hypothermia: Depression of tricarboxylic acid cycle flux and evidence for pentose phosphate shunt upregulation. J Neurosurg 1999;90:339-47.
Lee JM, Zipfel GJ, Choi DW. The changing landscape of ischaemic brain injury mechanisms. Nature 1999;399:A7-14.
Zipfel GJ, Lee JM, Choi DW. Reducing calcium overload in the ischemic brain. N
Engl J Med 1999;341:1543-4.
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;138:124-34.
Terao Y, Miyamoto S, Hirai K, Kamiguchi H, Ohta H, Shimojo M, et al.
Hypothermia enhances heat-shock protein 70 production in ischemic brains. Neuroreport 2009;20:745-9.
Cullen KE, Sarge KD. Characterization of hypothermia-induced cellular stress response in mouse tissues. J Biol Chem 1997;272:1742-6.
Janata A, Holzer M. Hypothermia after cardiac arrest. Prog Cardiovasc Dis 2009;52:168-79.
Weng Y, Sun S. Therapeutic hypothermia after cardiac arrest in adults: Mechanism of neuroprotection, phases of hypothermia, and methods of cooling. Crit Care Clin 2012;28:231-43.
Van Hemelrijck A, Hachimi-Idrissi S, Sarre S, Ebinger G, Michotte Y. Post-ischaemic mild hypothermia inhibits apoptosis in the penumbral region by reducing neuronal nitric oxide synthase activity and thereby preventing endothelin-1-induced hydroxyl radical formation. Eur J Neurosci 2005;22:1327-37.
Kader A, Frazzini VI, Baker CJ, Solomon RA, Trifiletti RR. Effect of mild hypothermia on nitric oxide synthesis during focal cerebral ischemia. Neurosurgery 1994;35:272-7.
Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 2012;13:267-78.
Fan J, Cai S, Zhong H, Cao L, Hui K, Xu M, et al
. Therapeutic hypothermia attenuates global cerebral reperfusion-induced mitochondrial damage by suppressing dynamin-related protein 1 activation and mitochondria-mediated apoptosis in a cardiac arrest rat model. Neurosci Lett 2017;647:45-52.
Gong P, Hua R, Zhang Y, Zhao H, Tang Z, Mei X, et al
. Hypothermia-induced neuroprotection is associated with reduced mitochondrial membrane permeability in a swine model of cardiac arrest. J Cereb Blood Flow Metab 2013;33:928-34.
Tang Y, Liu X, Zhao J, Tan X, Liu B, Zhang G, et al.
Hypothermia-induced ischemic tolerance is associated with drp1 inhibition in cerebral ischemia-reperfusion injury of mice. Brain Res 2016;1646:73-83.
Hasegawa M, Ogihara T, Tamai H, Hiroi M. Hypothermic inhibition of apoptotic pathways for combined neurotoxicity of iron and ascorbic acid in differentiated PC12 cells: Reduction of oxidative stress and maintenance of the glutathione redox state. Brain Res 2009;1283:1-3.
Hu WW, Du Y, Li C, Song YJ, Zhang GY. Neuroprotection of hypothermia against neuronal death in rat hippocampus through inhibiting the increased assembly of gluR6-PSD95-MLK3 signaling module induced by cerebral ischemia/reperfusion. Hippocampus 2008;18:386-97.
Zhao H, Shimohata T, Wang JQ, Sun G, Schaal DW, Sapolsky RM, et al.
Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J Neurosci 2005;25:9794-806.
Lee SM, Zhao H, Maier CM, Steinberg GK. The protective effect of early hypothermia on PTEN phosphorylation correlates with free radical inhibition in rat stroke. J Cereb Blood Flow Metab 2009;29:1589-600.
Shimohata T, Zhao H, Steinberg GK. Epsilon PKC may contribute to the protective effect of hypothermia in a rat focal cerebral ischemia model. Stroke 2007;38:375-80.
Zhang Z, Sobel RA, Cheng D, Steinberg GK, Yenari MA. Mild hypothermia increases bcl-2 protein expression following global cerebral ischemia. Brain Res Mol Brain Res 2001;95:75-85.
Kawamura N, Schmeichel AM, Wang Y, Schmelzer JD, Low PA. Multiple effects of hypothermia on inflammatory response following ischemia-reperfusion injury in experimental ischemic neuropathy. Exp Neurol 2006;202:487-96.
Deng H, Han HS, Cheng D, Sun GH, Yenari MA. Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation. Stroke 2003;34:2495-501.
Inamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, et al.
Post-ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol 2000;109:66-74.
Hassoun HT, Kozar RA, Kone BC, Safi HJ, Moore FA. Intraischemic hypothermia differentially modulates oxidative stress proteins during mesenteric ischemia/reperfusion. Surgery 2002;132:369-76.
Cao J, Xu J, Li W, Liu J. Influence of selective brain cooling on the expression of ICAM-1 mRNA and infiltration of PMNLs and monocytes/macrophages in rats suffering from global brain ischemia/reperfusion injury. Biosci Trends 2008;2:241-4.
Kawai N, Okauchi M, Morisaki K, Nagao S. Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats. Stroke 2000;31:1982-9.
Yenari MA, Han HS. Influence of hypothermia on post-ischemic inflammation: Role of nuclear factor kappa B (NFkappaB). Neurochem Int 2006;49:164-9.
Webster CM, Kelly S, Koike MA, Chock VY, Giffard RG, Yenari MA, et al.
Inflammation and NFkappaB activation is decreased by hypothermia following global cerebral ischemia. Neurobiol Dis 2009;33:301-12.
Choi JS, Park J, Suk K, Moon C, Park YK, Han HS, et al.
Mild hypothermia attenuates intercellular adhesion molecule-1 induction via activation of extracellular signal-regulated kinase-1/2 in a focal cerebral ischemia model. Stroke Res Treat 2011;2011:846716.
Meybohm P, Gruenewald M, Zacharowski KD, Albrecht M, Lucius R, Fosel N, et al.
Mild hypothermia alone or in combination with anesthetic post-conditioning reduces expression of inflammatory cytokines in the cerebral cortex of pigs after cardiopulmonary resuscitation. Crit Care 2010;14:R21.
Lee JH, Wei ZZ, Cao W, Won S, Gu X, Winter M, et al
. Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice. Neurobiol Dis 2016;96:248-60.
Fairchild KD, Singh IS, Patel S, Drysdale BE, Viscardi RM, Hester L, et al.
Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. Am J Physiol Cell Physiol 2004;287:C422-31.
Yanagawa Y, Kawakami M, Okada Y. Moderate hypothermia alters interleukin-6 and interleukin-1alpha reactions in ischemic brain in mice. Resuscitation 2002;53:93-9.
Gong P, Zhao H, Hua R, Zhang M, Tang Z, Mei X, et al
. Mild hypothermia inhibits systemic and cerebral complement activation in a swine model of cardiac arrest. J Cereb Blood Flow Metab 2015;35:1289-95.
Matsui T, Kakeda T. IL-10 production is reduced by hypothermia but augmented by hyperthermia in rat microglia. J Neurotrauma 2008;25:709-15.
Huang FP, Zhou LF, Yang GY. The effect of extending mild hypothermia on focal cerebral ischemia and reperfusion in the rat. Neurol Res 1998;20:57-62.
Lee JE, Yoon YJ, Moseley ME, Yenari MA. Reduction in levels of matrix metalloproteinases and increased expression of tissue inhibitor of metalloproteinase-2 in response to mild hypothermia therapy in experimental stroke. J Neurosurg 2005;103:289-97.
Baumann E, Preston E, Slinn J, Stanimirovic D. Post-ischemic hypothermia attenuates loss of the vascular basement membrane proteins, agrin and SPARC, and the blood-brain barrier disruption after global cerebral ischemia. Brain Res 2009;1269:185-97.
Duz B, Oztas E, Erginay T, Erdogan E, Gonul E. The effect of moderate hypothermia in acute ischemic stroke on pericyte migration: An ultrastructural study. Cryobiology 2007;55:279-84.
Nagel S, Su Y, Horstmann S, Heiland S, Gardner H, Koziol J, et al.
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 2008;1188:198-206.
Hamann GF, Burggraf D, Martens HK, Liebetrau M, Jäger G, Wunderlich N, et al
. Mild to moderate hypothermia prevents microvascular basal lamina antigen loss in experimental focal cerebral ischemia. Stroke 2004;35:764-9.
Truettner JS, Alonso OF, Dietrich WD. Influence of therapeutic hypothermia on matrix metalloproteinase activity after traumatic brain injury in rats. J Cereb Blood Flow Metab 2005;25:1505-16.
Kurisu K, Abumiya T, Nakamura H, Shimbo D, Shichinohe H, Nakayama N, et al.
Transarterial regional brain hypothermia inhibits acute aquaporin-4 surge and sequential microvascular events in ischemia/Reperfusion injury. Neurosurgery 2016;79:125-34.
Kawanishi M, Kawai N, Nakamura T, Luo C, Tamiya T, Nagao S, et al.
Effect of delayed mild brain hypothermia on edema formation after intracerebral hemorrhage in rats. J Stroke Cerebrovasc Dis 2008;17:187-95.
Vosler PS, Logue ES, Repine MJ, Callaway CW. Delayed hypothermia preferentially increases expression of brain-derived neurotrophic factor exon III in rat hippocampus after asphyxial cardiac arrest. Brain Res Mol Brain Res 2005;135:21-9.
D'Cruz BJ, Fertig KC, Filiano AJ, Hicks SD, DeFranco DB, Callaway CW, et al.
Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation. J Cereb Blood Flow Metab 2002;22:843-51.
Schmidt KM, Repine MJ, Hicks SD, DeFranco DB, Callaway CW. Regional changes in glial cell line-derived neurotrophic factor after cardiac arrest and hypothermia in rats. Neurosci Lett 2004;368:135-9.
Kanagawa T, Fukuda H, Tsubouchi H, Komoto Y, Hayashi S, Fukui O, et al.
Adecrease of cell proliferation by hypothermia in the hippocampus of the neonatal rat. Brain Res 2006;1111:36-40.
Xiong M, Li J, Ma SM, Yang Y, Zhou WH. Effects of hypothermia on oligodendrocyte precursor cell proliferation, differentiation and maturation following hypoxia ischemiain vivo
and in vitro
. Exp Neurol 2013;247:720-9.
Yu D, Wang X, Zhou F, Wang L, Yang G, Zhong W, et al
. Mild hypothermia modulates the expression of nestin and caspase-3 in the sub-granular zone and improves neurological outcomes in rats with ischemic stroke. Oncotarget 2017;8:109191-200.
Chung TN, Kim JH, Choi BY, Jeong JY, Chung SP, Kwon SW, et al.
Effect of adipose-derived mesenchymal stem cell administration and mild hypothermia induction on delayed neuronal death after transient global cerebral ischemia. Crit Care Med 2017;45:e508-e515.
Herz J, Köster C, Reinboth BS, Dzietko M, Hansen W, Sabir H, et al.
Interaction between hypothermia and delayed mesenchymal stem cell therapy in neonatal hypoxic-ischemic brain injury. Brain Behav Immun 2018. pii: S0889-1591(18) 30018-7.
Park WS, Sung SI, Ahn SY, Yoo HS, Sung DK, Im GH, et al.
Hypothermia augments neuroprotective activity of mesenchymal stem cells for neonatal hypoxic-ischemic encephalopathy. PLoS One 2015;10:e0120893.
Ichinose M, Kamei Y, Iriyama T, Imada S, Seyama T, Toshimitsu M, et al.
Hypothermia attenuates apoptosis and protects contact between myelin basic protein-expressing oligodendroglial-lineage cells and neurons against hypoxia-ischemia. J Neurosci Res 2014;92:1270-85.
Becerra-Calixto A, Cardona-Gomez GP. The role of astrocytes in neuroprotection after brain stroke: Potential in cell therapy. Front Mol Neurosci 2017;10:88.
Yenari MA, Han HS. Influence of therapeutic hypothermia on regeneration after cerebral ischemia. Front Neurol Neurosci 2013;32:122-8.
Xie YC, Li CY, Li T, Nie DY, Ye F. Effect of mild hypothermia on angiogenesis in rats with focal cerebral ischemia. Neurosci Lett 2007;422:87-90.
Silasi G, Klahr AC, Hackett MJ, Auriat AM, Nichol H, Colbourne F, et al.
Prolonged therapeutic hypothermia does not adversely impact neuroplasticity after global ischemia in rats. J Cereb Blood Flow Metab 2012;32:1525-34.
Muñiz J, Romero J, Holubiec M, Barreto G, González J, Saint-Martin M, et al.
Neuroprotective effects of hypothermia on synaptic actin cytoskeletal changes induced by perinatal asphyxia. Brain Res 2014;1563:81-90.
Schmitt KR, Boato F, Diestel A, Hechler D, Kruglov A, Berger F, et al.
Hypothermia-induced neurite outgrowth is mediated by tumor necrosis factor-alpha. Brain Pathol 2010;20:771-9.
|This article has been cited by|
||Targeted Temperature Management Experience of an Academic Emergency Department: A 5-Year Retrospective Study
| ||Yasemin Ozdamar, Ilter Agackiran, Nalan Metin Aksu |
| ||Therapeutic Hypothermia and Temperature Management. 2022; |
|[Pubmed] | [DOI]|
||Physiological Changes in Subjects Exposed to Accidental Hypothermia: An Update
| ||Lars J. Bjertnæs, Torvind O. Næsheim, Eirik Reierth, Evgeny V. Suborov, Mikhail Y. Kirov, Konstantin M. Lebedinskii, Torkjel Tveita |
| ||Frontiers in Medicine. 2022; 9 |
|[Pubmed] | [DOI]|
||Postcooling But Not Precooling Benefits Motor Recovery by Suppressing Cell Death After Surgical Spinal Cord Injury in Rats
| ||Ning Li, Charlene Y.C. Chau, Jiaxin Liu, Min Yao, Karrie M.Y. Kiang, Zhiyuan Zhu, Pingde Zhang, Huilin Cheng, Gilberto K.K. Leung |
| ||World Neurosurgery. 2021; |
|[Pubmed] | [DOI]|
||Studies Utilizing Therapeutic Hypothermia and Targeted Temperature Management
| ||Neeraj Badjatia,Benjamin S. Abella,Kees H. Polderman,Romergryko G. Geocadin,Robert Silbergleit |
| ||Therapeutic Hypothermia and Temperature Management. 2021; |
|[Pubmed] | [DOI]|
||Microglial Activation and Neurological Outcomes in a Murine Model of Cardiac Arrest
| ||Alaa Ousta,Lin Piao,Yong Hu Fang,Adrianna Vera,Thara Nallamothu,Alfredo J. Garcia,Willard W. Sharp |
| ||Neurocritical Care. 2021; |
|[Pubmed] | [DOI]|
||Cerebral and myocardial mitochondrial injury differ in a rat model of cardiac arrest and cardiopulmonary resuscitation
| ||Xianfei Ji,Jennifer L. Bradley,Guanghui Zheng,Weiwei Ge,Jing Xu,Juntao Hu,Fenglian He,Rabiya Shabnam,Mary Ann Peberdy,Joseph P. Ornato,Qun Chen,Edward J. Lesnefsky,Wanchun Tang |
| ||Biomedicine & Pharmacotherapy. 2021; 140: 111743 |
|[Pubmed] | [DOI]|
||Pharmacological torpor prolongs rat survival in lethal normobaric hypoxia
| ||Nadezhda M. Zakharova,Yury S. Tarahovsky,Natalia P. Komelina,Maxim O. Khrenov,Anatoly L. Kovtun |
| ||Journal of Thermal Biology. 2021; : 102906 |
|[Pubmed] | [DOI]|
||Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies
| ||Anamaria Jurcau, Aurel Simion |
| ||International Journal of Molecular Sciences. 2021; 23(1): 14 |
|[Pubmed] | [DOI]|
||Effects of extracellular vesicles from mesenchymal stem cells on oxygen-glucose deprivation/reperfusion-induced neuronal injury
| ||Shuang-shuang Gu,Xiu-wen Kang,Jun Wang,Xiao-fang Guo,Hao Sun,Lei Jiang,Jin-song Zhang |
| ||World Journal of Emergency Medicine. 2021; 12(1): 61 |
|[Pubmed] | [DOI]|
||Pharmacological Approach for Neuroprotection After Cardiac Arrest—A Narrative Review of Current Therapies and Future Neuroprotective Cocktail
| ||Rishabh C. Choudhary,Muhammad Shoaib,Samantha Sohnen,Daniel M. Rolston,Daniel Jafari,Santiago J. Miyara,Kei Hayashida,Ernesto P. Molmenti,Junhwan Kim,Lance B. Becker |
| ||Frontiers in Medicine. 2021; 8 |
|[Pubmed] | [DOI]|
||Cardiac Arrest: An Interdisciplinary Review of the Literature from 2018
| ||Sarah S. Gul,Scott A. Cohen,Leslie Avery,Meenakshi P. Balakrishnan,Ramani Balu,Muhammad Abdul Baker Chowdhury,David Crabb,Karl W. Huesgen,Charles W. Hwang,Carolina B. Maciel,Travis W. Murphy,Francis Han,Torben K. Becker |
| ||Resuscitation. 2020; |
|[Pubmed] | [DOI]|
||Temperature Variability Does Not Attenuate the Beneficial Effects of Therapeutic Hypothermia on Cellular Apoptosis and Endoplasmic Reticulum Stress in the Cerebral Cortex of a Swine Cardiac Arrest Model
| ||Beiyuan Zhang,Qin Gu,Xiancheng Chen,Yong You,Ming Chen,Yajun Qian,Yan Chen,Wenkui Yu |
| ||Neurocritical Care. 2020; |
|[Pubmed] | [DOI]|
||Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest
| ||Reggie Hui-Chao Lee,Mychal S. Grames,Celeste Yin-Chieh Wu,Chih-Feng Lien,Alexandre Couto e Silva,HarLee E. Possoit,Garrett A. Clemons,Cristiane T. Citadin,Jake T. Neumann,Donatella Pastore,Davide Lauro,David Della-Morte,Hung Wen Lin |
| ||American Journal of Physiology-Heart and Circulatory Physiology. 2020; 319(5): H1044 |
|[Pubmed] | [DOI]|
||Utility of Abnormal Head Computed Tomography in Predicting Outcome in Out-of-Hospital Cardiac Arrest Victims
| ||Rebecca Fisher,Michael J. Bernett,Ryan Paternoster,Patrick Karabon,William Devlin,Robert Swor |
| ||Therapeutic Hypothermia and Temperature Management. 2020; |
|[Pubmed] | [DOI]|
||Annexin A1 Bioactive Peptide Promotes Resolution of Neuroinflammation in a Rat Model of Exsanguinating Cardiac Arrest Treated by Emergency Preservation and Resuscitation
| ||Qing Ma,Zhiquan Zhang,Jae-Kwang Shim,Talaignair N. Venkatraman,Christopher D. Lascola,Quintin J. Quinones,Joseph P. Mathew,Niccolò Terrando,Mihai V. Podgoreanu |
| ||Frontiers in Neuroscience. 2019; 13 |
|[Pubmed] | [DOI]|
||Recent advances in personalizing cardiac arrest resuscitation
| ||Cyrus E. Kuschner,Lance B. Becker |
| ||F1000Research. 2019; 8: 915 |
|[Pubmed] | [DOI]|
||Effectiveness of Antiplatelet Drugs Under Therapeutic Hypothermia: A Comprehensive Review
| ||Ceren Eyileten,Aleksandra Soplinska,Justyna Pordzik,Jolanta M. Siller-Matula,Marek Postula |
| ||Clinical Pharmacology & Therapeutics. 2019; |
|[Pubmed] | [DOI]|
||Central serotonin prevents hypotension and hypothermia and reduces plasma and spleen cytokine levels during systemic inflammation
| ||Clarissa M.D. Mota,Gabriela S. Borges,Mateus R. Amorim,Ruither O.G. Carolino,Marcelo E. Batalhão,Janete A. Anselmo-Franci,Evelin C. Carnio,Luiz G.S. Branco |
| ||Brain, Behavior, and Immunity. 2019; |
|[Pubmed] | [DOI]|
||Inflammatory cytokines are involved in dihydrocapsaicin (DHC) and regional cooling infusion (RCI)-induced neuroprotection in ischemic rat
| ||Di Wu,Xinglong Zhi,Yunxia Duan,Mo Zhang,Hong An,Wenjing Wei,Kai Dong,Ying Zhang,Jingfei Shi,Xiaoduo He,Jun Zhang,Chuanjie Wu,Ran Meng,Yuchuan Ding,Xunming Ji |
| ||Brain Research. 2019; 1710: 173 |
|[Pubmed] | [DOI]|