piperidines and Brain-Edema

Brain edema is a severe morbid complication of brain injury, characterized by excessive fluid accumulation and an elevation of intracranial pressure. However, effective anti-brain edema drugs are lacking. One of the causes of brain edema is disruption of blood-brain barrier (BBB) function, which results in extravasation of intravascular fluid. After brain damage, astrocytes are activated, and astrocyte-derived vascular endothelial growth factor-A (VEGF-A) is known to induce BBB dysfunction. Therefore maintaining BBB integrity by regulating astrocyte function is a potentially effective strategy for treating brain edema. In this review, we focus on the endothelin ET

Topics: Animals; Astrocytes; Blood-Brain Barrier; Brain; Brain Edema; Claudin-5; Disease Models, Animal; Endothelin B Receptor Antagonists; Gene Expression; Mice; Oligopeptides; Piperidines; Receptor, Endothelin B; Tight Junction Proteins; Vascular Endothelial Growth Factor A

Early identification of acute stroke patients at risk of fatal brain swelling is necessary to facilitate implementation of aggressive therapies. Initial clinical, laboratory, and CT characteristics that may be used as selection criteria were analyzed to determine predictors of herniation and neurological death.. Data from the placebo arm of the Lubeluzole-International-9 trial were reviewed to identify patients with fatal brain edema. Early clinical, laboratory, and radiographic parameters were evaluated in a case-control design. Initial CT scans were analyzed for early ischemic abnormalities by 2 blinded investigators.. Twenty-three patients died from brain swelling, with minimum baseline National Institutes of Health Stroke Scale (NIHSS) scores of 20 (n=12; mean, 23.2+/-1.8) with left and 15 (n=11; mean, 17.6+/-2.2) with right hemispheric infarctions (P=0. 0001). A sample of 112 subjects with comparably severe strokes, but who did not die from brain swelling, was selected from the remaining population according to the same NIHSS scores. Among clinical and laboratory characteristics, nausea/vomiting within 24 hours after onset (odds ratio [OR], 5.1; 95% CI, 1.7 to 15.3; P=0.003) and 12-hour systolic blood pressure >/=180 mm Hg (OR, 4.2; 95% CI, 1.4 to 12.9; P=0.01) were independently associated with fatal brain swelling. Among radiographic factors, only hypodensity of >50% of the middle cerebral artery territory on initial CT scan was an independent predictor (OR, 6.1; 95% CI, 2.3 to 16.6; P=0.0004).. Patients with baseline NIHSS score >/=20 with left or >/=15 with right hemispheric infarctions within 6 hours of symptom onset who also have nausea/vomiting or >50% middle cerebral artery territory hypodensity are at high risk for developing fatal brain swelling.

Topics: Acute Disease; Aged; Brain Edema; Brain Ischemia; Case-Control Studies; Cerebral Arteries; Female; Hospital Mortality; Humans; Male; Middle Aged; Neuroprotective Agents; Piperidines; Prognosis; Risk Factors; Severity of Illness Index; Thiazoles; Tomography, X-Ray Computed

FK866 is an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), which exhibits neuroprotective effects in ischemic brain injury. However, in traumatic brain injury (TBI), the role and mechanism of FK866 remain unclear. The present research was aimed to investigate whether FK866 could attenuate TBI and clarified the underlying mechanisms.. A controlled cortical impact model was established, and FK866 at a dose of 5 mg/kg was administered intraperitoneally at 1 h and 6 h, then twice per day post-TBI until sacrifice. Brain water content, Evans blue dye extravasation, modified neurological severity scores (mNSS), Morris water maze test, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blot were performed.. The results demonstrated that FK866 significantly mitigated the brain edema, blood-brain barrier (BBB) disruption, and ameliorated the neurological function post-TBI. Moreover, FK866 decreased the number of Iba-1-positive cells, GFAP-positive astrocytes, and AQP4-positive cells. FK866 reduced the protein levels of proinflammatory cytokines and inhibited NF-κB from translocation to the nucleus. FK866 upregulated the expression of Bcl-2, diminished the expression of Bax and caspase 3, and the number of apoptotic cells. Moreover, p38 MAPK and ERK activation were significantly inhibited by FK866.. FK866 attenuated TBI-induced neuroinflammation and apoptosis, at least in part, through p38/ERK MAPKs signaling pathway.

Topics: Acrylamides; Animals; Apoptosis; Behavior, Animal; Blood-Brain Barrier; Brain Edema; Brain Injuries, Traumatic; Cytokines; Disease Models, Animal; Female; Inflammation; Male; MAP Kinase Signaling System; Maze Learning; Neuroprotective Agents; NF-kappaB-Inducing Kinase; Piperidines; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley

The integrity of the blood-brain barrier (BBB) plays a vital role in affecting the prognosis of subarachnoid hemorrhage (SAH). This study aimed to investigate activation of the Tropomyosin-related kinase receptor B (TrkB) and its downstream signaling pathway on preserving BBB breakdown after experimental SAH. An endovascular perforation SAH model was applied. N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2- oxopiperidine-3-carboxamide (HIOC), the derivative of N-acetyl serotonin (NAS), was intracerebroventricularly administered 3 h after SAH induction. The neurologic scores and brain water content were evaluated in an outcome study. Western blot and immunofluorescence staining were used to investigate the mechanism. The results indicated that HIOC activated the TrkB/Akt pathway, increased the tight junction expression, improved neurologic deficits, and ameliorated brain edema after SAH. Thus, we conclude that initiating the TrkB/Akt signaling cascade preserves BBB breakdown after experimental SAH in rats.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Glycogen Synthase Kinase 3 beta; Indoles; Male; Piperidines; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptor, trkB; Signal Transduction; Subarachnoid Hemorrhage; Water

Investigators are searching to find new therapeutic strategies to reduce stroke secondary injury. JZL-184 (JZL) is an inhibitory factor for production of arachidonic acid (AA). Thus, it suppresses production of AA metabolites which are the cause of inflammation and tissue edema. Therefore, JZL may be considered for suppression of stroke secondary injury in mice middle cerebral artery occlusion (MCAO) model. Additionally, Aspirin is a known anti-inflammatory factor which is used to reduce pro-inflammatory secondary injury. The aim of this study was to determine the effects of JZL on the reduction of stroke secondary injury and to compare them with Aspirin effects.. MCAO model has been induced and accordingly 83 male MCAO induced mice have been introduced to the study. The animals were divided to seven groups including intact, controls, vehicle, Aspirin, JZL 4, 8 and 16 mg/kg administrated groups. Brain edema and infarction, behavioral functions and brain levels of IL-10, TNF-α and matrix metaloperoteinase-9 (MMP9) have been examined in the evaluated groups.. The results revealed that JZL reduced brain edema, infarction, brain levels of TNF-α and MMP9 and also increased brain levels of IL-10 as well as improved behavioral functions in all three concentrations. The therapeutic effects of JZL were observed as well as Aspirin.. Based on the results, it seems that JZL can be considered as a good candidate for inhibition of stroke secondary injury in the case of delayed treatment.

Topics: Animals; Aspirin; Behavior, Animal; Benzodioxoles; Brain; Brain Edema; Brain Ischemia; Disease Models, Animal; Edema; Infarction, Middle Cerebral Artery; Inflammation; Interleukin-10; Male; Matrix Metalloproteinase 9; Mice; Monoacylglycerol Lipases; Neuroprotective Agents; Piperidines; Stroke; Tumor Necrosis Factor-alpha

Stroke is a prevalent disorder which is associated with several complications including inflammation. JZL-184 (JZL) inhibits arachidonic acid (AA) production and consequently results in two-arachidonoylglycerol (2-AG) accumulation. Both reduced production of AA metabolic products and increased 2-AG, the agonist of type 1 cannabinoid receptor (CB1), can result in reduced inflammation. In this study, we investigated the mechanisms of JZL in the improvement of stroke complications in mouse permanent cerebral ischemia (PPMCAO) model using AM251, the antagonist of CB1.. PMCAO mice were divided into six groups including intact, controls, vehicle, JZL, AM251 and JZL plus AM251 administrated groups. Brain infarction and edema, brain levels of matrix metalloperoteinase-9 (MMP9), interleukin (IL)-10 and tumor necrosis factor-α (TNF-α) and behavioral functions have been examined in all groups.. The results showed that JZL lowered brain infarction, neurological disorders, TNF-α and MMP9 more effectively than JZL plus AM251. JZL and JZL plus AM251 reduced brain edema and increased brain IL-10. JZL, AM251 and JZL plus AM251 improve behavioral functions.. JZL reduces brain infarction and brain pro-inflammatory molecules in CB1 pathway dependent manner. JZL also reduces brain edema and increased IL-10 in CB1 pathways or decreased AA metabolites. Further, AM251 improves behavioral functions via unknown mechanisms.

Topics: Animals; Benzodioxoles; Brain Edema; Brain Infarction; Cannabinoids; Down-Regulation; Enzyme Inhibitors; Inflammation; Interleukin-10; Male; Matrix Metalloproteinase 9; Mice; Monoacylglycerol Lipases; Piperidines; Pyrazoles; Signal Transduction; Tumor Necrosis Factor-alpha

Traumatic brain injury (TBI) and its consequences represent one of the leading causes of death in young adults. This lesion mediates glial activation and the release of harmful molecules and causes brain edema, axonal injury, and functional impairment. Since glial activation plays a key role in the development of this damage, it seems that controlling it could be beneficial and could lead to neuroprotective effects. Recent studies show that minocycline suppresses microglial activation, reduces the lesion volume, and decreases TBI-induced locomotor hyperactivity up to 3 months. The endocannabinoid system (ECS) plays an important role in reparative mechanisms and inflammation under pathological situations by controlling some mechanisms that are shared with minocycline pathways. We hypothesized that the ECS could be involved in the neuroprotective effects of minocycline. To address this hypothesis, we used a murine TBI model in combination with selective CB1 and CB2 receptor antagonists (AM251 and AM630, respectively). The results provided the first evidence for the involvement of ECS in the neuroprotective action of minocycline on brain edema, neurological impairment, diffuse axonal injury, and microglial activation, since all these effects were prevented by the CB1 and CB2 receptor antagonists.

Topics: Animals; Axons; Brain; Brain Edema; Brain Injuries; Cannabinoid Receptor Antagonists; Indoles; Male; Mice; Microglia; Minocycline; Motor Activity; Neuroprotective Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Brain edema is a potentially fatal pathological state that often occurs after brain injuries such as ischemia and trauma. However, therapeutic agents that fundamentally treat brain edema have not yet been established. We previously found that endothelin ETB receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice. In this study, the effects of ETB antagonists on matrixmetalloproteinase (MMP)9 and vascular endothelial growth factor (VEGF)-A expression were examined in the cold injury model. Cold injury was performed in the left brain of male ddY mice (5-6 weeks old) for the induction of vasogenic edema. Expression of MMP9 and VEGF-A mRNA in the mouse cerebrum was increased by cold injury. Immunohistochemical observations showed that the MMP9 and VEGF-A were mainly produced in reactive astrocytes in the damaged cerebrum. Intracerebroventricular administration of BQ788 (10 μg) or IRL-2500 (10 μg) (selective ETB antagonists) attenuated brain edema and disruption of the blood-brain barrier after cold injury. BQ788 and IRL-2500 reversed the cold injury-induced increases in MMP9 and VEGF-A expression. The induction of reactive astrocytes producing MMP9 and VEGF-A in the damaged cerebrum was attenuated by BQ788 and IRL-2500. These results suggest that attenuations of astrocytic MMP9 and VEGF-A expression by ETB antagonists may be involved in the amelioration of vasogenic brain edema.

Topics: Animals; Astrocytes; Biphenyl Compounds; Brain Edema; Cerebrum; Cold Injury; Dipeptides; Endothelin B Receptor Antagonists; Injections, Intraventricular; Male; Matrix Metalloproteinase 9; Mice; Oligopeptides; Piperidines; Vascular Endothelial Growth Factor A

The blood-brain barrier (BBB) is formed by the endothelial cells with specialized tight junctions (TJs) lining the blood vessels and astroglial endfeet surrounding the blood vessels. Although BBB disruption during brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process, little is known about the molecular and physiological events concerning vasogenic edema formation. In the present study, status epilepticus (SE) changed the expressions and subcellular localizations of TJ proteins (claudin-5, occludin and zonula occludens-1 (ZO-1)) in endothelial cells of the rat piriform cortex. Among TJ proteins, the alteration in ZO-1 expression was relevant to endothelin B (ETB) receptor-mediated endothelial nitric oxide synthase (eNOS) activation, which increased matrix metalloproteinase-9 (MMP-9) activity. Indeed, BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced vasogenic edema by inhibiting eNOS-mediated MMP-9 activation and ZO-1 protein degradation in endothelial cells, although astroglial endfeet were detached from endothelial cells. Therefore, we suggest that SE-induced ETB receptor/eNOS-mediated MMP-9 activation may lead to impairments of endothelial cell function via TJ protein degradation, which are involved in vasogenic edema formation independent of perivascular astroglial functions.

Topics: Animals; Astrocytes; Brain Edema; Claudin-5; Disease Models, Animal; Endothelin B Receptor Antagonists; Male; Matrix Metalloproteinase 9; Neuroprotective Agents; Nitric Oxide Synthase Type III; Occludin; Oligopeptides; Piperidines; Piriform Cortex; Rats, Sprague-Dawley; Receptor, Endothelin B; Status Epilepticus; Zonula Occludens-1 Protein

Diphenidol hydrochloride (DPN), a nonphenothiazinic antiemetic agent used primarily in patients with Meniere disease and labyrinthopathies to treat vomiting and vertigo, is considered to be a relatively safe drug. Since it was first approved in the United States in 1967, this drug has been widely used in Latin America and Asia and has contributed to sporadic suicidal and accidental poisonings in mainland China and Taiwan. However, its toxic or lethal concentration ranges have not yet been determined. We report a case of a 23-year-old female who suffered from DPN poisoning that resulted in death. At autopsy, there were no typical pathological findings, except for cerebral edema with high acetylcholinesterase expression. Postmortem analysis of DPN revealed 45 µg/ml in heart blood, 39 µg/ml in femoral vein blood, 141 µg/g in the liver, and 53 mg in the gastric contents. These concentrations indicated that the cause of death was DPN poisoning. The circumstances indicated that the manner of death was suicide. We also present a retrospective study, in which we review and summarize the literature from 1998 to 2014 and describe 16 cases of poisoning, including information from autopsy reports and postmortem drug concentrations. In forensic practice, drug residues at the scene, patients with convulsions and disturbance of consciousness, and rapidly occurring deaths, should draw attention to the possibility of this drug. Toxicological analysis and the exclusion of other diseases may ultimately be used to confirm DPN poisoning.

Topics: Antiemetics; Brain Edema; Female; Gastrointestinal Contents; Humans; Liver; Molecular Structure; Piperidines; Retrospective Studies; Suicide; Young Adult

The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)-1β processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH.. ICH was induced by injecting autologous arterial blood (30μl) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated.. ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloperoxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO.. The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1β and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH.ANN NEUROL 2014;75:209-219.

Topics: Animals; Antioxidants; Brain Edema; Carrier Proteins; Cerebral Hemorrhage; Cholestenones; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation; Hematoma; Inflammation; Injections, Intraventricular; Male; Mice; Neutrophil Infiltration; NLR Family, Pyrin Domain-Containing 3 Protein; Organophosphorus Compounds; Piperidines; RNA, Small Interfering

Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults.

Topics: Animals; Azepines; Biphenyl Compounds; Blood-Brain Barrier; Blotting, Western; Brain Edema; Brain Injuries; Cerebrum; Cold Temperature; Dipeptides; Endothelin Receptor Antagonists; Endothelins; Glial Fibrillary Acidic Protein; Indoles; Male; Mice; Oligopeptides; Piperidines; Real-Time Polymerase Chain Reaction; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Effective interventions that provide obvious neuroprotection are currently fairly limited. Glucagon-like peptide-1 (GLP-1), an enhancer of insulin production with a trophic effect on β cells in the islets, has been found to be trophic for neuronal cells. Alogliptin benzoate (AGL), a selective inhibitor of dipeptidylpeptidase-4 (DPP-4) functioning as a long-acting agonist of GLP-1, is in clinical use worldwide for patients with diabetes mellitus type 2. To clarify whether administration of AGL, independent of the insulinotropic effect, protects the brain against focal ischemia, we investigated the effect of AGL on the development of cerebral infarction in non-diabetic normal mice. Male C57BL/6J mice were administered AGL (7.5, 15, or 30μg) once a day for three weeks by intragastric gavage. After the induction of temporary focal ischemia, volumes of infarcted lesions and neurological deficits were analyzed at 24h (acute phase) and seven days (chronic phase). In the acute phase, significant reductions were observed in the volumes of infarcted lesions (p=0.009), and in the severity of neurological deficits (p=0.004), in the group treated with 15μg of alogliptin benzoate, but not the 7.5 or 30μg-treated groups. This significant reduction in volumes of infarcted lesions persisted into the chronic phase. At the end of the AGL treatment; before the induction of ischemia, the levels of brain-derived neurotrophic factor (BDNF), a potent neuroprotectant in the brain, were elevated in the cortex (p=0.008), or in the whole forebrain (p=0.023). AGL could be used as a daily neuroprotectant or an enhancer of BDNF production aiming to attenuate cerebral injuries, for the growing number of people who have the risk of ischemic stroke.

Topics: Analysis of Variance; Animals; Brain Edema; Brain Infarction; Brain Ischemia; Brain-Derived Neurotrophic Factor; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred C57BL; Microcirculation; Nervous System Diseases; Piperidines; Prosencephalon; Time Factors; Uracil

Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.

Topics: Animals; Aquaporins; Blotting, Western; Brain Edema; Brain Ischemia; Dioxanes; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Evoked Potentials, Somatosensory; Image Processing, Computer-Assisted; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Nervous System Diseases; Neuroprotective Agents; Oligopeptides; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Wistar; Stroke; Sulfonamides; Tetrazoles

We have reported that facilitation of central histaminergic activity prevents the development of ischemia-induced brain injury. Since cerebral edema is a major cause of brain damage, we studied effects on brain edema of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H(3)-receptor antagonist, both of which enhance central histaminergic activity. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery in rats, and the water content and infarct size were determined 24 h after reperfusion. Changes in the extracellular concentration of histamine were examined in the striatum by a microdialysis procedure, and effects of these compounds were evaluated. Repeated administration of L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the increase in the water contents in ischemic regions. Simultaneous administration of thioperamide (5 mg/kg, s.c.) with L-histidine (1000 mg/kg, i.p.) completely prevented edema formation and alleviated brain infarction, although a single dose of L-histidine, immediately after reperfusion, showed no benefits. The striatal histamine level was gradually increased after reperfusion as well as during ischemia. Simultaneous administration of thioperamide with L-histidine markedly increased the brain histamine concentration, and the value increased up to 230% of that in the saline group 5 - 6 h after reperfusion. L-Histidine alone did not affect the increase in the histamine output after ischemia. These findings suggest that further activation of the central histaminergic system after initiation of cerebral ischemia prevents development of ischemia-induced brain edema.

Topics: Animals; Blood Cell Count; Body Water; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebral Cortex; Cytokines; Histamine; Histamine Agonists; Histamine Antagonists; Histidine; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Microdialysis; Neostriatum; Piperidines; Rats; Rats, Wistar; Superoxide Dismutase

Topics: Adult; Anesthesia, Conduction; Anesthesia, General; Anesthesia, Obstetrical; Brain Edema; Cesarean Section; Contraindications; Emergencies; Female; Hemodynamics; Humans; Infant, Newborn; Intracranial Arteriovenous Malformations; Male; Piperidines; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, Third; Remifentanil; Respiratory Distress Syndrome, Newborn; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Vertebral Artery

Ifenprodil, a NMDA receptor polyamine site antagonist, reduces experimental cardiac arrest (CA)-elicited brain edema, which is associated with an up-regulation of aquaporin 4 (AQP4), a brain water-selective channel. However, the interacting roles of NMDA receptors and AQP4 in CA-elicited brain edema are unknown. The objective of this study was to test our hypothesis that ifenprodil treatment is associated with a down-regulation of brain AQP4.. Twenty-five rats were assigned to normal controls (group 1, n = 6) or subjected to eight minutes of asphyxial CA treated with placebo (group 2, n = 9) or ifenprodil (group 3, n = 10). Ifenprodil at 10 mg/kg or normal saline of equal volume was given intraperitoneally, 5 minutes before CA. The density of AQP4 protein and actin bands was scanned and expressed as the ratios of the optical density of AQP4 relative to that of actin. The ANOVA analysis was used to compare the group differences.. The ratios of the optical density of AQP4 to that of actin were 0.88 +/- 0.06 in group 1, 1.11 +/- 0.08 in group 2 (p < 0.05 vs. group 1), and 0.78 +/- 0.04 in group 3 (p < 0.01 vs. group 2; NS vs. group 1).. Ifenprodil given before CA is associated with a downregulation of brain AQP4 in rats.

Topics: Animals; Brain; Brain Edema; Down-Regulation; Heart Arrest; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Treatment Outcome; Vasodilator Agents

Brain edema occurs in experimental and clinical cardiac arrest (CA) and is predictive of a poor neurological outcome. N-Methyl--aspartate (NMDA) receptors contribute to brain edema elicited by focal cerebral ischemia/reperfusion (I/R). Ifenprodil, a NMDA receptor antagonist, attenuates brain edema and injury size in rats after focal cerebral I/R. We assessed the hypothesis that ifenprodil reduces CA-elicited brain edema.. Eighteen male Sprague-Dawley rats were assigned to group 1 (normal control, n=6), group 2 (placebo-treated CA, n=6), or group 3 (ifenprodil-treated CA, n=6). CA was induced by 8 min of asphyxiation and the animals were resuscitated with cardiopulmonary resuscitation (CPR), ventilation, epinephrine (adrenaline), and sodium bicarbonate (NaHCO3). Ifenprodil of 10 mg/kg or a placebo vehicle was given intraperitoneally 5 min before CA. Brain edema was determined by brain wet-to-dry weight ratio at 1 h after resuscitation.. There were no differences between groups 2 and 3 in all physiological variables at baseline. Time from asphyxiation to CA was 201.5 +/- 7.5 s in group 2 and 160.7 +/- 10.4 s in group 3 (P<0.001). Resuscitation time was 68.2 +/- 13.3 s in group 2 and 92.8 +/- 18.2 s in group 3 (P<0.05). Ifenprodil decreased mean arterial pressure (MAP) before asphyxiation, from 128 +/- 7 in group 2 to 82 +/- 15 mmHg in group 3 (P<0.001), and negated immediate post-resuscitation hypertension. Brain wet-to-dry weight ratio was 5.64 +/- 0.44 in group 1, 7.34 +/- 0.95 in group 2 (P<0.01 versus group 1), and 5.93 +/- 0.40 in group 3 (P<0.05 versus group 2).. Ifenprodil reduces CA-elicited brain edema. In addition, we observed significant hemodynamic changes caused by ifenprodil.

Topics: Animals; Asphyxia; Brain Edema; Brain Ischemia; Cardiopulmonary Resuscitation; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Heart Arrest, Induced; Hemodynamics; Male; Piperidines; Polyamines; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity

The endocannabinoid anandamide [N-arachidonoylethanolamine (AEA)] is thought to function as an endogenous protective factor of the brain against acute neuronal damage. However, this has never been tested in an in vivo model of acute brain injury. Here, we show in a longitudinal pharmacological magnetic resonance imaging study that exogenously administered AEA dose-dependently reduced neuronal damage in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain. At 15 min after injury, AEA (10 mg/kg) administered 30 min before ouabain injection reduced the volume of cytotoxic edema by 43 +/- 15% in a manner insensitive to the cannabinoid CB(1) receptor antagonist SR141716A. At 7 d after ouabain treatment, 64 +/- 24% less neuronal damage was observed in AEA-treated (10 mg/kg) rats compared with control animals. Coadministration of SR141716A prevented the neuroprotective actions of AEA at this end point. In addition, (1) no increase in AEA and 2-arachidonoylglycerol levels was detected at 2, 8, or 24 hr after ouabain injection; (2) application of SR141716A alone did not increase the lesion volume at days 0 and 7; and (3) the AEA-uptake inhibitor, VDM11, did not affect the lesion volume. These data indicate that there was no endogenous endocannabinoid tone controlling the acute neuronal damage induced by ouabain. Although our data seem to question a possible role of the endogenous cannabinoid system in establishing a brain defense system in our model, AEA may be used as a structural template to develop neuroprotective agents.

Topics: Animals; Animals, Newborn; Arachidonic Acids; Blotting, Western; Brain; Brain Edema; Brain Injuries; Cannabinoid Receptor Modulators; Cannabinoids; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Glycerides; Longitudinal Studies; Magnetic Resonance Imaging; Microinjections; Neurons; Ouabain; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

N-methyl-D-aspartate (NMDA) and non-NMDA receptors were found to be involved in development of functional disorders caused by hexachlorophene. In order to specify the role of glutamate receptors we studied the protective effects of the selective antagonist of the kainate/(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor/channel 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline-7-sulphonamide disodium (NBQX) and of the non-competitive NMDA receptor antagonist ifenprodil tartrate on coordinative motor behaviour of adult male Wistar rats as assessed in a simple 'ladder-test'. Neurotoxic injury of the cerebrum after hexachlorophene administration and putative amelioration after treatment with test substances was demonstrated histologically. Hexachlorophene-induced motor disturbance remitted spontaneously when stopping the noxis, but remittance occurred significantly earlier when NBQX [0.45 and 0.6 mg/kg intraperitoneal (i.p.)] was applied as well. Ifenprodil (0.15 to 1.2 mg/kg) did not improve the motor function. Vacuolation of white matter of the whole cerebrum was observed after 3 weeks of treatment with hexachlorophene. These morphological alterations caused by hexachlorophene treatment [central nervous system (CNS) vacuolation] spontaneously revert only after 5-6 weeks. The 5-day duration with test substances was too short for remission of vacuolation which thus may not apply to the situation after treatment with glutamate antagonists, despite improvement of motor function. The results suggest that kainate/AMPA receptor channels are at least partially involved in the mechanism of brain damage induced by hexachlorophene, however, the polyamine binding site of the NMDA receptor evidently is not involved.

Topics: Animals; Behavior, Animal; Brain; Brain Edema; Excitatory Amino Acid Antagonists; Hexachlorophene; Male; Motor Activity; Motor Skills Disorders; Piperidines; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

Traumatic brain injury (TBI) has been shown to induce a significant change in polyamine metabolism. Polyamines and polyamine-dependent calcium influx play an important role in mediating the effects of excitotoxic amino acids at the N-methyl-D-aspartate (NMDA) receptor site. We studied the effects of ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, on brain edema formation, blood-brain barrier breakdown, and volume of injury after TBI.. Experimental TBI was induced in Sprague-Dawley rats by a controlled cortical impact device, functioning at a velocity of 3 m/s to produce a 2-mm deformation. Ifenprodil or saline (10 mg/kg) was injected intraperitoneally immediately after the cortical impact injury and then every 90 minutes until 6 hours after TBI. Blood-brain barrier breakdown was evaluated quantitatively 6 hours after injury by fluorometric assay of Evans blue extravasation. Brain water content, an indicator of brain edema, was measured with the wet-dry method 24 hours after TBI. Injury volume was quantitated from the brain slices stained with 2% cresyl violet solution 7 days after TBI.. Blood-brain barrier breakdown was significantly lower in the traumatic cortex of the ifenprodil-treated group than in the saline-treated group (84.4 +/- 26.8 microg/g versus 161.8 +/- 27 microg/g, respectively, P < 0.05). Brain edema was significantly reduced in the cortex of the ifenprodil-treated group relative to that in the saline-treated group (80.9 +/- 0.5% versus 82.4 +/- 0.6% respectively, P < 0.05). Ifenprodil treatment reduced injury volume significantly (14.9 +/- 8.1 mm3 versus 24.4 +/- 6.7 mm3, P < 0.05).. The polyamine-site NMDA receptor antagonist ifenprodil affords significant neuroprotection in a controlled cortical impact brain injury model and may hold promise for the discovery and treatment of the mechanism of delayed neurological deficits after TBI.

Topics: Animals; Blood-Brain Barrier; Body Water; Brain; Brain Edema; Brain Injuries; Capillary Permeability; Excitatory Amino Acid Antagonists; Male; Piperidines; Polyamines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Recent experimental evidence suggests that centrally released arginine vasopressin plays a significant role in brain capillary water permeability as well as in pathogenesis of vasogenic brain edema. The purpose of this study was to examine the effects of orally administered OPC-21268, a nonpeptide arginine vasopressin V1 receptor antagonist, on cold-induced brain edema in rats.. Cold brain injury was induced for 1 minute in 140 rats. Treatment with OPC-21268, at dosages of 100 mg (n = 20), 200 mg (n = 20), and 300 mg/kg (n = 15), or with saline (n = 17) was started 1 hour after the induction of cold injury and was continued every 8 hours for 24 hours. Two percent Evans blue in saline (1 ml/kg) was administered intravenously before cold injury in another group of rats, 15 of which were saline-treated and 55 of which were OPC-21268-treated at the above dosages. After 24 hours, brain tissue water and electrolytes, brain tissue swelling, blood-brain barrier permeability to Evans blue, and plasma electrolytes and osmolality were determined.. Compared with the saline-treated group, OPC-21268 treatment at the dosages of 200 and 300 mg/kg significantly reduced brain water content in both hemispheres (P<0.01). Swelling of the traumatized hemispheres was also significantly reduced at 200 and 300 mg/kg dosages (P<0.05). Brain tissue sodium content was significantly reduced at the dosage of 300 mg/kg (P<0.05). Blood-brain barrier permeability to Evans blue was significantly decreased in a dose-dependent manner compared with the saline-treated group (P<0.01). No significant changes were observed in other parameters.. Our results indicate that OPC-21268 predominantly exerts a protective effect in areas where the maximum amount of blood-brain barrier breakdown occurs, and it is effective in the treatment of cold-induced vasogenic brain edema.

Topics: Administration, Oral; Animals; Antidiuretic Hormone Receptor Antagonists; Blood-Brain Barrier; Brain Edema; Dose-Response Relationship, Drug; Male; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Water-Electrolyte Balance

Lubeluzole, a novel nitric oxide synthase (NOS) pathway modulator, was shown to be neuroprotective in cerebral ischemia as studied in animal models and clinical trials. The present study investigated the effect of lubeluzole on contusion volume and brain edema following traumatic brain injury. Sprague-Dawley rats (n = 36) were subjected to cortical impact injury. Lubeluzole (0.8 mg/kg i.v.; n = 18) or a corresponding volume of vehicle (n = 18) was injected 15 and 75 minutes following trauma. Animals were sacrificed 24 hours following trauma. Contusion volume was measured planimetrically from coronal slices stained with hematoxylin and eosin. In this group, T2-weighted magnetic resonance imaging (MRI) was also performed 90 minutes and 6 and 24 hours after trauma. Hemispheric swelling and water content were determined gravimetrically 24 hours after trauma. In this group, intracranial pressure (ICP), mean arterial blood pressure (MABP), and cerebral perfusion pressure (CPP) were monitored for 30 minutes before sacrifice. Lubeluzole did not reduce contusion volume, hemispheric swelling, or water content. ICP, MABP, and the resulting CPP did not differ between treated and untreated rats 24 hours after injury. T2-weighted MRI revealed a higher volume of edema at 90 minutes after trauma in treated rats. However, at 6 and 24 hours after trauma, no significant difference was discernible. Under these experimental conditions, lubeluzole fails to exert beneficial effects following experimental traumatic brain injury (TBI).

Topics: Animals; Blood Gas Analysis; Blood Pressure; Body Water; Brain Edema; Brain Injuries; Enzyme Inhibitors; Intracranial Pressure; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Piperidines; Rats; Rats, Sprague-Dawley; Thiazoles; Time Factors

Reactive oxygen-derived species were previously implicated in mediation of post-traumatic brain damage; however, the efficacy of traditional antioxidants in preventing/reversing the damage is sometimes limited. The present work focused on the mechanisms underlying the neuroprotective activity of cell permeable, nontoxic, antioxidants, namely stable nitroxide radicals in an experimental model of rat closed-head injury. Brain damage was induced by the weight-drop method and the clinical status was evaluated according to a neurological severity score at 1 h and 24 h, where the difference between these scores reflects the extent of recovery. The metal chelator deferoxamine as well as three nitroxide derivatives, differing in hydrophilicity and charge, and one hydroxylamine (a reduced nitroxide) facilitated the clinical recovery and decreased the brain edema. The nitroxides, but neither the hydroxylamine nor deferoxamine, protected the integrity of the blood-brain barrier. Superoxide dismutase also improved the clinical recovery but did not affect brain edema or the blood-brain barrier. The results suggest that by switching back and forth between themselves, the nitroxide and hydroxylamine act catalytically as self-replenishing antioxidants, and protect brain tissue by terminating radical-chain reactions, oxidizing deleterious metal ions, and by removal of intracellular superoxide.

Topics: Animals; Antioxidants; Blood-Brain Barrier; Brain Diseases; Brain Edema; Deferoxamine; Head Injuries, Closed; Hydroxylamine; Male; Neuroprotective Agents; Nitrogen Oxides; Piperidines; Rats; Superoxide Dismutase

The present study examined the effects of CP-98,113, an N-methyl-d-aspartate (NMDA) receptor blocker, on cardiovascular variables, neurobehavioral motor function, spatial memory deficits, and cerebral edema formation following lateral (parasagittal) fluid-percussion (FP) brain injury in the rat. In Study 1, we compared the cardiovascular effects of i.p. administration of CP-98, 113 at 15 min postinjury at doses of 1 mg/kg, 2 mg/kg, 5 mg/kg, or 20 mg/kg (n=8/dose). Animals receiving 1 mg/kg to 5 mg/kg CP-98,113 showed slight but nonsignificant decreases in blood pressure, while those receiving the highest dose (20 mg/kg) showed significant hypotension. Based upon those observations, the 5 mg/kg dose was chosen as the optimal dose for subsequent behavioral studies. In Study 2, 15 min following lateral FP brain injury of moderate severity (2.5 atm), animals randomly received either CP-98,113 (5 mg/kg, i.p., n=23) followed by a 24-h subcutaneous infusion (1.5 mg kg-1 h-1) by means of a miniature osmotic pump, or identical volume of vehicle (n=24), and were evaluated for neurologic motor function (n=11/drug vs. 11/vehicle), memory function, and cerebral edema (n=12/drug vs. 13/vehicle). CP-98,113 (5 mg/kg) significantly attenuated neurologic motor dysfunction at 24 h (p<0.01) and 2 weeks (p<0.05) postinjury, reduced posttraumatic impairment in spatial memory observed at 48 h postinjury (p<0.001), and significantly reduced focal brain edema in the cortex adjacent to the site of maximal injury at 48 h postinjury (injury penumbra) (p<0.001). These results suggest that blockade of the NMDA receptor may attenuate the deleterious sequelae of traumatic brain injury.

Topics: Animals; Behavior, Animal; Body Temperature; Brain Edema; Brain Injuries; Cardiovascular Physiological Phenomena; Cognition; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Ifenprodil, a polyamine site N-methyl-D-aspartate receptor/channel antagonist, has been reported to decrease infarction volume after cerebral ischemia. However, the possible mechanisms of this protective effect have not been studied in detail. We investigated the effects of ifenprodil on ischemic injury size, blood-brain barrier (BBB) permeability, regional brain edema, and cerebral blood flow.. Focal ischemia for 6 hours was produced by permanent occlusion of the middle cerebral artery in 15 anesthetized cats. Treatment with drug (n = 8) or vehicle (n = 7) was initiated at 5 minutes after ischemia and continued for 3 hours. Physiological variables were continuously monitored during experiments. We measured ischemic injury size, brain edema, and BBB permeability to Evans blue and determined regional cerebral blood flow by using laser doppler flowmetry.. Both ischemic injury size and BBB permeability were smaller in the ifenprodil-treated group, compared with the saline-treated group (P < 0.05). Ifenprodil treatment also attenuated brain edema formation in the dense ischemic region, compared with saline treatment (1.035 +/- 0.002 versus 1.028 +/- 0.002, P < 0.05). There was no significant change in cerebral blood flow with ifenprodil treatment.. Findings from this study confirm that ifenprodil treatment results in a significant decrease in the size of ischemic injury after focal ischemia. The tissue-sparing effect of ifenprodil is not related to its vasoactive properties. It is likely that its neuroprotective effects are related to its ability to antagonize N-methyl-D-aspartate receptors, which results in a decrease in brain edema and BBB permeability.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Brain Ischemia; Capillary Permeability; Cats; Cerebral Infarction; Excitatory Amino Acid Antagonists; Female; Male; Piperidines; Regional Blood Flow; Vasodilator Agents

The present study evaluated the effects of two novel N-methyl-D-aspartate (NMDA) receptor blockers and ifenprodil derivatives, CP-101,606 and CP-101,581, and their racemic mixture CP-98,113, on spatial memory and regional cerebral edema following experimental fluid-percussion (FP) brain injury in the rat (n = 66). Fifteen minutes after brain injury (2.5 atm), animals received either (1) CP-98,113 (5 mg/kg, i.p., n = 11), (2) CP-101,581 (5 mg/kg, i.p., n = 13), (3) CP-101,606 (6.5 mg/kg, i.p., n = 12), or (4) DMSO vehicle (equal volume, n = 12); followed by a continuous 24-h subcutaneous infusion of drug at a rate of 1.5 mg/kg/h by means of miniature osmotic (Alzet) pumps implanted subcutaneously. Control (uninjured) animals were subjected to identical anesthesia and surgery without injury and received DMSO vehicle (n = 8); CP-98,113 (5 mg/kg, i.p., n = 3); CP-101,581 (5 mg/kg, i.p., n = 3); or CP-101,606 (6.5 mg/kg, i.p., n = 3). FP brain injury produced a significant cognitive impairment assessed at 2 days postinjury using a well-characterized testing paradigm of visuospatial memory in the Morris Water Maze (MWM) (p < 0.001). Administration of either CP-98,113, CP-101,581, or CP-101,606 had no effect on sham (uninjured) animals, but significant attenuated spatial memory impairment assessed at 2 days postinjury (p = 0.004, p = 0.02, or p = 0.02, respectively). Administration of CP-89,113 but not CP-101,581 or CP-101,606 significantly reduced the extent of regional cerebral edema in the cortex adjacent to the site of injury (p < 0.05) and in the ipsilateral hippocampus (p < 0.05) and thalamus (p < 0.05). These results suggest that excitatory neurotransmission may play a pivotal role in the pathogenesis of memory dysfunction following traumatic brain injury (TBI) and that blockade of the NMDA receptor may significantly attenuate cognitive deficits associated with TBI.

Topics: Animals; Brain Edema; Brain Injuries; Cognition; Excitatory Amino Acid Antagonists; Infusions, Parenteral; Male; Maze Learning; Memory; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate

The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke.. Seventeen adult cats were allocated to control (n = 7) and CP101,606-treated groups (n = 10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)-stained section, with and without neuroprotective agents, was used to determine the value of these potential "surrogate markers" of ischemic damage.. The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P < .001).. CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.

Topics: Animals; Arterial Occlusive Diseases; Brain; Brain Edema; Brain Ischemia; Cats; Cerebral Arteries; Cerebral Infarction; Dialysis Solutions; Excitatory Amino Acid Antagonists; Female; Lactates; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Piperidines; Receptors, N-Methyl-D-Aspartate; Staining and Labeling; Tetrazolium Salts

Polyamines and N-methyl-D-aspartate (NMDA) receptors are both thought to play an important role in secondary neuronal injury after cerebral ischemia. Ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, was studied after transient focal cerebral ischemia occurred. Spontaneously hypertensive male rats, each weighing between 250 and 350 g, underwent 3 hours of tandem middle cerebral artery (MCA) and common carotid artery occlusion followed by reperfusion for a period of 3 hours or 21 hours. Intravenous ifenprodil (10 microg/kg/minute) or saline infusion was started immediately after the onset of MCA occlusion and continued throughout the ischemic period. Physiological parameters including blood pressure, blood gas levels, blood glucose, hemoglobin, and rectal and temporal muscle temperatures were monitored. Six rats from each group were evaluated at 6 hours postocclusion for brain water content, an indicator of brain edema, and Evans blue dye extravasation for blood-brain barrier breakdown. Infarct volume was also measured in six rats from each group at 6 and 24 hours postocclusion. Ifenprodil treatment significantly reduced brain edema (82.5 +/- 0.4% vs. 83.5 +/- 0.4%, p < 0.05) and infarct volume (132 +/- 14 mm3 vs. 168 +/- 25 mm3, p < 0.05) compared with saline treatment, with no alterations in temporal muscle (brain) or rectal (body) temperature (35.9 +/- 0.4 degrees C vs. 36.2 +/- 0.2 degrees C; 37.7 +/- 0.4 degrees C vs. 37.6 +/- 0.6 degrees C; not significant). These results demonstrate that ifenprodil has neuroprotective properties after ischemia/reperfusion injury in the absence of hypothermia. This indicates that antagonists selective for the polyamine site of the NMDA receptors may be a viable treatment option and helps to explain some of the pathophysiological mechanisms involved in secondary injury after transient focal cerebral ischemia has occurred.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Pressure; Blood-Brain Barrier; Body Temperature; Body Water; Brain; Brain Edema; Cerebral Infarction; Coloring Agents; Evans Blue; Excitatory Amino Acid Antagonists; Hemoglobins; Infusions, Intravenous; Ischemic Attack, Transient; Male; Neuroprotective Agents; Oxygen; Piperidines; Rats; Rats, Inbred SHR; Receptors, N-Methyl-D-Aspartate; Reperfusion Injury; Sodium Chloride; Temporal Muscle; Vasodilator Agents

We examined the effect of orally administered OPC-21268, a nonpeptide Arginine Vasopressin V1 receptor antagonist, on cold induced vasogenic brain edema in rat. Cold brain injury was induced by applying a copper rode cooled with liquid nitrogen for one minute. To mimic clinical use, one hour after induction of the cold lesion, rats were treated with orally administered OPC-21268 at doses of 100 mg, 200 mg, and 300 mg/kg every 8 hr for 24 hours. Two percent Evans blue in saline, in a volume of 1 ml/kg was given intravenously prior to cold injury. Twenty four hours after induction the cold lesion, brain water, brain tissue electrolytes, and plasma osmolality and electrolytes were measured. Quantitative evaluation of BBB permeability was performed using the Evans blue fluorescence method. The injury resulted in significant increases in the brain water and brain tissue sodium, and Evans blue concentration in both the lesioned and contralateral hemispheres (p < 0.01). OPC-21268 at doses of 200 mg and 300 mg/kg significantly decreased brain water and Evans blue concentrations in both the lesioned and contralateral hemispheres (p < 0.01). Brain tissue sodium content was significantly reduced at a dose of 300 mg/kg in the lesioned side (p < 0.05). There were no significant changes in other parameters throughout the experiments. Our results indicate that OPC-21268 exerts a protective effect in areas where the maximal amount of BBB breakdown occurs.

Topics: Administration, Oral; Animals; Antidiuretic Hormone Receptor Antagonists; Blood-Brain Barrier; Brain Edema; Cold Temperature; Male; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley

Histamine has potent effects on cerebral blood vessels which include increased permeability and dilatation. Since its concentrations are found to be increased in brain tissue in different experimental models of brain injury, histamine may act as a mediator of secondary brain damage. Using the cold-lesion model of vasogenic brain edema the effects of application of antihistaminics were studied in rats. Neither mepyramine, an H1 receptor blocker nor zolantidine, an H2 blocker provided any decrease in brain swelling or water content. Experiments with application of dexamethasone yielded a small non-significant decrease of edema while the amino-steroid U74389F did not reduce swelling. The results indicate that histamine is obviously not involved in mediating cold lesion-induced brain edema. Furthermore, generation of lipid peroxides after activation of phospholipase A2 also appears not to have a significant influence on edema in the present study.

Topics: Animals; Antioxidants; Benzothiazoles; Blood-Brain Barrier; Brain Edema; Dexamethasone; Freezing; Histamine; Histamine Antagonists; Histamine H2 Antagonists; Lipid Peroxidation; Male; Parietal Lobe; Phenoxypropanolamines; Piperidines; Pregnatrienes; Pyrilamine; Rats; Rats, Sprague-Dawley; Thiazoles; Water-Electrolyte Balance