Presently, few treatments for spinal cord injury (SCI) are available and none have facilitated neural regeneration and/or significant functional improvement. Agmatine (Agm), a guanidinium compound formed from decarboxylation of L-arginine by arginine decarboxylase, is a neurotransmitter/neuromodulator and been reported to exert neuroprotective effects in central nervous system injury models including SCI. The purpose of this study was to demonstrate the multifaceted effects of Agm on functional recovery and remyelinating events following SCI. Compression SCI in mice was produced by placing a 15 g/mm2 weight for 1 min at thoracic vertebra (Th) 9 segment. Mice that received an intraperitoneal (i.p.) injection of Agm (100 mg/kg/day) within 1 hour after SCI until 35 days showed improvement in locomotor recovery and bladder function. Emphasis was made on the analysis of remyelination events, neuronal cell preservation and ablation of glial scar area following SCI. Agm treatment significantly inhibited the demyelination events, neuronal loss and glial scar around the lesion site. In light of recent findings that expressions of bone morphogenetic proteins (BMPs) are modulated in the neuronal and glial cell population after SCI, we hypothesized whether Agm could modulate BMP- 2/4/7 expressions in neurons, astrocytes, oligodendrocytes and play key role in promoting the neuronal and glial cell survival in the injured spinal cord. The results from computer assisted stereological toolbox analysis (CAST) demonstrate that Agm treatment dramatically increased BMP- 2/7 expressions in neurons and oligodendrocytes. On the other hand, BMP- 4 expressions were significantly decreased in astrocytes and oligodendrocytes around the lesion site. Together, our results reveal that Agm treatment improved neurological and histological outcomes, induced oligodendrogenesis, protected neurons, and decreased glial scar formation through modulating the BMP- 2/4/7 expressions following SCI.

Objective

Reperfusion after stroke leads to infiltration of inflammatory cells into the ischemic brain. NADPH oxidase (NOX2) is a major enzyme system which generates superoxide in immune cells. We studied the effect of NOX2 derived from the immune cells in the brain and in blood cells in experimental stroke.

Methods

To establish whether NOX2 plays a role in brain ischemia, strokes were created in mice, then mice were treated with the NOX2 inhibitor, apocynin or vehicle and compared to mice deficient in NOX2's gp91 subunit and their wildtype littermates. To determine whether NOX2 in circulating cells versus brain resident cells contribute to ischemic injury, bone marrow chimeras were generated by transplanting bone marrow from wildtype or NOX2 deficient mice into NOX2 or wildtype hosts, respectively.

Results

Apocynin and NOX2 deletion both significantly reduced infarct size, blood-brain barrier disruption and hemorrhagic transformation of the infarcts, compared to untreated wildtype controls. This was associated with decreased MMP-9 expression and reduced loss of tight junction proteins. NOX2 deficient mice receiving wildtype marrow had better outcomes compared to the wildtype mice receiving wildtype marrow. Interestingly, wildtype mice receiving NOX2 deficient marrow had even smaller infarct sizes and less hemorrhage than NOX2 deficient mice receiving wildtype marrow.

Interpretation

This indicates that NOX2, whether present in circulating cells or brain resident cells, contributes to ischemic brain injury and hemorrhage. However, NOX2 from the circulating cells contributed more to the exacerbation of stroke than that from brain resident cells. These data suggest the importance of targeting the peripheral immune system for treatment of stroke.

Hypothermia improves neurological outcome from cardiac arrest. The mechanisms of protection are multifold, but identifying some may be useful in exploring potential therapeutic targets. The extracellular calcium-sensing receptor (CaSR) was originally found in parathyroid cells in which the receptor senses minute changes in extracellular [Ca2+] and promotes Ca2+ influx and intracellular Ca2+ release. The CaSR is broadly expressed in the CNS and colocalized with the inhibitory γ-aminobutyric acid-B receptor 1 (GABA-B-R1). In hippocampal neurons, GABA-B-R1 heterodimerizes with CaSR and suppresses CaSR expression. To study the interplay between these two receptors in the development of ischemic cell death and neuroprotection by hypothermia, we subjected C57/BL6 mice to global cerebral ischemia by performing bilateral carotid artery occlusion (10 min) followed by reperfusion for 1–3 days with or without therapeutic hypothermia (33°C for 3 h at the onset of reperfusion). Terminal deoxynucleotidyl transferase dUTP nick end labeling staining and immunohistochemistry showed that forebrain ischemia increased CaSR expression, decreased GABA-B-R1 expression, and promoted cell death. These changes were particularly evident in hippocampal neurons and could be reversed by mild hypothermia. The induction of CaSR, along with reciprocal decreases in GABA-B-R1 expression, may together potentiate ischemic neuronal death, suggesting a new therapeutic target for treatment of ischemic brain injury.

Mild hypothermia is an established neuroprotectant in the laboratory, showing remarkable and consistent effects across multiple laboratories and models of brain injury. At the clinical level, mild hypothermia has shown benefits in patients who have suffered cardiac arrest and in some pediatric populations suffering hypoxic brain insults. Its role, however, in stroke therapy has yet to be established. Translating preclinical data to the clinical arena presents unique challenges with regard to cooling in patients who are generally awake and may require additional therapies, such as reperfusion. We review the state of therapeutic hypothermia in ischemic and hemorrhagic stroke and provide an outlook for its role in stroke therapy.

A spectrophotometric hemoglobin assay is widely used to estimate the extent of brain hemorrhage by measuring the amount of hemoglobin in the brain. However, this method requires using the entire brain sample, leaving none for histology or other assays. Other widely used measures of gross brain hemorrhage are generally semi-quantitative and can miss subtle differences. Semi-quantitative brain hemorrhage scales may also be subject to bias. Here, we present a method to digitally quantify brain hemorrhage using Photoshop and Image J, and compared this method to the spectrophotometric hemoglobin assay. Male Sprague-Dawley rats received varying amounts of autologous blood injected into the cerebral hemispheres in order to generate different sized hematomas. 24 hours later, the brains were harvested, sectioned, photographed then prepared for the hemoglobin assay. From the brain section photographs, pixels containing hemorrhage were identified by Photoshop® and the optical intensity was measured by Image J. Identification of hemorrhage size using optical intensities strongly correlated to the hemoglobin assay (R=0.94). We conclude that our method can accurately quantify the extent of hemorrhage. An advantage of this technique is that brain tissue can be used for additional studies.

At laboratory and clinical levels, therapeutic hypothermia has been shown to improve neurologic outcomes and mortality following cardiac arrest. We reviewed each cardiac arrest in our community-based Veterans Affairs Medical Center over a three-year period. The majority of cases were in-hospital arrests associated with initial pulseless electrical activity or asystole. Of a total of 100 patients suffering 118 cardiac arrests, 29 arrests involved comatose survivors, with eight patients completing therapeutic cooling. Cerebral performance category scores at discharge and six months were significantly better in the cooled cohort versus the noncooled cohort, and, in every case except for one, cooling was offered for appropriate reasons. Mean time to initiation of cooling protocol was 3.7 hours and mean time to goal temperature of 33°C was 8.8 hours, and few complications clearly related to cooling were noted in our case series. While in-patient hospital mortality of cardiac arrest was high at 65% mortality during hospital admission, therapeutic hypothermia was safe and feasible at our center. Our cooling times and incidence of favorable outcomes are comparable to previously published reports. This study demonstrates the feasibility of implementing, a cooling protocol a community setting, and the role of neurologists in ensuring effective hospital-wide implementation.

Background

In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors.

Methodology/Principal Findings

Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [3H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha).

Conclusions/Significance

Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.

Following neuronal injury, microglia initiate repair by phagocytosing dead neurons without eliciting inflammation. Prior evidence indicates TREM2 (triggering receptor expressed by myeloid cells-2) promotes phagocytosis and retards inflammation. However, evidence that microglia and neurons directly interact through TREM2 to orchestrate microglial function is lacking. We here demonstrate that TREM2 interacts with endogenous ligands on neurons. Staining with TREM2-Fc identified TREM2 ligands (TREM2-L) on Neuro2A cells and on cultured cortical and dopamine neurons. Apoptosis greatly increased the expression of TREM2-L. Furthermore, apoptotic neurons stimulated TREM2 signaling, and an anti-TREM2 mAb blocked stimulation. To examine the interaction between TREM2 and TREM2-L in phagocytosis, we studied BV2 microglial cells and their engulfment of apoptotic Neuro2A. One of our anti-TREM2 mAb, but not others, reduced engulfment, suggesting the presence of a functional site on TREM2 interacting with neurons. Further, CHO cells transfected with TREM2 conferred phagocytic activity of neuronal cells demonstrating that TREM2 is both required and sufficient for competent uptake of apoptotic neuronal cells. Finally, while TREM2-L are expressed on neurons, TREM2 is not; in the brain, it is found on microglia. TREM2 and TREM2-L form a receptor-ligand pair connecting microglia with apoptotic neurons, directing removal of damaged cells to allow repair.

Background

We previously showed that microglia damage blood brain barrier (BBB) components following ischemic brain insults, but the underlying mechanism(s) is/are not well known. Recent work has established the contribution of toll-like receptor 4 (TLR4) activation to several brain pathologies including ischemia, neurodegeneration and sepsis. The present study established the requirement of microglia for lipopolysaccharide (LPS) mediated endothelial cell death, and explored pathways involved in this toxicity. LPS is a classic TLR4 agonist, and is used here to model aspects of brain conditions where TLR4 stimulation occurs.

Methods/Results

In monocultures, LPS induced death in microglia, but not brain derived endothelial cells (EC). However, LPS increased EC death when cocultured with microglia. LPS led to nitric oxide (NO) and inducible NO synthase (iNOS) induction in microglia, but not in EC. Inhibiting microglial activation by blocking iNOS and other generators of NO or blocking reactive oxygen species (ROS) also prevented injury in these cocultures. To assess the signaling pathway(s) involved, inhibitors of several downstream TLR-4 activated pathways were studied. Inhibitors of NF-κB, JAK-STAT and JNK/SAPK decreased microglial activation and prevented cell death, although the effect of blocking JNK/SAPK was rather modest. Inhibitors of PI3K, ERK, and p38 MAPK had no effect.

Conclusions

We show that LPS-activated microglia promote BBB disruption through injury to endothelial cells, and the specific blockade of JAK-STAT, NF-κB may prove to be especially useful anti-inflammatory strategies to confer cerebrovascular protection.

Hypothermia is a well established cytoprotectant, with remarkable and consistent effects demonstrated across multiple laboratories. At the clinical level, it has recently been shown to improve neurological outcome following cardiac arrest and neonatal hypoxia ischemia. It is increasingly being embraced by the medical community, and could be considered an effective neuroprotectant. Conditions such as brain injury, hepatic encephalopathy and cardiopulmonary bypass seem to benefit from this intervention. It's role in direct myocardial protection is also being explored. A review of the literature has demonstrated that in order to appreciate the maximum benefits of hypothermia, cooling needs to begin soon after the insult, and maintained for relatively long period periods of time. In the case of ischemic stroke, cooling should ideally be applied in conjunction with the re-establishment of cerebral perfusion. Translating this to the clinical arena can be challenging, given the technical challenges of rapidly and stably cooling patients. This review will discuss the application of hypothermia especially as it pertains to its effects neurological outcome, cooling methods, and important parameters in optimizing hypothermic protection.

Minocycline, a tetracycline antibiotic, is now known to protect cells via an anti-inflammatory mechanism. We further explored this effect using an in vitro model of ischemia-like injury to neurons. Coculturing neurons with microglia, the brain's resident immune cell, modestly increased cell death due to oxygen and glucose deprivation (OGD), compared to neurons alone. Treatment of cocultures with minocycline decreased cell death to a level significantly lower than that of neurons alone. Treatment of cocultures with minocycline or inhibitors of various immune mediators, also led to decreased cell death. Importantly, treatment of neuron cultures without added microglia with these same inhibitors of tissue plasminogen activator, matrix metalloproteinases, TNF-alpha and inducible nitric oxide synthase as well as minocycline also led to decreased cell death. Thus, anti-inflammatory treatments appear to be directly protective of neurons from in vitro ischemia.

Pyruvate, a key intermediate in glucose metabolism, was explored as a potential treatment in models of experimental stroke and inflammation. Pyruvate was administered to rodents after the onset of middle cerebral artery occlusion (MCAO). Since the extent of inflammation is often proportional to the size of the infarct, we also studied a group of animals given lipopolysaccharide (LPS) to cause brain inflammation without cell death. Following MCAO, pyruvate did not affect physiological parameters but significantly reduced infarct volume, improved behavioral tests and reduced numbers of neutrophils, microglial and NF-kB activation. Animals given LPS showed increased microglial and NF-kB activation which was almost completely abolished by pyruvate. Lactate, a major metabolite of pyruvate, was increased after pyruvate administration. However, administration of lactate itself did not have any anti-inflammatory effects. Pyruvate protects against ischemia possibly by blocking inflammation, but lactate itself does not appear to explain pyruvate's anti-inflammatory properties.

This chapter will discuss the current knowledge of the contribution of systemic and local inflammation in acute and sub-chronic stages of experimental stroke in both the adult and neonate. It will review the role of specific cell types and interactions among blood cells, endothelium, glia, microglia, the extracellular matrix and neurons – cumulatively called "neurovascular unit" – in stroke induction and evolution. Intracellular inflammatory signaling pathways such as nuclear factor kappa beta and mitogen-activated protein kinases, and mediators produced by inflammatory cells such as cytokines, chemokines, reactive oxygen species and arachidonic acid metabolites, as well as the modifying role of age on these mechanisms, will be reviewed as well as the potential for therapy in stroke and hypoxic-ischemic injury.

Abstract

Mild hypothermia is an established neuroprotectant in the laboratory, showing remarkable and consistent effects across multiple laboratories and models of brain injury. At the clinical level, mild hypothermia has shown benefits in patients who have suffered cardiac arrest and in some pediatric populations suffering hypoxic brain insults. However, a review of the literature has demonstrated that in order to appreciate the maximum benefits of hypothermia, brain cooling needs to begin soon after the insult, maintained for relatively long period periods of time, and, in the case of ischemic stroke, should be applied in conjunction with the re-establishment of cerebral perfusion. Translating this to the clinical arena can be challenging, especially rapid cooling and the re-establishment of perfusion. The addition of a second neuroprotectant could potentially (1) enhance overall protection, (2) prolong the temporal therapeutic window for hypothermia, or (3) provide protection where hypothermic treatment is only transient. Combination therapies resulting in recanalization following ischemic stroke would improve the likelihood of a good outcome, as the experimental literature suggests more consistent neuroprotection against ischemia with reperfusion, than ischemia without. Since recombinant tissue plasiminogen activator (rt-PA) is the only FDA approved treatment for acute ischemic stroke, and acts to recanalize occluded vessels, it is an obvious initial strategy to combine with hypothermia. However, the effects of thrombolytics are also temperature dependent, and the risk of hemorrhage is significant. The experimental data nevertheless seem to favor a combinatorial approach. Thus, in order to apply hypothermia to a broader range of patients, combination strategies should be further investigated.

Mild hypothermia is an established neuroprotectant in the laboratory, showing remarkable and consistent effects across multiple laboratories and models of brain injury. At the clinical level, mild hypothermia has shown benefits in patients who have suffered cardiac arrest and in some pediatric populations suffering hypoxic brain insults. However, a review of the literature has demonstrated that in order to appreciate the maximum benefits of hypothermia, brain cooling needs to begin soon after the insult, maintained for relatively long period periods of time, and, in the case of ischemic stroke, should be applied in conjunction with the re-establishment of cerebral perfusion. Translating this to the clinical arena can be challenging, especially rapid cooling and the reestablishment of perfusion. The addition of a second neuroprotectant could potentially (1) enhance overall protection, (2) prolong the temporal therapeutic window for hypothermia, or (3) provide protection where hypothermic treatment is only transient. Combination therapies resulting in recanalization following ischemic stroke would improve the likelihood of a good outcome, as the experimental literature suggests more consistent neuroprotection against ischemia with reperfusion, than ischemia without. Since recombinant tissue plasiminogen activator (rt-PA) is the only FDA approved treatment for acute ischemic stroke, and acts to recanalize occluded vessels, it is an obvious initial strategy to combine with hypothermia. However, the effects of thrombolytics are also temperature dependent, and the risk of hemorrhage is significant. The experimental data nevertheless seem to favor a combinatorial approach. Thus, in order to apply hypothermia to a broader range of patients, combination strategies should be further investigated.

Hypothermia has long been known to be a potent neuroprotectant. In this mini review, we highlighted clinical experience that hypothermia protects the brain from cerebral injury. We discussed the clinical practice of hypothermia in ischemic stroke. Multiple factors play a significant role in the mechanisms. Clinical application drew first from two clinical trials with comatose patients after cardiac arrest is attractive. The Australian and European study have led to renewed interest in these patients. More and more evidence bring insight into its effects on cerebral ischemia. The type of cooling technique to be used, the duration of cooling and speed of rewarming appear to be key factors in determining whether hypothermia is effective in preventing or mitigating neurological injury. Although until now, there are no clear therapeutic standards of the parameters in therapeutic hypothermia, it is well accepted that cooling should be initiated as soon as possible. By combining hypothermia with other neuroprotectants, it may be possible to enhance protective effects, reduce side effects and lengthen the maximum time. In addition to its neuroprotective properties hypothermia may extend the therapeutic window for other neuroprotective treatment. Thus, combination therapies with neuroprotective, anti-inflammatory and thrombolytic agents are likely to be investigated in the clinical setting in the future.

We previously showed that hypothermia attenuates inflammation in focal cerebral ischemia (FCI) by suppressing activating kinases of nuclear factor-kappa B (NFκB). Here we characterize the inflammatory response in global cerebral ischemia (GCI), and the influence of mild hypothermia. Rodents were subjected to GCI by bilateral carotid artery occlusion. The inflammatory response was accompanied by microglial activation, but not neutrophil infiltration, or blood brain barrier disruption. Mild hypothermia reduced CA1 damage, decreased microglial activation and decreased nuclear NFκB translocation and activation. Similar anti-inflammatory effects of hypothermia were observed in a model of pure brain inflammation that does not cause brain cell death. Primary microglial cultures subjected to oxygen glucose deprivation (OGD) or stimulated with LPS under hypothermic conditions also experienced less activation and less NFκB translocation. However, NFκB regulatory proteins were not affected by hypothermia. The inflammatory response following GCI and hypothermia’s anti-inflammatory mechanism is different from that observed in FCI.

Protection by mild hypothermia has previously been associated with better mitochondrial preservation and suppression of the intrinsic apoptotic pathway. It is also known that the brain may undergo apoptotic death via extrinsic, or receptor mediated pathways, such as that triggered by Fas/FasL. Male Sprague Dawley rats subjected to 2h middle cerebral artery occlusion with 2h intraischemic mild hypothermia (33C) were assayed for Fas, FasL and caspase-8 expression. Ischemia increased Fas, but decreased FasL by ~50–60% at 6 and 24h post insult. Mild hypothermia significantly reduced expression of Fas and processed caspase-8 both by ~50%, but prevented ischemia-induced FasL decreases. Fractionation revealed that soluble/shed FasL (sFasL) was decreased by hypothermia, while membrane-bound FasL (mFasL) increased. To more directly assess the significance of the Fas/FasL pathway in ischemic stroke, primary neuron cultures were exposed to oxygen glucose deprivation. Since FasL is cleaved by matrix metalloproteinases (MMPs), and mild hypothermia decreases MMP expression, treatment with a pan-MMP inhibitor also decreased sFasL. Thus, mild hypothermia is associated with reduced Fas expression and caspase-8 activation. Hypothermia prevented total FasL decreases, and most of it remained membrane bound. These findings reveal new observations regarding the effect of mild hypothermia on the Fas/FasL and MMP systems.

In response to mild ischemic stress, the brain elicits endogenous survival mechanisms to protect cells against a subsequent lethal ischemic stress, referred to as ischemic tolerance. The molecular signals that mediate this protection are thought to involve the expression and activation of multiple kinases, including protein kinase C (PKC). Here we demonstrate that εPKC mediates cerebral ischemic tolerance in vivo. Systemic delivery of ψεRACK, an εPKC-selective peptide activator, confers neuroprotection against a subsequent cerebral ischemic event when delivered immediately prior to stroke. In addition, activation of εPKC by ψεRACK treatment decreases vascular tone in vivo, as demonstrated by a reduction in microvascular cerebral blood flow. Here we demonstrate the role of acute and transient εPKC in early cerebral tolerance in vivo and suggest that extra-parenchymal mechanisms, such as vasoconstriction, may contribute to the conferred protection.

The immature brain is prone to hypoxic-ischemic encephalopathy and stroke. The incidence of arterial stroke in newborns is similar to that in the elderly. However, the pathogenesis of ischemic brain injury is profoundly affected by age at the time of the insult. Necrosis is a dominant type of neuronal cell death in adult brain, whereas widespread neuronal apoptosis is unique for the early postnatal synaptogenesis period. The inflammatory response, in conjunction with excitotoxic and oxidative responses, is the major contributor to ischemic injury in both the immature and adult brain, but there are several areas where these responses diverge. We discuss the contribution of various inflammatory mechanisms to injury and repair after cerebral ischemia in the context of CNS immaturity. In particular, we discuss the role of lower expression of selectins, a more limited leukocyte transmigration, undeveloped complement pathways, a more rapid microglial activation, differences in cytokine and chemokine interplay, and a different threshold to oxidative stress in the immature brain. We also discuss differences in activation of intracellular pathways, especially nuclear factor κB and mitogen-activated protein kinases. Finally, we discuss emerging data on both the supportive and adverse roles of inflammation in plasticity and repair after stroke.

Inflammation following ischemic stroke is known to contribute to injury. NADPH oxidase (NOX) is a major enzyme system originally studied in immune cells that leads to superoxide (O•-) generation. Apocynin is a NOX inhibitor that has been studied as a potential treatment in experimental stroke. Here we explored the effect of different doses of apocynin in a mouse model of 2 h transient middle cerebral artery occlusion (tMCAO) followed by 22 h reperfusion. Apocynin, given intravenously at a dose of 2.5 mg/kg 30 minutes before reperfusion, improved neurological function (P<0.01), reduced infarct volume (P<0.05), and the incidence of cerebral hemorrhage (P<0.05), but not at higher doses of 3.75 and 5 mg/kg, where it actually increased brain hemorrhage. Apocynin also tended to reduce mortality at the lower dose, but not at higher doses. Using hydroethine fluorescence to delineate O•- in the brain, neurons and some microglia/macrophages, but not vascular endothelial cells were found to contain O•-. Apocynin at protective doses markedly prevented ischemia induced increases in O•-. Our data suggested that apocynin can protect against experimental stroke, but with a narrow therapeutic window.

Background and Purpose

The search for effective neuroprotectants remains frustrating, particularly with regard to specific pharmaceuticals. However, laboratory studies have consistently shown remarkable neuroprotection with 2 nonpharmacological strategies—therapeutic hypothermia and ischemic preconditioning. Recent studies have shown that the mechanism of protection underlying both of these treatments is correlated to downregulation of cellular and tissue metabolism. Thus, understanding the mechanisms underlying such robust protective effects could lead to appropriate translation at the clinical level. In fact, hypothermia is already being used at many centers to improve neurological outcome from cardiac arrest.

Methods

A systematic review of both topics is presented in terms of underlying pathophysiological mechanisms and application at the clinical level.

Results

Although the mechanisms of protection for both therapeutic strategies are multifold, both share features of downregulating metabolism. Both therapeutic strategies are robust neuroprotectants, but translating them to the clinical arena is challenging, though not impossible, and clinical studies have shown or suggest benefits of both treatments.

Conclusions

The strategy of metabolic downregulation should be further explored to identify effective neuroprotectants that can be easily applied clinically.

Recent work in the area of stroke and brain ischemia has demonstrated the significance of the inflammatory response accompanying necrotic brain injury. Acutely, this response appears to contribute to ischemic pathology, and anti-inflammatory strategies have become popular. This chapter will discuss the current knowledge of the contribution of systemic and local inflammation in experimental stroke. It will review the role of specific cell types including leukocytes, endothelium, glia, microglia, the extracellular matrix and neurons. Intracellular inflammatory signaling pathways such as nuclear factor kappa beta and mitogen-activated protein kinases, and mediators produced by inflammatory cells such as cytokines, chemokines, reactive oxygen species and arachidonic acid metabolites will be reviewed as well as the potential for therapy in stroke and hypoxic-ischemic injury.