Prevention Of Brain Edema Research Articles

Brain‐Targeted 9‐Phenanthrol‐Loaded Lipid Nanoparticle Prevents Brain Edema after Cerebral Ischemia‐Reperfusion Injury by Inhibiting the Trpm4 Channel in Mice

AbstractBrain edema robustly increases mortality and hinders functional recovery after acute ischemic stroke. However, there are currently no effective therapies available for treating or preventing it. The unchecked opening of the transient receptor potential M4 (TRPM4) channel results in an excessive influx of Na+ and water, which contributes significantly to the formation of brain edema after ischemic stroke. 9‐phenanthrol (9‐Phe), a potent TRPM4 inhibitor, has limited clinical applicability due to its potential cytotoxicity and poor solubility. A brain‐targeting T7 (HAIYPRH)‐modified lipid nanoparticle (LNP) encapsulated 9‐Phe (9‐Phe@T7‐LNP) is designed and synthesized to improve the physicochemical properties and pharmacokinetic properties of 9‐Phe for treating brain edema in vivo. These results demonstrated that 9‐Phe@T7‐LNP can penetrate the intact blood‐brain barrier (BBB) in normal mice and target the brain parenchyma. Moreover, 9‐Phe@T7‐LNP effectively reduced infarct volume and brain edema, prevented neuronal loss and BBB disruption, improved survival, and facilitated neurological function recovery after transient middle cerebral artery occlusion in mice. Additionally, 9‐Phe@T7‐LNP scavenged oxygen‐free radicals and prevented neuronal apoptosis in cultured neurons subjected to oxygen and glucose deprivation/reperfusion. In summary, these findings showed that 9‐Phe@T7‐LNP holds strong potential as a promising targeted therapy for brain edema after stroke, providing superior pharmacological neuroprotection against brain edema.

Ameliorative Effect of Natural Sesquiterpene Alcohol Cedrol Against Cerebral Ischemia Infarction-In Vitro and In Vivo Studies.

Cedrol is a major bioactive compound present in the Cedrus atlantica with numerous biological properties. In this study, we elucidated the neuroprotective properties of cedrol against ischemic infarction in animal and in vitro studies. A cerebral ischemic/reperfusion model was induced in adult Wistar rats, and oxygen-glucose deprivation/reperfusion was induced in SH-SY5Y neuronal cells and treated with different concentrations of cedrol. The percentage of water content, cerebral infarct, and neurological deficit score was assessed in experimental rats. The acetylcholinesterase activity and inflammatory cytokines were quantified to analyze the anti-inflammatory potency of cedrol. Oxidative stress marker malondialdehyde and antioxidants were quantified to evaluate the antioxidant potency of cedrol in an ischemic condition. The neuroprotective potency of cedrol was confirmed by histopathological analysis of the brain tissue of cedrol-treated I/R-induced rats. In in vitro studies, the MTT and LDH assays were performed in cedrol-treated OGD/R SH-SY5Y cells to analyze the cytoprotective effect of cedrol. The anti-inflammatory property of cedrol was confirmed by quantifying the pro-inflammatory cytokine levels in OGD/R-induced cedrol-treated SH-SY5Y cells. The results obtained prove that cedrol significantly prevents brain edema, neurological deficits, acetylcholinesterase activity, and oxidative damage in ischemic-induced rats. It inhibited neuroinflammation in ischemic-induced rats and also in in vitro models. The neuroprotective effect of cedrol during an ischemic condition was authentically established with histological analysis in an animal model and cell survival assays in an in vitro model. Overall, our results confirm that cedrol is a potent alternative drug to treat cerebral ischemia in the future.

Electroacupuncture Therapy Effectively Protects the Rat Brain after Intracerebral Hemorrhage

Objective. Electroacupuncture (Ea) is a useful complementary and alternative therapy for intracerebral hemorrhage (ICH). However, the neurobiological basis for the Ea treatment of ICH is still unclear. The primary aim of the present study was to explore whether Ea prevents brain edema, apoptosis, excitotoxicity, and neuroinflammation in rats after hemorrhagic stroke. Methods. Rats were randomly divided into Sham, Control, and Ea groups. We used modified neurological severity score (mNSS) and gait analysis to estimate neurological function in rats, and PET/CT to assess glucose uptake and the hemorrhagic focus volume. Measurement of the brain water content and TUNEL staining were used to evaluate brain edema and cell apoptosis, respectively. The serum myelin basic protein (MBP), neuron-specific enolase (NSE), calcium-binding protein B (S100B), and tumor necrosis factor-α (TNF-α) concentrations were examined with ELISA. The expression levels of the CD68, GALC, Arg-1, iNOS, NR2A, Glu2R, AQP4, MAP2, GFAP, AQP9, Bcl-2, Bax, and Glu proteins around the hematoma were detected via immunohistochemistry staining. Western blot was used to analyze the levels of the AQP4, AQP9, Bax, Bcl-2, iNOS, and Arg-1 proteins. Results. Ea treatment improved neurological function and reduced the hemorrhagic area and brain water content in rats after ICH. The serum concentrations of MBP, NSE, S100B, and TNF-α all decreased significantly in the Ea group compared with the Control group. Expression levels of the Glu, NR2A, AQP4, AQP9, Bax, GFAP, iNOS, and CD68 proteins in brain tissue surrounding the hematoma were obviously suppressed in ICH rats following Ea treatment. Moreover, Ea stimulation increased the levels of the MAP2, GALC, Glu2R, Arg-1, and Bcl-2 proteins, but reduced the number of TUNEL-positive cells in rats after ICH. Conclusion. The results of this study suggest that Ea may exert neuroprotective effects by suppressing brain edema, apoptosis, excitotoxicity, and neuroinflammation.

The role of periprocedural hemodynamic variables during carotid stenting for the mid-term general mortality in advanced age patients.

Carotid stenting may produce significant bradycardia and/or hypotension. This may have negative short- and long-term effects for the elderly high-risk patients. Their cerebral hemodynamics is with exhausted adaptive capacity because of the multiple cardiovascular risk factors, advanced age, and significant stenosis.

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology.

Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication. Benzodiazepines are the currently accepted treatment for OP-induced convulsions, but the convulsions become refractory to these GABAA agonists and repeated dosing has diminishing effectiveness. As such, adjunct anticonvulsant treatments are needed to provide improved protection against recurrent and prolonged convulsions and the associated excitotoxic CNS damage that results from them. Previously we have shown that brief, 4-min administration of 3%-5% isoflurane in 100% oxygen has profound anticonvulsant and CNS protective effects when administered 30min after a lethal dose of paraoxon. In this report we provide an extended time course of the effectiveness of 5% isoflurane delivered for 5min, ranging from 60 to 180min after a lethal dose of paraoxon in rats. We observed substantial effectiveness in preventing neuronal loss as shown by Fluoro-Jade B staining when isoflurane was administered 1h after paraoxon, with diminishing effectiveness at 90, 120 and 180min. In vivo magnetic resonance imaging (MRI) derived T2 and mean diffusivity (MD) values showed that 5-min isoflurane administration at a concentration of 5% prevents brain edema and tissue damage when administered 1h after a lethal dose of paraoxon. We also observed reduced astrogliosis as shown by GFAP immunohistochemistry. Studies with continuous EEG monitoring are ongoing to demonstrate effectiveness in animal models of soman poisoning.

Potential of Agmatine as a New Neuroprotective Molecule in Brain Disorders

Agmatine, a cationic endogenous polyamine in the central nervous system, is obtained from the decarboxylation of arginine. Agmatine exerts neuroprotective properties, according to a growing body of experimental data. This review aims to describe the present understanding of the involvement of agmatine in the central nervous system and highlight its potential as a new pharmacological therapy as a neuroprotective agent. A few molecular pathways for agmatine’s neuroprotective properties are also highlighted. Several studies have shown that agmatine has neuroprotective properties in a variety of neurological conditions, including stroke and traumatic brain damage. The prevention of brain edema, blood-brain barrier protection, anti-oxidation, anti-apoptosis, and anti-inflammation is some of the proposed neuroprotective mechanisms of agmatine. Agmatine is extremely effective in treating neurological diseases, as evidenced by its safety and low occurrence of side effects. However, the majority of the studies on agmatine that is now accessible were conducted using different experimental models; further, clinical trials are required before agmatine may be used extensively in clinical settings.

Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema.

Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema.

Adaptation of the Brain to Hyponatremia and Its Clinical Implications.

Hyponatremia is the most common electrolyte disorder, occurring in up to 25% of hospitalized patients. Hypo-osmotic hyponatremia when severe and left untreated invariably results in cell swelling, which can lead to fatal consequences, especially in the central nervous system. The brain is particularly vulnerable to the consequences of decreased extracellular osmolarity; because of being encased in the rigid skull, it cannot withstand persistent swelling. Moreover, serum sodium is the major determinant of extracellular ionic balance, which in turn governs crucial brain functions such as the excitability of neurons. For these reasons, the human brain has developed specific ways to adapt to hyponatremia and prevent brain edema. On the other hand, it is well known that rapid correction of chronic and severe hyponatremia can lead to brain demyelination, a condition known as osmotic demyelination syndrome. In this paper, we will discuss the mechanisms of brain adaptation to acute and chronic hyponatremia and the neurological symptoms of these conditions as well as the pathophysiology and prevention of osmotic demyelination syndrome.

Hyperbaric oxygen preconditioning for prevention of acute high-altitude diseases: Fact or fiction?

Acute high-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), have been recognized as potentially lethal diseases for altitude climbers. Various preconditioning stimuli, including hyperbaric oxygen (HBO), have been proposed to prevent acute high-altitude diseases. Herein, we reviewed whether and how HBO preconditioning could affect high-altitude diseases and summarized the results of current trials. Evidence suggests that HBO preconditioning may be a safe and effective preventive method for acute high-altitude diseases. The proposed mechanisms of HBO preconditioning in preventing high-altitude diseases may involve: 1) protection of the blood-brain barrier and prevention of brain edema, 2) inhibition of the inflammatory responses, 3) induction of the hypoxia-inducible factor and its target genes, and 4) increase in antioxidant activity. However, the optimal protocol of HBO preconditioning needs further exploration. Translating the beneficial effects of HBO preconditioning into current practice requires the "conditioning strategies" approach. More large-scale and high-quality randomized controlled studies are needed in the future.

Daidzein Ameliorates Cerebral Ischemic-reperfusion Induced Neuroinflammation in Wistar Rats via Inhibiting NF-κB Signaling Pathway

Background Cerebral ischemia is a condition of acute brain damage due to the depletion of oxygenated blood supply to cerebral tissues. Daidzein is an isoflavonoid predominantly present in soya, Pueraria species, and red cloves. Traditional Chinese medicine utilizes daidzein to alleviate diseases such as inflammation, hyperglycemia, gastric diseases, allergies and aches. The neuroprotective effect of daidzein on cerebral ischemic conditions and its mechanism of action was not yet elucidated. Materials and Methods 24 healthy male adult Wistar rats were grouped into four and the control rats were sham-operated, cerebral ischemic-reperfusion induced rats subjected to middle cerebral artery occlusion (MCAO). Low- and high-dose daidzein rats were treated with 25 and 50 mg/kg daidzein respectively for 7 consecutive days before the induction of cerebral ischemic reperfusion. On completion of treatment, the rats were assessed for neurological deficit scoring and then euthanized for further analysis. The percentage of brain water content and cerebral infarct was evaluated. The ability of daidzein on preventing oxidative stress-induced damage was assessed by quantifying lipid peroxidation and antioxidant levels. The neuroprotective Daidzein was evaluated by measuring the acetylcholinesterase activity and brain ATP levels. The anti-inflammatory role of Daidzein was measured by quantifying the nitric oxide (NO) and inflammatory cytokines. Further, the anti-ischemic role of Daidzein was confirmed by estimating nuclear factor-kappa B (NF-κB) p65 and Caspase 3 levels. Results Daidzein treatment significantly prevented brain edema and cerebral infarction and neurological deficit in cerebral I/R injured rats. It also scavenged the free radicals and prevented the decline in antioxidant levels of ischemic rats. Daidzein decreased the acetylcholinesterase activity, NO, and inflammatory and significantly increased the brain ATP levels signifying its neuroprotective role in ischemic-induced rats. The reduction in the levels of NF-κB p65 and Caspase 3 confirms daidzein prevents neuroinflammation and neuronal apoptosis in ischemic rats. Conclusion Overall our analysis confirms daidzein is a potent neuroprotective drug which can effectively inhibit postischemic complications.

Challenges in Perioperative management of spontaneous acute subdural hematoma in haemophilia patients

Intracranial hemorrhage in patients with hemophilia is associated with high mortality and morbidity. We report a case of 15 years old boy with haemophilia A, who presented with a spontaneous acute subdural hematoma and underwent craniotomy for clot evacuation. The patient also received Factor VIII infusions peri-operatively along with other measures, to decrease blood loss. The patient presented with signs of raised intracranial pressure and received mannitol intra-operatively and postoperatively to prevent brain edema. Hypertonic saline (3 ml/kg of 3% solution) was also given over 30 minutes for brain relaxation. Recommendations for peri-operative preparation and management of haemophilia, especially in the setting of emergency major surgery were also reviewed.

Rapid correction of severe hyponatremia and control of subsequent overcorrection in operative hysteroscopy intravascular absorption syndrome: A case report

Operative hysteroscopy intravascular absorption syndrome (OHIAS) results from systemic absorption of hypotonic solution during hysteroscopy, which may induce severe hyponatremia within hours. Depending on the serum sodium (Na+) level, this can be life-threatening and requires prompt and careful remedial treatment. A 53-year-old woman underwent hysteroscopic myomectomy for submucosal leiomyoma. Approximately 3 hours postoperatively, the serum Na+ level decreased to 82 mM/L, accompanied by pulmonary edema and lactic acidosis. The patient was strongly suspicious of OHIAS. A rapid correction was made using 3% NaCl to prevent brain edema as an initial response. After the serum Na+ level reached 120 mM/L, gradual correction was performed considering osmotic demyelination syndrome, and desmopressin was administered to prevent overcorrection caused by excessive water diuresis. Serum Na+ level normalized in 4 days and the patient recovered without any specific sequelae. The detection of OHIAS may be delayed under general anesthesia, and prior vigilance is important if the operation time is prolonged. In severe hyponatremia with an apparently rapid onset, such as OHIAS, a two-step correction process may be safe and useful: rapid correction followed by more gradual correction.

Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation In Microglia.

Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. However, it remains unknown whether the anti-inflammatory effect of GLB is independent of its role in preventing brain edema, and how GLB inhibits the NLRP3 inflammasome is not fully understood. Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. The Trpm4 siRNA and GLB were injected to block sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel in rats. Western blotting, quantitative real-time polymerase chain reaction, behavioral analysis, and histological examination were used to evaluate the role of GLB in preventing NLRP3-mediated neuroinflammation through inhibiting SUR1-TRPM4, and corresponding neuroprotective effect. To further explore the underlying mechanism, BV2 cells were subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion. Here, in rat model of cardiac arrest with brain edema combined with neuroinflammation, GLB significantly alleviated neurocognitive deficit and neuropathological damage, via the inhibition of microglial NLRP3 inflammasome activation by blocking SUR1-TRPM4. Of note, the above effects of GLB could be achieved by knockdown of Trpm4. In vitro under circumstance of eliminating distractions from brain edema, SUR1-TRPM4 and NLRP3 inflammasome were also activated in BV2 cells subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion, which could be blocked by GLB or 9-phenanthrol, a TRPM4 inhibitor. Importantly, activation of SUR1-TRPM4 in BV2 cells required the P2X7 receptor-mediated Ca2+ influx, which in turn magnified the K+ efflux via the Na+ influx-driven opening of K+ channels, leading to the NLRP3 inflammasome activation. These findings suggest that GLB has a direct anti-inflammatory neuroprotective effect independent of its role in preventing brain edema, through inhibition of SUR1-TRPM4 which amplifies K+ efflux and promotes NLRP3 inflammasome activation.

A Novel Targeted Nanoparticle for Traumatic Brain Injury Treatment: Combined Effect of ROS Depletion and Calcium Overload Inhibition.

Survival after severe traumatic brain injury (TBI) depends on minimizing or avoiding secondary insults to the brain. Overproduction of reactive oxygen species (ROS) and Ca2+ influx at the damaged site are the key factors that cause secondary injury upon TBI. Herein, a TBI-targeted lipid covered radical scavenger nanoparticle is developed to deliver nimodipine (Np) (CL-PPS/Np), in order to inhibit Ca2+ influx in neurons by Np and to scavenge ROS in the brain trauma microenvironment by poly(propylene sulfide)60 (PPS60 ) and thus prevent TBI-associated secondary injury. In post-TBI models, CL-PPS/Np effectively accumulates into the wound cavity and prolongs the time of systemic circulation of Np. CL-PPS/Np can markedly protect the integrity of blood-brain barrier, prevent brain edema, reduce cell death and inflammatory responses, and promote functional recovery after TBI. These findings may provide a new therapy for TBI to prevent the spread of the secondary injury.

Resveratrol prevents brain edema, blood-brain barrier permeability, and altered aquaporin profile in autism animal model.

Autism spectrum disorder can present a plethora of clinical conditions associated with the disorder, such as greater brain volume in the first years of life in a significant percentage of patients. We aimed to evaluate the brain water content, the blood-brain barrier permeability, and the expression of aquaporin 1 and 4, and GFAP in a valproic acid-animal model, assessing the effect of resveratrol. On postnatal day 30, Wistar rats of the valproic acid group showed greater permeability of the blood-brain barrier to the Evans blue dye and a higher proportion of brain water volume, prevented both by resveratrol. Prenatal exposition to valproic acid diminished aquaporin 1 in the choroid plexus, in the primary somatosensory area, in the amygdala region, and in the medial prefrontal cortex, reduced aquaporin 4 in medial prefrontal cortex and increased aquaporin 4 levels in primary somatosensory area (with resveratrol prevention). Valproic acid exposition also increased the number of astrocytes and GFAP fluorescence in both primary somatosensory area and medial prefrontal cortex. In medial prefrontal cortex, resveratrol prevented the increased fluorescence. Finally, there was an effect of resveratrol per se on the number of astrocytes and GFAP fluorescence in the amygdala region and in the hippocampus. Thus, this work demonstrates significant changes in blood-brain barrier permeability, edema formation, distribution of aquaporin 1 and 4, in addition to astrocytes profile in the animal model of autism, as well as the use of resveratrol as a tool to investigate the mechanisms involved in the pathophysiology of autism spectrum disorder.

Improved spatial memory, neurobehavioral outcomes, and neuroprotective effect after progesterone administration in ovariectomized rats with traumatic brain injury: Role of RU486 progesterone receptor antagonist.

Objective(s):The contribution of classic progesterone receptors (PR) in interceding the neuroprotective efficacy of progesterone (P4) on the prevention of brain edema and long-time behavioral disturbances was assessed in traumatic brain injury (TBI). Materials and Methods:Female Wistar rats were ovariectomized and apportioned into 6 groups: sham, TBI, oil, P4, vehicle, and RU486. P4 or oil was injected following TBI. The antagonist of PR (RU486) or DMSO was administered before TBI. The brain edema and destruction of the blood-brain barrier (BBB) were determined. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and beam walk (BW) task were evaluated previously and at various times post-trauma. Long-time locomotor and cognitive consequences were measured one day before and on days 3, 7, 14, and 21 after the trauma. Results:RU486 eliminated the inhibitory effects of P4 on brain edema and BBB leakage (P<0.05, P<0.001, respectively). RU486 inhibited the decremental effect of P4 on ICP as well as the increasing effect of P4 on CPP (P<0.001) after TBI. Also, RU486 inhibited the effect of P4 on the increase in traversal time and reduction in vestibulomotor score in the BW task (P<0.001). TBI induced motor, cognitive, and anxiety-like disorders, which lasted for 3 weeks after TBI; but, P4 prevented these cognitive and behavioral abnormalities (P<0.05), and RU486 opposed this P4 effect (P<0.001). Conclusion:The classic progesterone receptors have neuroprotective effects and prevent long-time behavioral and memory deficiency after brain trauma.

Reperfusion combined with intraarterial administration of resveratrol-loaded nanoparticles improved cerebral ischemia–reperfusion injury in rats

Endovascular thrombectomy (EVT) has been recommended as the first line therapy for large artery occlusion (LAO) stroke. However, abrupt recovery of blood flow induces oxidative stress which breaks down the blood–brain barrier (BBB), activates apoptosis and inhibits neurogenesis. Supplement of exogenous antioxidants to relieve the injuries related to oxidative stress is a rational treatment combined to EVT for acute LAO therapy. Resveratrol (RES), an antioxidant, was encapsulated into polymeric nanoparticles (RES-NPs). In transient middle cerebral artery occlusion (tMCAO) rats, intraarterial administration of RES-NPs demonstrated significant protection against cerebral ischemia/reperfusion (I/R) injuries. RES-NPs attenuated the oxidative stress induced by I/R, prevented brain edema, protected neurons from undergoing apoptosis, and contributed to neurogenesis through enhanced expression of brain-derived neurotrophic factor (BDNF). These results suggested that intra-arterial infusion of RES-NPs in conjunction with EVT could be a potential strategy for the LAO stroke therapy.

Treatment of Brain Edema by Wogonoside Is Associated with Inhibition of Neuronal Apoptosis and SIRT1 Activation in Rats.

BackgroundBrain edema and neuronal apoptosis are closely associated with loss of neurological function and death in rats with subarachnoid hemorrhage (SAH). The present study investigated the effect of wogonoside on brain edema induced by SAH in rats and studied the mechanism involved.Material/MethodsThe rats were intra-gastrically administered 10, 20, 50, 100, 150 and 200 mg/kg doses of wogonoside 24 h prior to SAH induction. Western blotting was used to assess levels of pro-apoptotic protein, SIRT1, ZO-1, and p53 protein expression. Apoptotic nuclei were detected using immunofluorescence and TUNEL staining.ResultsWogonoside treatment significantly suppressed edema formation in SAH-induced rats. Pre-treatment with wogonoside exhibited an inhibitory effect on SAH-induced extravascular Evans blue staining in rats. The expression of ZO-1, Occludin, and Claudin-5 proteins was increased by wogonoside in the SAH-induced rats. The inhibitory effect of SAH was completely reversed in the rats treated with the 200 mg/kg dose of wogonoside. The expression of SIRT1 protein was upregulated, and p53 and AC-p53 were downregulated by wogonoside in SAH rats. Wogonoside treatment significantly reduced SAH-mediated promotion of Bax, Puma, Noxa, Bid, and cleaved Caspase-3 expression. In the SAH-induced rats, pre-treatment with wogonoside reduced the TUNEL-positive cell count.ConclusionsThe present study demonstrated that wogonoside prevents brain edema development and apoptosis of neurons in rats by promoting SIRT1 expression and suppression of p53 activation. Therefore, wogonoside has therapeutic potential for the treatment of edema and needs to be investigated further to completely define the mechanism involved.

Isoflurane attenuates carbogen-induced blood-brain barrier disruption independent of body temperature in mice and rats.

Isoflurane protects the blood-brain barrier (BBB) against cerebral extravasation of Evans blue dye (EBD), a commonly used serum protein tracer, in animals subjected to BBB disruption. As such, it has been implicated as a therapeutic agent that can prevent brain edema and damage caused by a number of brain insults, including focal ischemia and subarachnoid hemorrhage. Recently, it has been shown that isoflurane inhibits the cerebral extravasation of EBD following ischemic stroke chiefly by inducing hypothermia, raising the intriguing possibility that isoflurane protected against other causes of BBB disruption also through hypothermia. To test this hypothesis, we subjected mice and rats to inhalation of 20-30% carbogen, an inducer of BBB disruption, in the presence or absence of isoflurane while measuring their rectal temperature. In mice, carbogen inhalation on its own decreased rectal temperature from 36.4 ± 0.4 to 26.2 ± 0.6°C over a period of 60 minutes, and under this condition, isoflurane had no additional effect on body temperature. Nevertheless, isoflurane protected against carbogen-induced cerebral extravasation of EBD. In addition, when the body temperature was maintained in the normothermic range using an automated heating pad, isoflurane remained protective against cerebral extravasation of EBD. In rats, isoflurane also protected against cerebral extravasation of EBD, while having no effect on plasma pH, electrolyte concentrations, or osmolarity. In conclusion, isoflurane protected against BBB disruption caused by carbogen inhalation in mice and rats, but unlike isoflurane-mediated protection against ischemic BBB disruption, the effect could not be explained by anesthesia-induced hypothermia.

The Changes of Brain Edema and Neurological Outcome, and the Probable Mechanisms in Diffuse Traumatic Brain Injury Induced in Rats with the History of Exercise.

Since no definitive treatment has been suggested for diffuse traumatic brain injury (TBI), and also as the effect of exercise has been proven to be beneficial in neurodegenerative diseases, the effect of endurance exercise on the complications of TBI along with its possible neuroprotective mechanism was investigated in this study. Our objective was to find out whether previous endurance exercise influences brain edema and neurological outcome in TBI. We also assessed the probable mechanism of endurance exercise effect in TBI. Rats were randomly assigned into four groups of sham, TBI, exercise + sham and exercise + TBI. Endurance exercise was carried out before TBI. Brain edema was assessed by calculating the percentage of brain water content 24h after the surgery. Neurological outcome was evaluated by obtaining veterinary coma scale (VCS) at - 1, 1, 4 and 24h after the surgery. Interleukin-1β (IL-1β), total antioxidant capacity (TAC), malondialdehyde (MDA), protein carbonyl and histopathological changes were evaluated 24h after the surgery. Previous exercise prevented the increase in brain water content, MDA level, histopathological edema and apoptosis following TBI. The reduction in VCS in exercise + TBI group was lower than that of TBI group. In addition, a decrease in the level of serum IL-1β and the content of brain protein carbonyl was reported in exercise + TBI group in comparison with the TBI group. We suggest that the previous endurance exercise prevents brain edema and improves neurological outcome following diffuse TBI, probably by reducing apoptosis, inflammation and oxidative stress.