Electron microscopy study of microcirculation in the rat cerebral cortex after total neutron irradiation

It was established that the ultrastructure of blood capillaries of the brain changes during the first six hours following whole-body neutron irradiation of rats (10 Gy) which was indicative of the capillary wall swelling, the increase in the microcirculatory bed permeability, and pericapillary edema development. Those processes seemed to be reversible since during this period no severe destructive changes were detected in the microvessel wall.     

Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation

Cerebral microvessel endothelial cells that form the blood-brain barrier (BBB) have tight junctions (TJ) that are critical for maintaining brain homeostasis and low permeability. Both integral (claudin-1 and occludin) and membrane-associated zonula occluden-1 and -2 (ZO-1 and ZO-2) proteins combine to form these TJ complexes that are anchored to the cytoskeletal architecture (actin). Disruptions of the BBB have been attributed to hypoxic conditions that occur with ischemic stroke, pathologies of decreased perfusion, and high-altitude exposure. The effects of hypoxia and posthypoxic reoxygenation in cerebral microvasculature and corresponding cellular mechanisms involved in disrupting the BBB remain unclear. This study examined hypoxia and posthypoxic reoxygenation effects on paracellular permeability and changes in actin and TJ proteins using primary bovine brain microvessel endothelial cells (BBMEC). Hypoxia induced a 2.6-fold increase in [(14)C]sucrose, a marker of paracellular permeability. This effect was significantly reduced (~58%) with posthypoxic reoxygenation. After hypoxia and posthypoxic reoxygenation, actin expression was increased (1.4- and 2.3-fold, respectively). Whereas little change was observed in TJ protein expression immediately after hypoxia, a twofold increase in expression was seen with posthypoxic reoxygenation. Furthermore, immunofluorescence studies showed alterations in occludin, ZO-1, and ZO-2 protein localization during hypoxia and posthypoxic reoxygenation that correlate with the observed changes in BBMEC permeability. The results of this study show hypoxia-induced changes in paracellular permeability may be due to perturbation of TJ complexes and that posthypoxic reoxygenation reverses these effects.     

The GABA-ergic system and brain edema

It has been shown in rats with experimental toxic and traumatic edemas that picrotoxin (1 mg/kg) removes the antiedematous action of diazepam, phenazepam, phenibut and amizyl and reduces the action of phentolamine. When the dose of picrotoxin is minimized to 0.5 mg/kg such an effect is not observed. Prolonged daily administration of picrotoxin in a dose of 1 mg/kg results in the development of brain edema. It is recommended that GABA-positive drugs be included into a complex of treatment measures for edema.     

Effects of an anti-inflammatory agent of benzamide structure, dexamethasone and indomethacin on experimental cerebral edema induced by phospholipase 2 in rats

Only a few molecules show any efficacy against brain edema. Different methods such as brain copper-wire implantation or arachidonic acid injection are used in the research of active drugs. A new model, involving injection of phospholipase A2, is described. The effect of an anti-inflammatory compound, N-(4,6-dimethyl 2-pyridinyl) benzamide, was evaluated on the three different experimental brain edemas mentioned above; dexamethasone and indomethacin were used as reference drugs. The studied molecule is, like dexamethasone, active on the three brain edema models. It has no direct inhibitory effect on phospholipase A2, cannot block cyclooxygenase activity but does reduce prostaglandin biosynthesis. Other factors, such as dopaminergic and alpha 2-adrenergic agonist activities, could also interfere.     

Nitric oxide mediates hypoxia-induced changes in paracellular permeability of cerebral microvasculature

Ischemic stroke from a reduction in blood flow to the brain microvasculature results in a subsequent decreased delivery of oxygen (i.e., hypoxia) and vital nutrients to endothelial, neuronal, and glial cells. Hypoxia associated with stroke has been shown to increase paracellular permeability of the blood-brain barrier, leading to the release of cellular mediators and brain tissue injury. Whereas reperfusion does not occur in all ischemic strokes, increased permeability has been seen in posthypoxic reoxygenation. Currently, it is unknown whether these deleterious effects result from cellular mechanisms stimulated by decreased oxygen during stroke or posthypoxic reoxygenation stress. This study used primary bovine brain microvessel endothelial cells (BBMECs) to examine the involvement of nitric oxide (NO) as a mediator in hypoxia-induced permeability changes. Hypoxia-induced increased transport of [14C]sucrose across BBMEC monolayers compared with normoxia was attenuated by either posthypoxic reoxygenation or inhibition of NO synthase (NOS). The hypoxia-induced permeability effect was further reduced when NOS inhibition was combined with posthypoxic reoxygenation. Additionally, a significant increase in total NO was seen in BBMECs after hypoxic exposure. This correlation was supported by the increased [14C]sucrose permeability observed when BBMECs were exposed to the NO donor diethylenetriaamine NONOate. Western blot analyses of NOS isoforms showed a significant increase in the inducible isoform after hypoxic exposure with a subsequent reduction in expression on reoxygenation. Results from this study suggest that hypoxia-induced blood-brain barrier breakdown can be diminished by inhibition of NO synthesis, decreased concentration of NO metabolites, and/or reoxygenation.     

Protection of cultured hippocampal neurons in hypoxia and subsequent reoxygenation by antioxidant from the spatially hindered phenols class]

The influence of antioxidant from hindered phenols (U-18) on a hypoxic neurodestructive effect in mouse hippocampal cell cultures was studied. Morphological and biochemical quantitative analysis of neuronal damage showed that U-18 attenuates nerve cell death resultant from 6-7-hour hypoxia and subsequent 12-hour posthypoxic reoxygenation. This antidestructive action of U-18 was observed upon its introduction in nutrient medium both before and immediately after hypoxic period. Thus, our results suggest that peroxidant reactions play a pivotal role in hypoxic neuronal injury and probably participate in this neurodestructive process mainly during posthypoxic reoxygenation period.     

The genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factor.

Cerebral edema and fluid-filled cysts are common accompaniments of brain tumors. They contribute to the mass effect imposed by the primary tumor and are often responsible for a patient''s signs and symptoms. Cerebral edema significantly increases the morbidity associated with tumor biopsy, excision, radiation therapy, and chemotherapy. Both edema and cyst formation are thought to result from a deficiency in the blood-brain barrier, with consequent extravasation of water, electrolytes, and plasma proteins from altered tumor microvessels. The resultant expansion of the cerebral interstitial space contributes to the elevated intracranial pressure observed with brain tumors. Departure from the typical blood-brain barrier microvascular architecture may only partially explain the occurrence of edema and tumor cyst formation. Biochemical mediators have also been implicated in vascular extravasation. Vascular permeability factor or vascular endothelial growth factor (VPF/VEGF) is a protein that has recently been isolated from a variety of tumors including human brain tumors. VPFb is an extraordinarily potent inducer of both microvascular extravasation (edemagenesis) and the formation of new blood vessels (angiogenesis). Its role in tumor growth and progression would therefore appear pivotal. Herein, the author presents an updated account of the investigation of VPF. Historical and clinical perspectives of the study and treatment of tumor associated edema are provided. The efficacy of high-dose dexamethasone in the treatment of neoplastic brain edema is discussed. A hypothetical role for VPF in edemagenesis is presented and discussed. It is hoped that an expanded understanding of the mechanisms responsible for the genesis of edema will ultimately facilitate therapeutic intervention.     

Short-term hypoxia induces a selective death of GABAergic neurons

It is known that brief episodes of hypoxia protect neurons from death caused by global ischemia and hypoxia (hypoxic preconditioning). At the same time, brief hypoxia may cause a phenomenon of posthypoxic hyperexcitability during reoxygenation, which can lead to the death of separate neurons due to their individual differences. In this work we compare the effects of short-term hypoxia on the initiation of preconditioning and posthypoxic hyperexcitability in two populations of neurons: inhibitory GABAergic neurons and excitatory glutamatergic neurons. Preconditioning effect was evaluated according to the suppression of the NMDA-receptor activity. The phenomenon of posthypoxic hyperexcitability was estimated by the appearance of spontaneous synchronized Ca²⁺ spikes in the neuronal network during reoxygenation after each episode of hypoxia. It is shown that the preconditioning effect occurs only in glutamatergic neurons. In the GABAergic neurons the effect of preconditioning was not observed. The activity of NMDA receptors in these neurons was not suppressed but increased after each episode of hypoxia. At the moment of posthypoxic synchronous Ca²⁺-spike generation, a global increase of the cytoplasmic Ca²⁺ concentration occurred in a few of GABAergic neurons, followed by the apoptotic death of these cells. The anti-inflammatory cytokine, interleukin-10 (IL-10) prevented the development of posthypoxic hyperexcitability, inhibiting spontaneous synchronous Ca²⁺ spike, and protected GABAergic neurons from the death, restoring the preconditioning effect in them. PI3-kinase inhibitors wortmannin and LY294002 prevented the IL-10 protective effect abolishing the inhibiting effect of IL-10 on the generation of the Ca²⁺ synchronous spike. These findings point out to the leading role of GABAergic neurons in the development of posthypoxic hyperexcitability. We suggest that the reason for posthypoxic hyperexcitability in the network is a weakening of the inhibiting effect of GABAergic neurons. Activation of different signaling pathways leading to activation of PKB- and PKG-dependent phosphorylation in the neurons of this type represents a possible strategy to protect neurons from death during hypoxia.     

甲泼尼龙琥珀酸钠对外伤性脑水肿患者血清NO、ET、LPO和SOD水平的影响

目的:观察甲泼尼龙琥珀酸钠用于治疗外伤性脑水肿的疗效及对患者血清一氧化氮(NO)、内皮素(ET)、过氧化脂质(LPO)、超氧化物歧化酶(SOD)水平的影响。方法:选择我院2014年11月~2016年11月收治的104例外伤性脑水肿患者,按治疗方式分为对照组与研究组,每组52例。对照组采用常规治疗,研究组在对照组基础上联合甲泼尼龙琥珀酸钠治疗,两组均持续治疗7天。观察并比较两组临床疗效,治疗前后血清NO、ET、LPO、SOD水平、脑水肿体积、神经功能缺损程度评分(NIHSS)、格拉斯哥昏迷评分(GCS)的变化及并发症的发生情况。结果:治疗后,研究组的治疗总有效率高于对照组(P0.05);两组血清NO、SOD、GCS水平均较治疗前显著上升,且研究组明显高于对照组;两组血清ET、LPO、NIHSS、脑水肿体积均较治疗前明显降低,且研究组显著低于对照组,差异均有统计学意义(P0.05)。两组并发症的发生情况比较差异无统计学意义(P0.05)。结论:甲泼尼龙琥珀酸钠可显著提高外伤性脑水肿的临床疗效,可能与其能够有效调节血清NO、ET、LPO、SOD水平有关。     

Cytoprotective effect of iloprost on isolated cortical brain tissue grafts in rats.

The cytoprotective effect of iloprost was studied on isolated embryonic cortical brain tissue grafts of rats, using light and transmission electronmicroscopy. The brain tissue pieces were stored either in saline or 50 ng/ml iloprost solution for 30 minutes, 3, 6, 24 hours at +4 degrees C. It was demonstrated that iloprost significantly protected the neuronal integration of the tissue pieces compared with saline preserved pieces. Tissues preserved in iloprost showed only minimal dissolution of the tissue with minimal extracellular edema only in the later stages of preservation. The mechanism of action of the cytoprotective effect of iloprost is discussed.     

Tin-mesoporphyrin, a potent heme oxygenase inhibitor, for treatment of intracerebral hemorrhage: in vivo and in vitro studies.

Spontaneous intracerebral hemorrhage (ICH) is the stroke subtype with highest mortality and morbidity. ICH can also occur following traumatic brain injury and thrombolysis for ischemic stroke and myocardial infarction. Development of ICH-induced hemispheric edema can elevate intracranial pressure and cause death. In survivors, edema-related white matter injury can lead to life-long neurological deficits. At present, there are no scientifically proven treatments for ICH. Heme oxygenase products, particularly iron and bilirubin, can be toxic to cells. In cerebral ischemia models, metalloporphyrins that are potent heme oxygenase inhibitors, reduce edema and infarct size. Tin-mesoporphyrin (SnMP) is a neuroprotectant that has also been used clinically to treat hyperbilirubinemia. Presently, we tested the hypothesis that SnMP treatment would reduce edema development following experimental ICH. We produced hematomas in pentobarbital-anesthetized pigs (9-11 kg) by infusing autologous blood into the frontal white matter. To maximize tissue concentrations, SnMP (87.5 microM in DMSO) or DMSO (vehicle controls) was included in the infused blood. Pig brains were frozen in situ at 24 hrs. following ICH and hematoma and edema volumes were determined on coronal sections by computer-assisted image analysis. We also examined the effects of SnMP in vitro on ferritin iron release, the formation of iron-induced thiobarbituric acid reactive substances (TBARS) and initial clot formation and hemolysis. SnMP treatment significantly reduced intracerebral mass following ICH. This was due to significant decreases in hematoma (0.68+/-0.08 vs. 1.39+/-0.30 cc, vehicle controls p<0.025) and edema volumes (edema = 1. 16+/-0.33 vs. 1.77+/-0.31 cc, p<0.05). In vitro, SnMP did not stabilize ferritin iron against reductive release nor did it decrease iron-induced TBARS formation in brain homogenates. SnMP or DMSO added to pig blood did not alter clot weights. In conclusion, SnMP reduced intracerebral mass in an ICH model by decreasing both hematoma and edema volumes SnMP's mechanism of action is presently unknown but may involve its potent inhibition of heme oxygenase activity. SnMP's effect appears unrelated to ferritin iron release, antioxidant activity or initial clot formation. Since SnMP treatment could be brain protective following ICH, further investigations into neurological and neuropathological outcomes and as well as into its mechanism of action are warranted.     

Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets

It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.     

Reprint of: Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets

It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.     

Action of lysosomotropic modulators on the thyroid cells of rats

Hydrocortisone, ammonium chloride, pepstatin and contrykal have been studied for their effect on incubated and cultured fragments of rat thyroid gland. It is found that the radioactive iodine uptake by thyroid gland cells is inhibited by hydrocortisone, ammonium chloride and pepstatin. Pepstatin induces formation of vacuoles with nonhydrolyzed thyroglobulin in thyrocytes.     

The effects of trifluoperazine on brain edema,aquaporin-4 expression and metabolic markers during the acute phase of stroke using photothrombotic mouse model

Stroke is the second leading cause of death and the third leading cause of disability globally. Edema is a hallmark of stroke resulting from dysregulation of water homeostasis in the central nervous system (CNS) and plays the major role in stroke-associated morbidity and mortality. The overlap between cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema. Water balance in the brain is tightly regulated, primarily by aquaporin 4 (AQP4) channels, which are mainly expressed in perivascular astrocytic end-feet. Targeting AQP4 could be a useful therapeutic approach for treating brain edema; however, there is no approved drug for stroke treatment that can directly block AQP4. In this study, we demonstrate that the FDA-approved drug trifluoperazine (TFP) effectively reduces cerebral edema during the early acute phase in post-stroke mice using a photothrombotic stroke model. This effect was combined with an inhibition of AQP4 expression at gene and protein levels. Importantly, TFP does not appear to induce any deleterious changes on brain electrolytes or metabolic markers, including total protein or lipid levels. Our results support a possible role for TFP in providing a beneficial extra-osmotic effect on brain energy metabolism, as indicated by the increase of glycogen levels. We propose that targeting AQP4-mediated brain edema using TFP is a viable therapeutic strategy during the early and acute phase of stroke that can be further investigated during later stages to help in developing novel CNS edema therapies.     

Toxic effects of putrescine in rat brain: Polyamines can be involved in the action of excitotoxins

Summary After treatment with putrescine (PUT) 200 mg/kg, i.p., male rats displayed a behavioural pattern that included wet dog shakes and motor inco-ordination. The concentration of PUT in the brain paralleled the severity of clinical signs. Histological examination showed the presence of perivascular edema and moderate spongiosis. These biochemical and histological features were present 2 h after treatment. At 24 h PUT levels in frontal cortex decreased but the histological status of brain tissue remained. Pretreatment with hyperosmolal glycerol did not modify the effect of PUT on the brain content of polyamine or the histological condition at 2 h. These results support a neurotoxic role for putrescine. Such effects were similar to those of kainic acid at convulsant doses, suggesting a role for putrescine in the action of this excitotoxin.     

On the application of cannabis in paediatrics and epileptology

An initial report on the therapeutic application of delta 9-THC (THC) (Dronabinol, Marinol) in 8 children resp. adolescents suffering from the following conditions, is given: neurodegenerative disease, mitochondriopathy, posthypoxic state, epilepsy, posttraumatic reaction. THC effected reduced spasticity, improved dystonia, increased initiative (with low dose), increased interest in the surroundings, and anticonvulsive action. The doses ranged from 0.04 to 0.12 mg/kg body weight a day. The medication was given as an oily solution orally in 7 patients, via percutaneous gastroenterostomy tube in one patient. At higher doses disinhibition and increased restlessness were observed. In several cases treatment was discontinued and in none of them discontinuing resulted in any problems. The possibility that THC-induced effects on ion channels and transmitters may explain its therapeutic activity seen in epileptic patients is discussed.     

Relation between the dynamics of early ultrastructural changes in the cerebral cortex of the rat and radiation dose

The electron microscopic investigation of the sensomotor zone in the cerebral cortex of mature male rats after total neutron and gamma radiation of high doses has demonstrated, that during first three hours after the influence the dynamics of ultrastructural changes in neurons, glial elements and microcirculatory bed depends on the radiation dose. After gamma radiation of 150 Gy, destructive changes in neurons, increased permiability of blood capillaries and development of perivascular edema are noted at earlier time than after radiation dose of 10 Gy. When the greater dose of radiation is used, also earlier reaction of the barrier structures in the brain is observed.     

Role of an Indole-Thiazolidine Molecule PPAR Pan-Agonist and COX Inhibitor on Inflammation and Microcirculatory Damage in Acute Gastric Lesions

The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan) and cyclooxygenase (COX) inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl) gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o.) 1 hour before oral administration of Et/HCl (60%/0.03M). In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME) before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) protein and PPARγ protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPARγ gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPARγ agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO), as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H⁺ in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling neutrophil influx and microcirculatory blood flow mediated by NO.     

Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: relation to nuclear factor kappaB (NF-kappaB), inflammatory gene expression, and leukocyte infiltration

The ubiquitin proteasome system (UPS) is a major cellular protein degradation pathway that involves the modulation of key proteins controlling inflammation, cell cycle regulation and gene expression. Modulation of the UPS with proteasome inhibitors has indicated efficacy in the treatment of several disease states including cancer and neuro-inflammatory disorders. In particular, a series of recent reports have evaluated the pre-clinical efficacy of the proteasome inhibitor MLN519 for the treatment of focal ischemic/reperfusion brain injury in rats. Evidence from these studies indicate that the neuroprotection provided by MLN519 is related to an anti-inflammatory effect linked to the modulation of nuclear factor kappaB (NF-kappaB) activity, attenuation of cytokine (TNF-alpha, IL-1beta, and IL-6) and cellular adhesion molecule (ICAM-1 and E-selectin) expression, and reduction of neutrophil and macrophage infiltration into the injured rat brain. It is the aim of this paper to review the experimental neuroprotection data reported using MLN519 with a focus on the molecular and cellular mechanisms of anti-inflammatory action.