|Year : 2015 | Volume
| Issue : 1 | Page : 14-25
Hypothermia for treatment of stroke
Jong Youl Kim, Midori A Yenari
Department of Neurology, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco, California, USA
|Date of Submission||12-Apr-2015|
|Date of Acceptance||08-Aug-2015|
|Date of Web Publication||30-Sep-2015|
Midori A Yenari
Neurology 127, VAMC, 4150 Clement St., San Francisco, California - 94121
Source of Support: None, Conflict of Interest: None
Stroke is a major cause of neurological disability and death in industrialized nations. Therapeutic hypothermia has been shown to protect the brain from ischemia, stroke, and other acute neurological insults at the laboratory level. It has been shown to improve neurological outcome in certain clinical settings including anoxic brain injury due to cardiac arrest and hypoxic-ischemic neonatal encephalopathy. Hypothermia seems to affect multiple aspects of brain physiology and it is likely that multiple mechanisms underlie its protective effect. Understanding the events that occur in the ischemic brain during hypothermia might help lead to an understanding of how to protect the brain against acute injuries.
Keywords: Apoptosis, blood-brain barrier (BBB) and edema, hypoxic-ischemic injury, inflammation, intracerebral hemorrhage (ICH), multiple mechanisms, neuroprotection, subarachnoid hemorrhage (SAH)
|How to cite this article:|
Kim JY, Yenari MA. Hypothermia for treatment of stroke. Brain Circ 2015;1:14-25
| Introduction|| |
Several laboratories have shown over the years that hypothermia protects the brain from various insults such as stroke, hypoxia ischemia, forebrain ischemia, neonatal hypoxia-ischemia, and brain trauma. It is an effective therapy against brain cell death, especially when cooling is initiated within a few hours of injury onset. Therapeutic hypothermia has been extensively studied at the experimental level, and has been correlated to several salutary effects including reduction of metabolic activity, glutamate release, inflammation, production of reactive oxygen species, and mitochondrial cytochrome c release.  Such observations have been shown by several laboratories using different models and methods. Recent clinical studies have established that therapeutic cooling improves neurological outcome from cardiac arrest , and neonatal hypoxia-ischemia. ,, There are fewer randomized multicenter trials in stroke patients, with a few studies mostly demonstrating its feasibility ,, and safety. , However, there have been no studies demonstrating efficacy in human stroke. Clinical stroke studies seem to be hampered by unique challenges such as effective cooling strategies in awake patients and the potential for adverse events in a typically older patient population. Thus, while hypothermia has been shown to be efficacious in multiple laboratory models of stroke, it has not yet been demonstrated to do the same in humans. Further, hypothermia might be used as a model of neuroprotection by which mechanisms of stroke evolution could be better understood and as a means by which therapeutic targets may be identified. This review will cover basic and preclinical studies of hypothermia in experimental stroke and corresponding clinical studies as well as the many underlying mechanisms of hypothermic brain protection.
| Preclinical Studies and Clinical Correlation|| |
Optimal target temperature for therapeutic hypothermia
Therapeutic hypothermia is defined as an intentionally induced, controlled reduction from a normal body temperature of 37~38°C to temperatures in the range of 32-35°C (mild hypothermia), 28-32°C (moderate hypothermia), 20~28°C (deep hypothermia), and 5-20°C (profound hypothermia).
In earlier studies, deep to profound hypothermia was frequently applied; however, cooling to such low temperatures led to numerous complications, and was also difficult to achieve and maintain. In the late 1980s, there was a renewed interest in therapeutic cooling when studies showed that mild to moderate hypothermia was equally effective and better tolerated.  The scientific literature indicates that lowering brain temperature to the mild to moderate range is similarly protective as deep hypothermia. , In a meta-analysis of animal studies, the benefits of hypothermia were inversely related to the temperature attained and hypothermia reduced infarct size by >40% with temperatures of 34°C or below.  However, specific studies that directly compared different temperatures failed to show dose dependent neuroprotection comparing temperatures of 27°C to 32°C  and 30°C to 33°C.  In a rodent study of experimental stroke, cooling to temperatures of 36°C, 35°C, 34°C, 33°C, and 32°C for 4 h was carriedout. Cooling to 35°C failed to improve the outcome while the largest benefit was obtained at 34°C. 
Most clinical studies of hypothermia in acute ischemic stroke ,, as well as in postanoxic encephalopathy after cardiac arrest,  perinatal hypoxic-ischemic encephalopathy (HIE),  and traumatic brain injury , have studied cooling to levels of 32~34°C. Unfortunately, discomfort and shivering increased with lower temperatures in awake stroke patients, and cooling to these levels therefore required sedation, mechanical ventilation, and admission to an intensive care unit (ICU).  On the other hand, cooling patients with severe head injury to 35°C appeared to be as beneficial as 33°C while causing fewer complications.  In addition, temperature reductions to 35°C or 35.5°C via surface cooling have been shown to be safe in stroke patients without sedation but these patients were instead provided drugs such as meperidine to prevent shivering.  Using a similar strategy, the Nordic Cooling Stroke Study (NoCSS) was a randomized trial that tested the effect of temperature reduction to 35°C in patients who were awake with surface cooling for 9 h, started within 6 h of ischemic stroke onset but the trial was unfortunately terminated owing to slow recruitment.
A recent international clinical study of over 900 comatose survivors of cardiac arrest cooled patients in two separate groups to 33°C and 36°C. After 3 months of follow-up, both the groups had similar outcomes.  The results of this study led some groups to speculate that cooling to 36°C was as beneficial as 33°C. Certainly, cooling to 36°C is more feasible and better tolerated by most patients. However, this study did not include a group where normothermia was maintained. Thus, it is unclear whether cooling to 36°C was beneficial compared to no cooling, or if all cooling was ineffective.
In sum, the current literature suggests that cooling to 32~34°C may be the optimal target temperature. Cooling to 35°C may be safe but its neuroprotective potential is less clear.
Treatment window and duration of hypothermia
Numerous laboratory studies have demonstrated the benefit of timing and duration of hypothermia determining the effects of cooling, with early initiation of cooling before the brain injury to confer significant neuroprotective outcome. Though early initiation is not always feasible in clinical settings, it is still important from a treatment perspective to determine the optimal therapeutic window for hypothermia. In a prior review, it was reported that infarct size reduction was often observed when cooling was begun within 60 min of stroke onset in permanent middle cerebral artery (MCA) occlusion models  and within 180 min of stroke onset in temporary MCA occlusion models.  In global cerebral ischemia, hypothermia delayed by 6 h after ischemia onset was reported to be advantageous compared to normothermic control groups, with CA1 hippocampal cell loss as a histologic endpoint.  A study in hippocampal slices subjected to in vitro ischemia showed hippocampal neuron protection when cooling was delayed as late as 8 h.  However, similar delays have not been shown for focal cerebral ischemia.
The optimal duration of therapeutic hypothermia is also not known. Some groups have used brief durations of hypothermia (0.5~5 h), whereas others have used longer periods (12~48 h). In a few studies of focal cerebral ischemia where the duration of intraischemic hypothermia was compared directly, durations of 1-3 h appeared effective, whereas durations between 30 min and 1 h were not effective. , In global cerebral ischemia, intraischemic hypothermia (rectal temperature 28~32°C) completely prevented hippocampal cell damage if continued for 4 h or 6 h, whereas 2 h of hypothermia protected less well and 1 h or 30 min did not protect at all.  Longer durations may be necessary especially when the initiation of cooling is delayed. Some studies showed that postischemic hypothermia merely delayed the onset of irreversible neuronal injury, unless combined with a second neuroprotectant. , However, these latter studies only applied hypothermia for 3 h. Other investigators have shown that prolonged hypothermia initiated 4~6 h after forebrain ischemia for 24 h can provide sustained functional and histological neuroprotection as late as 6 months after ischemia onset.  Rodent data indicated that prolonged reduction in temperature induced robust neuroprotection when hypothermia is delayed by several hours, provided cooling is maintained for more than 24 h.  Thus, the extent of a neuroprotection also appears to be influenced by the length of the delay and the duration of cooling.
In clinical stroke, hypothermia may be a more effective neuroprotection strategy if applied for a long duration after the ischemic event as most patients do not present until hours after the onset of stroke.  Although a long cooling period seems attractive, this may be offset by an increased risk of complications. Furthermore, many studies in animal models were carried out for relatively short time periods, and the cooling duration was somewhat brief. Extensive analysis on the methodological aspects of therapeutic cooling raises questions as to whether the observed effects in the laboratory are durable, and whether studies in young laboratory animals apply to older adult animals with various comorbidities. ,
Hypothermia in brain ischemia
Global cerebral ischemia
Several experimental studies have demonstrated the neuroprotective effects of mild or moderate hypothermia for cardiac arrest (global ischemia). , These studies have shown the durability of this protective effect and have defined a temporal therapeutic window that can be lengthened, provided cooling is prolonged. A global ischemia study in gerbils found that cooling in the range of 30~34°C leads to robust neuroprotection.  Mild hypothermia for 12 h enhances neuroprotection of hippocampal CA1 after a 3 min insult, whereas neuroprotection was less pronounced after a 5 min insult, unless hypothermia was maintained for 24 h.  Thus, longer cooling may be suited for more severe insults.
The clinical benefit of hypothermia has also been demonstrated in two large-scale clinical studies based on data from multiple medical centers conduced in 2002. , These clinical studies showed that mild hypothermia for 12~24 h reduces mortality and improves functional recovery from cardiac attest. , Cooled patients had improved neurological outcome 6 months later, compared to those who were normothermic.  Since then, therapeutic cooling has been increasingly embraced by both tertiary medical centers and community hospitals. ,, However, a recent study comparing cooling of 33°C to 36°C in this patient population showed no difference in outcomes,  thus raising the issue of whether treatment of such patients should really focus on preventing hyperthermia. 
Therapeutic hypothermia has also been shown to be effective in preventing perinatal brain injury from HIE. There have been four clinical trials of newborns with HIE. , These studies have shown benefit in infants with moderate and severe HIE; however, long-term, lifelong benefits are especially key in pediatric populations, and there are no reports of outcomes beyond 21 months of age. This condition has also been studied in the laboratory although not as extensively as in adult models. However, hypothermic protection in neonatal animal models has shown similar associations such as reduced excitatory amino acid accumulation, preservation of metabolic substrates, and inhibition of caspase activation. ,
Focal cerebral ischemia
In abundant studies of experimental stroke (focal cerebral ischemia), mild or moderate hypothermia has been shown to decrease infarct size and lead to functional improvement when cooling was initiated within a few hours of ischemia onset. Hypothermia reduced infarct volume and improved neurological function in the temperature range of 24°C to 33°C. , The timing of hypothermia is important, as studies found that hypothermia initiated within 2~3 h of ischemia onset led to significant neuroprotection. Delays of 2~3 h were neuroprotective when cooling was maintained for either a few hours  or 48 h.  Recently, many experimental studies also demonstrated that reperfusion after ischemic stroke increases the likelihood of a good outcome.  In models of transient middle cerebral artery occlusion (tMCAO), hypothermia consistently showed neuroprotection, whereas in models of permanent MCAO (pMCAO), the results were conflicting. Thus, therapeutic hypothermia in conjunction with reperfusion strategies in clinical trial design becomes important. 
As therapeutic hypothermia was shown to be neuroprotective in cardiac arrest patients, there is hope that hypothermia may similarly reduce morbidity and mortality following ischemic stroke. Indeed, a few preclinical studies show that mild therapeutic hypothermia initiated during acute ischemic stork or after a delay reduces infarct size and mitigates functional impairment in a recent meta-analysis. , In addition to these studies, another study showed feasibility and tolerability as well as regimens to prevent or reduce shivering in the awake stroke patient using intravascular cooling devices to cool acute ischemic stroke patients. , In a recent randomized multicenter study, an endovascular cooling device was used in combination with the administration of a tissue plasminogen activator in acute stroke patients. Here, patients could be treated within 0-6 h of symptom onset followed by endovascular cooling to 33°C for 24 h. While the study was not designed to evaluate relative efficacy of hypothermia treatment, this regimen appeared well tolerated although there was an increased incidence of pneumonia among cooled patients.  However, these studies were all small and larger prospective studies have yet to be published.
Hypothermia in hemorrhagic stroke
Intracerebral hemorrhage (ICH)
ICH is a devastating stroke, and the resulting morbidity and mortality is much higher than ischemic stroke. While less studied compared to ischemic stroke, experimental studies have been directed at determining the pathophysiology of ICH and at identifying effective treatments that includes the study of hypothermia. A few reports have shown that hypothermia reduced brain edema, inflammation, and blood-brain barrier (BBB) disruption after intrastriatal thrombin injections  and following injection of autologous whole blood ,, but this was not as a consistent finding across laboratories. In fact, some laboratories have observed that histological and functional benefits are not consistently found  and one report described increased bleeding in the brain among cooled animals.  Although this appears to depend on the model, insult severity, and timing of treatment, another study of delayed mild hypothermia (48 h) after ICH failed to reduce the lesion size when started soon after collagenase-induced ICH, whereas treatment was delayed 12 h led to neuroprotection.  Although earlier cooling appears more favorable in brain ischemia, studies in brain hemorrhage models found increased bleeding with early cooling (delays to 12 h post collagenase injection) but some protection occurred when cooling was delayed 12-24 h. , It is possible that hypothermia could affect critical procoagulant and thrombolytic systems and predispose to bleeding in the acute period or that hypothermia exacerbated complications of the initial increased blood pressure that occurs in this model. These findings bear further investigation to clarify the reasons for worsening in certain scenarios, and whether cooling might be detrimental if not applied in an optimal manner. At the clinical level, Kollmar et al. recently reported that 12 patients with large ICH were treated with hypothermia to 35°C for 10 days (initiated 3-12 h after symptoms onset) and these patients were compared to data from a local hemorrhage data bank.  In the hypothermia group, edema volume remained stable during 14 days, whereas edema significantly increased in the control group. However, larger controlled clinical trials of hypothermia in ICH are lacking.
Subarachnoid hemorrhage (SAH)
SAH is typically due to aneurysmal rupture, and hypothermia is often used intraoperatively during aneurysm repair. There are several animal model studies of SAH that showed that hypothermia exhibited neuroprotection. Mild hypothermia applied for 2 h led to improved posthemorrhagic neurological deficits and reduced intracranial pressure and postoperative weight gain at 1-7 days if cooling was delayed 3 h after SAH.  Another study demonstrated the neuroprotective effects of hypothermia on acute imaging changes after experimental SAH using diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS).  The investigators established that hypothermia improved early development of cytotoxic edema, lactate accumulation, and general metabolic stress after SAH in the rat. The mechanisms underlying this protective effect have not been explored as extensively as in the brain ischemia models but one study showed that hypothermia interrupted the early expression of genes associated with cellular stress such as c-jun and heat shock protein (Hsp) 70.  At the clinical level, Muroi et al. assessed the anti-inflammatory effects of combining hypothermia and high-dose barbiturates. The inflammatory response in seven patients with this intervention showed decreased systemic and cerebrospinal fluid levels of interleukin (IL)-1β, IL-6, and leukocyte counts compared to a group of eight patients who received no intervention although cooling increased tumor necrosis factor alpha (TNF-α). 
However, in a large multicenter randomized study, mild intraoperative hypothermia during surgery for intracranial aneurysm did not lead to improved neurologic outcomes among patients with mild SAH.  As a follow-up to this study, more recent trials have focused on therapeutic hypothermia for patients with poor grade SAH. One clinical study conducted by Seule et al. evaluated the feasibility and safety of mild hypothermia in patients with poor grade SAH and increased intracranial pressure and/or cerebral vasospasm.  However, there were several complications among cooled patients, leading the investigators to conclude that prolonged systemic hypothermia might be considered a last-resort option for a carefully selected group of younger SAH patients with persistent intracranial hypertension and/or cerebral vasospasm. Thus, the clinical effectiveness of therapeutic cooling for SAH remains unclear.
Mechanisms of hypothermic protection in ischemic stroke
Metabolism and cerebral blood flow (CBF)
The neuroprotective properties of hypothermia have a profound effect on decreasing metabolic rate and reduce blood flow during ischemic stroke.  Hypothermia decreases brain oxygen consumption and glucose metabolism and on an average decreases brain oxygen consumption by approximately 5%/°C fall in body temperature in the range of 22~37°C,  and in anesthetized animals, oxygen consumption decreases linearly when brain temperature is lowered from 38°C to 18°C.  Hypothermia can interrupt downstream consequences of increased lactate production due to dependence on anaerobic metabolism and the development of acidosis by preserving the brain's metabolic stores.  Hypothermia conserves high-energy phosphate compounds such as adenosine triphosphate (ATP) and maintains tissue pH. This may be relative to the effect of hypothermia on brain metabolism that conserves tissue ATP levels. ATP is needed to maintain ion gradients and when these concentration gradients are disturbed, such as in the case of ischemic stroke, calcium influx occurs and leads to increased extracellular glutamate levels.  Several investigators also demonstrated that hypothermia significantly decreases the release of excitotoxic amino acids and subsequent calcium influx due to cerebral ischemia. , Further, the glutamate receptor 2 (GluR2) subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is thought to limit calcium influx. GluR2 suppression by ischemia is thought to increase calcium entry that in turn potentiates neuronal injury. Some investigators have hypothesized that one neuroprotective mechanism of hypothermia is that it could salvage neurons from delayed calcium influx by upregulating GluR 2 receptors.  In a recent work, our group has established that hypothermia decreases ischemia-induced upregulation of calcium influx through a newly characterized calcium-sensing receptor (CaSR). CaSR is thought to sense changes in extracellular calcium levels but also appears to reciprocally downregulate gamma-aminobutyric acid (GABA) receptors, thereby decreasing inhibitory tone. Cerebral ischemia increases expression of CaSR while inhibiting GABA-B-R1 expression, while mild hypothermia prevents this.  Thus, CaSR might be studied as a potential target for treatment of stroke and related conditions. Excitotoxic neurotransmitters are released early after ischemia onset, and it is well known that glutamate antagonists have a rather narrow temporal therapeutic window of 1-2 h even in models of temporary middle cerebral artery occlusion (MCAO). Since earlier cooling is superior to delayed cooling, this may explain some of the protective effect of hypothermia. However, when cooling is applied after glutamate is already released, neuroprotection is still observed,  and points to additional mechanisms of protection.
Hypothermia generally leads to reduced CBF. Under injury conditions such as stroke, CBF decreases linearly between 18 °C and 37°C, and CBF and brain metabolism are preserved at lower temperatures. Ischemic stroke leads to initial CBF decreases as a result of vessel occlusion but upon reperfusion, hyperemia occurs followed by a gradual decline in CBF that occurs over a period of hours. Mild hypothermia reduces this hyperemia and prevents the gradual CBF reduction during reperfusion.  However, the effects of hypothermia on this delayed CBF reduction are conflicting. Some reports showed that hypothermia increases CBF during ischemia, whereas others showed reduced or no effect on CBF.  Reasons for these discrepancies are unclear but could be explained by the dynamic nature of CBF, especially in the poststroke period and the different CBF assays used by different laboratories. Regardless of this, these observations indicate that these mechanisms do not fully explain the protective effect of hypothermia in experimental models.
Early molecular events
Hypothermia also influences the ischemic stress response including the induction of immediate early genes.  Several studies examined the effect of hypothermia on the stress response, namely, the expression of HSPs that are upregulated in response to a variety of cellular stress. Indeed, some investigators have shown that 70 kD inducible Hsp70 was upregulated by ischemic stroke model and was further increased by hypothermia although hypothermia itself did not induce Hsp70 in nonischemic model , and this might be consistent with its neuroprotective properties.  However, other investigators have shown that hypothermia downregulates Hsp70 expression under similar condition,  while others have shown no influence of cooling on its expression.  Thus, it is unclear whether hypothermic neuroprotection is mediated through the stress response. Further, the significance of hypothermia's effect on the immediate early gene is unclear, as no subsequent studies have been carried out to establish causality.
MicroRNAs (miRNAs), a subset of noncoding RNAs, have been a topic of recent investigation in brain injury models. They have been shown to increase in expression as early as 2 h after ischemia onset.  These miRNAs are thought to play a role in silencing mRNA and they have been found to regulate a variety of signaling pathways. The exact roles of specific miRNAs remain under investigation but a report in a model of brain trauma showed that miRNA expression is affected by cooling.  In particular, a few miRNAs including miR-874 and miR-451 were decreased by cooling. These same investigators then overexpressed miR-34a, miR-451, and miR-874 in cultured neurons and found that these miRNAs led to increased cellular vulnerability to stretch injury, suggesting that one mechanism of hypothermic protection might be through the downregulation of these miRNAs. 
Several studies have examined the influence of hypothermia on cell death via apoptosis. There are two main apoptotic pathways: the intrinsic pathway that occurs within the cell at the level of the mitochondria and the extrinsic pathway that is triggered via a cell surface receptor.  Hypothermia interrupts apoptosis through both pathways but whether cooling has any effect on neuron survival depends on whether apoptosis is occurring in a given model or paradigm. In models of global cerebral ischemia, hypothermia can interfere with the expression of Bcl-2 family members such as Bax and Bcl-2. Hypothermia has also been shown to reduce cytochrome c release and decrease caspase activation. Downstream of Bcl-2 family proteins, protein kinase C delta (PKC-delta) (a protein kinase C isoform) has been shown to contribute negatively to ischemic injury.  Caspase-3 leads to transport of PKC-delta from the cytosol to the mitochondria and nucleus, where it interacts with other molecules to induce apoptosis.  In contrast, a different isoform, epsilon-PKC is antiapoptotic, and is degraded by caspases. Hypothermia did not appear to alter overall levels of PKC-delta,  but it blocked its translocation to the mitochondria and the nucleus and stimulated the activity of epsilon-PKC after ischemia. 
Extrinsic apoptotic pathways also appear to be activated by brain ischemia. The most widely studied apoptosis-inducing receptor and ligand are Fas and Fas ligand (FasL), respectively. How FasL binds Fas is somewhat unclear, as many reports indicate that FasL must be present on the cell's surface in order to engage Fas but other reports indicate that FasL must first be cleaved from the surface by activated matrix metalloproteinases (MMPs) and solubilized. Hypothermia seems to prevent this cleavage, as levels of soluble FASL are decreased in cooled rodent brains, as are the levels of several MMPs. , The decreased level of soluble FASL was also associated with decreased caspase-8 activation. 
In models of more severe stroke (MCAO of 2 h or longer), hypothermia does not appear to affect Bcl-2 family members or caspase activation but prevents cytochrome c release.  These observations might be explained by a third apoptotic pathway that involves direct cell death by mitochondrial apoptosis-inducing factor (AIF) release. Hypothermia was shown to reduce apoptotic cell death in a more severe model of MCAO while suppressing AIF translocation. 
Other studies have also investigated other molecules implicated in apoptotic pathways that have been shown to be affected by hypothermia as well. Phosphatase and tensin homolog (PTEN) is a tumor suppressor molecule with proapoptotic functions. PTEN deletion has previously been shown to prevent ischemic brain injury.  However, PTEN phosphorylation leads to its deactivation and is normally decreased by brain ischemia.  Under conditions of neuroprotective hypothermia, phosphorylated PTEN levels remained unchanged but were decreased under nonneuroprotective hypothermia.  Thus, the deactivated form of this proapoptotic protein seems to correlate to neuroprotection.
Several neurotrophic factors in the brain have been studied with regard to their therapeutic potential in acute ischemic stroke. These factors are involved in multiple neuronal cell processes such as synaptic function and plasticity and to sustain neuronal cell differentiation. In brain ischemia models, exogenous administration of one or more of these factors seemed to improve functional neurological outcome without necessarily affecting the lesion size. Hypothermia increased several of these factors including brain-derived neurotrophic factor (BDNF) after ischemic brain insults, , glial-derived neurotrophic factor (GDNF)  and neurotrophin.  Hypothermia also activated extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation, a downstream element of BDNF signaling.  In other cases, hypothermia has been reported to induce protective effects of ERK1/2. 
Studies of hypothermia on survival signals such as Bcl-2 and Akt have been reported. Hypothermia appears to upregulate Bcl-2, and promotes activation of Akt. , After phosphorylation by phosphoinositol 3-kinase (PI3K), activated Akt phosphorylates (and thus inactivates) proapoptotic proteins such as glycogen synthase-3beta (GSK-3beta) and Bcl-xL/Bcl-2-associated death promoter (BAD). In a animal model of cerebral ischemia, hypothermia reduced infarct size by maintaining Akt activity. This effect disappeared when an Akt inhibitor was added to hypothermia. 
Interestingly, although hypothermia downregulates a majority of cell death pathways, it also upreglates several cell survival and growth pathways. Hypothermia has been shown to upregulate a family of cold shock protein such as cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3), , that might be relevant to neuroprotection after ischemic stroke. CIRP has been speculated to protect and restore native RNA conformation during stress, and protects against apoptosis by upregulating ERK. RBM3 may the protect the brain from injury, as protection from cooling is no longer possible with gene knockdown in cultured neurons.  Further, in a model of Alzheimer's, RBM3 appeared to be important in synapse regeneration, and synapse loss could be prevented by cooling or RBM3 overexpression.  Using a model of apoptosis in the brain slices and neuron cultures, Chip et al.  showed that the cold shock protein RBM3 was induced by hypothermia, and its knockdown prevented any protective effect of cooling. In an in vitro model of neuronal apoptosis, CIRP overexpression led to the inhibition of apoptosis in a manner similar to that of hypothermia.  Thus, cold shock responses and corresponding proteins may prove to be important mechanisms underlying hypothermic protection, especially when such protection cannot be fully explained by salutary changes in brain metabolism, CBF, and excitotoxin release.
Inflammation is well-known to accompany a variety of acute neurological conditions such as stroke and other neuronal damage. Dead cells are known to trigger the activation of several immune responses via microglia and infiltrating immune cells from the circulation.  Further, there is evidence that brain cells not normally viewed as immunologic, including astrocytes and even neurons, can elaborate immune molecules. Several animal studies have now shown that inhibiting various aspects of this immune response by hypothermia may improve outcome following brain ischemia and injury.  Following ischemic stroke, inflammation can be detected within a few hours after the onset of the insult. Due to the acute nature of these brain insults, the ensuing immune response is most likely innate, rather than adaptive. The innate immune response is a triggered by signals that, unlike the adaptive immune response, do not require antigen recognition. Mild and moderate hypothermia influence several inflammatory response pathways.  Microglia play an important role in this innate response.  They display a ramified appearance while in the resting state but when activated, undergo a series of morphologic changes often leading to an amoeboid morphology. Microglial activation is the initial step in the CNS inflammatory response. Depending on the stimulus, this step may be followed by infiltration of circulating monocytes, neutrophils, and T cells, and by reactive astrocytosis.  Microglial activation is a complex series of events and the changes associated with microglial activation vary depending on the type, severity, and duration of the stimulus.  Hypothermia appears to decrease tissue density and the activation of microglia.
Endogenous immune stimulators, collectively referred to as damage-associated molecular patterns (DAMPs) are increased after ischemia. DAMPs include hyaluronan, surfactant protein, and uric acid. These substances can then bind to and stimulate receptors on microglia and other immune cells leading to the upregulation of many immune mediators through activation of several proinflammatory transcription factors including nuclear factor kappa B (NF-kB),  hypoxia-inducible factor 1 (HIF-1), interferon regulator factor 1, and signal transducer and activator of transcription 3 (STAT3).  Several studies showed that hypothermia also suppresses NF-kB, a transcription factor that activates many inflammation-related genes. NF-kB is normally present in the cytosol bound to its inhibitor protein IkB. When activated, IkB kinase (IKK) degrades IkB and releases NF-kB to enter the nucleus where it binds its consensus sequences. In focal cerebral ischemia, hypothermia inhibited IKK activity and prevented NF-kB translocation to the nucleus.  However, in a model of global ischemia, hypothermia appeared to associate with NF-kB, and IkB and IKK were unaffected.  Hypothermia also attenuated phosphorylation of STAT-3 that suppressed intercellular adhesion molecule-1 (ICAM-1) induction in the vascular system of stroke models. 
Cytokines were originally described as mediators involved in regulating the innate and adaptive immune systems. Cytokines are quickly and extensively upregulated in the brain in a variety of disease states. , The most studied cytokines related to inflammation in acute brain injury are tumor necrosis factor-α (TNF-α), the ILs, especially IL-1, IL-4, IL-6, IL-10, and IL-18 and transforming growth factor (TGF)-β. Among these cytokines, mild hypothermia can reduce the expression levels of pro-inflammatory cytokine (IL-1β) and TNF- α in ischemic area. , However, hypothermia also suppressed anti-inflammatory cytokines such as IL-10 and TGF-beta. 
Oxidative and nitrosative stresses may play a central role in this inflammatory response. ROS are also released by inflammatory cells. Studies have now shown that hypothermia attenuates ROS formation.  Similarly, nitrosative stresses include the increase of nitric oxide (NO) via the different nitric oxide synthase (NOS) isoforms, particularly the inducible NOS (iNOS) that is primarily found in immune cells.  In experimental stroke, hypothermia significantly attenuates increases in NOS isoforms  and subsequent NO generation. 
While hypothermia's effect on inflammation is largely suppressive, some immune signaling pathways may be important to stroke outcome. Recent work from our laboratory showed that while hypothermia largely suppressed microglial activation, selective upregulation of the novel innate immune receptor, triggering receptor expressed on myeloid cells-2 (TREM-2) was actually higher among microglia in brains protected by therapeutic cooling.  Deficiency of TREM-2 led to impaired phagocytosis and exacerbation of outcome in experimental stroke.  Thus, therapeutic cooling appears to differentially express immune molecules in such a way as to promote cell survival.
Blood-brain barrier and edema
Secondary injury due to BBB disruption leads to edema and hemorrhage. Studies have shown that mild and moderate hypothermia protects the BBB  and reduces edema formation  and attenuates loss of vascular basement proteins.  MMPs are proteases that break down the extracellular matrix, and disrupt the BBB leading to further infiltration of circulating immune cells, serum proteins and hemorrhage.  Inactivated MMPs are normally found in the cytosol, but in pathologic states, are transported extracellularly where they are cleaved to an active form and degrade substrates of the extracellular matrix.  MMP-2, -3, and -9 have been described in cerebral ischemia but MMP-9 appears to be expressed in traditional immune cells. Neutrophil MMP-9 expression after stroke correlates to worse outcome.  Studies using bone marrow chimeras suggest that MMP-9 derived from circulating leukocytes contributes significantly to stroke pathology.  Hypothermia reduces proteolytic activities of MMPs and consequent degradation of vascular basement membrane proteins  and the extracellular matrix. ,, Hypothermia also prevented the degradation of extracellular matrix proteins agrin and laminin, both targets of activated MMPs.  In addition to suppressing MMPs, hypothermia has been shown to increase expression of endogenous MMP inhibitors such as tissue inhibitor of metalloproteinase-2 (TIMP-2). 
Brain edema also results from upregulation of water channel proteins known as the aquaporins. Aquaporins facilitate water flux through the plasma membrane. In rodent brain, several studies have demonstrated the presence of different aquaporins. Among these aquaprins, aquaprin-4 (AQP4) is the predominant type of aquaporin in the microvasculature of the brain, present on astrocytic end-feet in contact with brain vessels. AQP4 expression is increased in reactive astrocytes in cerebral ischemic lesions,  and its deficiency has been shown to reduce brain edema following MCAO.  Mild hypothermia reduced brain edema formation by suppressing AQP4 expression in models of ICH  and cardiac arrest. 
Studies have also shown that hypothermia reduces brain hemorrhage which result from ischemic stroke (hemorrhagic transformation).  However, in models of protease-induced brain hemorrhage, hypothermia has resulted in conflicting results. Although several laboratories have shown neurological improvement in primary brain hemorrhage models, others reported no effect or even worsening outcomes. , This may be because hypothermia causes a potential deficit in fibrinogen availability and a delay in thrombin generation, thereby inhibiting coagulation pathways. The net result of cooling may thus, lead to an increase in bleeding and exacerbation of hemorrhage.  Thus, hypothermia may be a less effective treatment in brain hemorrhage than in brain ischemia.
Recovery and repair
Studies investigating the long-term impact of hypothermia have observed trends after acute phases of injury and treatment, from weeks to months after cooling has ceased. Recent work concerning the question of hypothermia's lasting effects has specifically examined ongoing recovery and repair mechanisms after insults such as focal cerebral ischemia and traumatic brain injury.  Though the research has yet to reach a detailed consensus on the matter, studies have identified correlations between therapeutic hypothermia and the injured brain's regenerative capacity in stem-cell retention, neuronal synaptic connectivity repair, and neurogenesis as well as gliogenesis and angiogenesis.
Neurons in the injured brain are known to change morphology and lose synaptic connectivity as they undergo cell death.  More recent research has shown that, concurrent to neuronal loss, endogenous recovery mechanisms are also activated after injury, leading to some neurogenesis and synaptogenesis. Though neurogenesis appears rarely in the injured brain,  rodent studies have shown that acute brain insults initiate the proliferation of neural stem cells in the subventricular and subgranular zones.  However, spontaneous recovery by neurogenesis is limited in brain injury, and there is an obvious need to develop strategies to improve regenerative processes including the proliferation of neuronal precursor cells, migration of precursor cells to the injury area, differentiation into mature neurons, and reconnection between neurons. 
To date, the relationship between hypothermia and neurogenesis has only been studied by a few groups and is far from clear. Studies examining mild hypothermia in cultured neural stem cells showed decreased apoptosis, an increase in nestin-positive cells, and inhibition of stem cell differentiation into astrocytes,  suggesting an overall inductive role for hypothermia in neurogenesis. However, the effects of hypothermia on neurogenesis have also been shown to vary according to conditions such as age, injured versus noninjured state, and the severity or duration of hypothermia. One study in the developing brain showed that cooling to 30°C for 21 h decreased the number of proliferating cells in the subgranular zone of the hippocampus but not in the periventricular zone.  After hypoxic-ischemic injury, cooling the developing brain to 33°C showed an increase in neural progenitor cell differentiation in the striatum as well as protection of proliferating neural stem cells that had been produced in response to ischemic stimuli.  This pattern of reduced neural stem cell apoptosis has been associated with hypothermia-induced increases in the expression of Bcl-2. Meanwhile, forebrain ischemia studies in adult rodents showed that mild hypothermia increased neurogenesis in the dentate gyrus relative to similarly injured normothermic animals.  Another study involving adult rats and forebrain ischemia showed that cooling after injury had no effect on neurogenesis.  This second study employed a similar model of forebrain ischemia but a shorter window of hypothermia (33°C for 45 min) that was applied either in the acute and subacute phases of stroke, whether during injury or the immediate reperfusion phase.  The findings in the adult brain suggest that hypothermia can only influence neurogenesis within time windows that remain poorly defined.
Reports of hypothermia's effects on endogenous cell genesis in injured brains relative to uninjured brains have been inconsistent. There are conflicting reports as to whether hypothermia suppresses stem cell proliferation , or induces it; , some even suggest that hypothermia may preferentially promote cell differentiation toward neurogenesis over gliogenesis. Studies also indicate that the effect of hypothermia on gliogenesis is dependent on cooling temperature. Hypothermia to temperatures lower than 30°C has been shown to induce apoptosis/necrosis and cell cycle arrest as a result of reduced energy supply, thereby suppressing cell proliferation. , On the contrary, mild hypothermia has shown to be protective against progenitor cell death. ,
Brain injury studies have observed astrogliogenesis and angiogenesis contributing to brain recovery following insult. , As of yet, the role of newborn astrocytes or endothelial cells in the brain has not been studied extensively. Astrocytes comprise the largest population of cells in the ischemic core following the acute period of stroke.  Glial scarring is thought to obstruct new neurite outgrowth. , However, the inhibition of astrocytic activation can exacerbate injury responses.  As for angiogenesis, mild hypothermia has been observed to increase angiogenic signals in focal ischemia,  spinal cord injury,  and traumatic brain injury models  but the research has yet to qualify the significance of these trends. In fact, some of the research suggests that angiogenesis may be detrimental to brain repair. One clinical study measured the levels of angiogenic factors in samples from acute stroke patients including platelet-derived growth factors (PDGFs), vascular endothelial growth factors (VEGFs) and their receptors, stromal cell-derived factor 1 (SDF-1), and hepatocyte growth factor (HGF). The study concluded that acute antiangiogenic status predicted worse long-term functional outcomes. However, the data also showed that an early predominance of proangiogenic factors is associated with milder short-term neurological deficits. 
Though less well-understood, oligodendrocytes are known to respond to brain injury in a manner similar to neurons. Hypothermia has also been shown to attenuate trauma-induced oligodendrocyte death, demyelination, and circuit disruption.  Hypothermia improved survival in primary cultures of mouse oligodendrocyte precursor cells,  demonstrating that cooling can help the prenatal brain retain a greater number of actively replicating, less differentiated oligodendrocyte precursor cells. Meanwhile, an in vivo study of fetal sheep in utero exposed to hypoxic conditions showed that hypothermia (30°C) reduced overall immature oligodedrocyte loss but did not prevent injury-induced decreases in proliferating oligodendrocytes within the periventricular white matter.
Few studies have examined the role of hypothermia on neuronal circuit repair. After stem cell protection and proliferation, repair of synaptic connectivity is crucial to functional recovery after brain injury. Deep hypothermia (17C) showed neurite and axonal outgrowth in brain slices, , suggesting that cooling may have a restorative effect on cell morphology. Mild hypothermia has also been shown to significantly alter hipppocampal gene expression in rat brains after traumatic brain injury. One study identified 133 transcripts altered by brain injury, the expression profiles of which were statistically different between the hypothermic and normothermic groups. Of the 57 transcripts that were upregulated by hypothermia, prominent increases were observed among genes related to synapse organization and biogenesis. While the full effect of cooling in brain repair is still unclear, the current research suggests that therapeutic hypothermia may have a beneficial role under specific conditions, whether by protecting stem cells, promoting their proliferation and differentiation, increasing growth factor signaling, or encouraging the recovery of neural circuitry.
| Conclusions|| |
Hypothermia has long been known to be a potent neuroprotective intervention that preserves tissues and limits injury after ischemic stroke. Experimental evidence and clinical experience show that induced hypothermia affects nearly every metabolic, molecular, and cellular event in cell death to promote tissue preservation. More recent insights suggest that hypothermia can also favorably modulate endogenous regenerative and restorative properties. The many ways therapeutic hypothermia effects protection has shown that the goal of neuroprotection requires multitarget approaches after acute ischemic stroke.
It may also be possible to extend the therapeutic window for other neuroprotective treatments by hypothermia, and combination therapies with neuroprotective drugs such as anti-inflammatory and thrombolytic agents. This effect of hypothermia may lead to the reexamination of the many failed neuroprotectant drugs at the clinical level since many drugs may not have been studied under optimal conditions. In spite of the robust protective effect demonstrated in the laboratory, there are still clinical obstacles to overcome including effective cooling in humans, prevention of harmful side-effects, and identifying patient populations most likely to benefit. There is also a need to develop more sophisticated translational research tools in the laboratory. Animal models and the method of cooling used in the laboratory are quite different from those employed clinically. Thus, an effort to simulate the clinical condition more precisely might provide solutions for better and wider application of therapeutic hypothermia in human patients. Second, there are few investigations into overcoming the complications of systemic hypothermia such as shivering, infection, and coagulopathies. Though these complications are largely ignored in the laboratory, they are significant at the clinical level and will need to be addressed.
As such, it seems wise to approach stroke therapy with combination therapies including neuroprotective, anti-inflammatory, and antiapoptotic treatments plus recanalization. In essence, the usage of combination therapies do all that cooling does without the risks.
This work was supported by grants from the National Institutes of Health (NS40516), and the Veteran's Merit Award to MY and an American Heart Association Western States Affiliate Postdoctoral Fellowship (13POST14810019) to JYK. These grants were administered by the Northern California Institute for Research and Education and supported by resources of the Veterans Affairs Medical Center, San Francisco, California, USA.
Financial support and sponsorship
NIH, AHA, VA merit.
Conflicts of interest
There are no conflicts of interest.
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