benzofurans and Ischemic-Attack--Transient

The present paper reviews recent studies in monkey and man adding further to understanding of the role of perivascular peptides in the pathophysiology of subarachnoid haemorrhage. 1. The perivascular fibers, sympathetic fibers (storing noradrenaline, neuropeptide Y), parasympathetic fibers (storing acetylcholine, vasoactive intestinal peptide, peptide histidine methionine and neuropeptide Y) and sensory fibers (storing tachykinins, calcitonin gene-related peptide) were traced using True Blue in monkey. 2. Tracing studies of the monkey middle-cerebral artery (MCA) innervation confirmed earlier studies in rats and cats, with superior cervical and trigeminal ganglia as main immunostaining areas, and contralateral involvement in the superior cervical and trigeminal ganglia. Sphenopalatine immunostaining was scarce. 3. The release of neuropeptides in the external jugular vein in humans in the postoperative course after subarachnoid hemorrhage, using radioimmunoassay, was correlated to hemodynamical changes (vasoconstriction) monitored with Doppler ultrasound on middle cerebral (MCA) and internal carotid arteries (ICA)). 4. Neuropeptide Y-like immunoreactivity (NPY-LI) levels were increased compared to controls in patients with hemodynamic changes, and in some patients a relationship was found between velocities and NPY-LI. 5. Calcitonin gene-related peptide-LI levels were also increased in connection with vasospasm. In patients with MCA lesions a correlation of 0.61, p = 0.0002 was found between hemodynamic index (V MCA/V ICA) and CGRP-LI. The possible sympathetic and trigemino-cerebrovascular activation are discussed.

Topics: Animals; Benzofurans; Calcitonin Gene-Related Peptide; Cerebral Arteries; Cerebrovascular Circulation; Haplorhini; Hemodynamics; Humans; Ischemic Attack, Transient; Nerve Fibers; Neuropeptide Y; Neuropeptides; Subarachnoid Hemorrhage; Ultrasonography; Vasoconstriction

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Brain Infarction; Diffusion Magnetic Resonance Imaging; Female; Humans; Injections; Ischemic Attack, Transient; Male; Middle Aged; Neuroprotective Agents; Outcome Assessment, Health Care; Severity of Illness Index

Stroke is the third leading cause of death and disability in North America and is becoming the most frequent cause of death in the rapid developing China. Protecting neurons in order to minimize brain damage represents an effective approach towards stroke therapeutics. Our recent study demonstrated that 2-(-2-benzofuranyl)-2-imidazoline (2-BFI), a ligand for imidazoline I(2) receptors, is potently neuroprotective against stroke, possibly through transiently antagonizing NMDA receptor activities. In this study, we further investigated the characteristics and mechanisms of 2-BFI-mediated neuroprotection using a rat stroke model of transient occlusion of the middle cerebral artery. Here, we show that 2-BFI was most effective at the dose of 3mg/kg in vivo, with significantly reduced brain infarct size and improved neurological deficits. Lower doses of 2-BFI at 1.5mg/kg, or higher dose of 2-BFI at 6 mg/kg, were either not effective, or toxic to the brain, respectively. Treating stroke rats with 3mg/kg 2-BFI significantly reduced the number of TUNEL positive cells and preserved the integrity of subcellular structures such as nuclear membranes and mitochondria as shown under the electron microscope, confirming neuroprotection. Most interestingly, 2-BFI-treated brains exhibited significant expression of Bcl-2, a gene with a known function in neuroprotection. Taken together, these studies not only demonstrated that 2-BFI at 3mg/kg was effective in neuroprotection, but also, for the first time, showed that 2-BFI provided neuroprotection through up-regulating the neuroprotective gene Bcl-2. 2-BFI can be further developed as a therapeutic drug for stroke treatment.

Topics: Animals; Apoptosis; Benzofurans; Brain; Cell Death; Consciousness; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Imidazoline Receptors; Immunohistochemistry; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Microscopy, Electron; Motor Activity; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome; Up-Regulation; Walking

To investigate the effect of dl-3n-butylphthalide (NBP) on the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in protein and mRNA levels in the treatment of cerebral infarction with transient middle cerebral artery occlusion (MCAO) in rats.. The model of transient MCAO was established using the suture method of Longa by blocking middle cerebral artery (MCA) with a nylon suture. The MCA blood flow was restored by the withdrawal of the nylon suture 2 h after occlusion. Sham-operated rats (n=20) were prepared in similar fashion, but without occlusion of the MCA. Operated rats were randomizely divided into 2 groups (n=20 for each): vehicle group rats were only administered vegetable oil 2 mL twice daily for 3 days and NBP group rats were administrated NBP 25 mg/kg twice daily for 3 days. The infarct volume and neurological deficit were determined by TTC staining and Longa's score. VEGF and bFGF protein and mRNA were detected by immunohistochemistry and in situ hybridization.. NBP markedly inhibited the neurological deficit and reduced the infarct volumes as compare to vehicle group (P<0.05). NBP significantly upregulated VEGF and bFGF expression in both protein and mRNA levels in the peripheral infarct and hippocampus regions in contrast with sham-operated and vehicle group (P<0.05).. NBP has protective effects for cerebral ischemia through upregulating the expression of VEGF and bFGF.

Topics: Animals; Benzofurans; Fibroblast Growth Factor 2; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Endothelial Growth Factor A

2-(1-Hydroxypentyl)-benzoate (dl-PHPB), a derivate of 3-n-butylphthalide (dl-NBP), is a novel drug candidate used for treatment of cerebral ischemia. The goal of the present study was to investigate the effects of dl-PHPB on infarct volume, neurological function, and cerebral blood flow (CBF) in transient focal cerebral ischemia. Therefore, an animal model of 2-h middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion was used. Rats received dl-PHPB (1.3, 3.9, or 12.9 mg/kg) intravenously 10 min after the onset of MCAO. Compared with the vehicle control group (37.4%), infarct volume in dl-PHPB-treated groups was reduced significantly and dose-dependently to 25.4, 17.4, and 13.7%, respectively. The changes in neurological deficient were also observed in neurobehavioral test in a dose-dependent manner, and the neuronal score was improved significantly from the vehicle control of 3.2 to 2.7, 2.1, and 1.8, respectively. At the highest dose, the potency of dl-PHPB was similar to those of dl-NBP. CBF was quantified by using laser-Doppler flowmetry. During the ischemia, the regional CBF values of dl-PHPB groups were significantly higher than that of vehicle group. In addition, our study showed that dl-PHPB converted into dl-NBP very quickly in blood in vitro. Approximately 70% of dl-PHPB converted into dl-NBP in 5 min when dl-PHPB was added into plasma at final concentrations of 6, 30, and 60 mug/ml. This result demonstrated that the neuronal protection effects of dl-PHPB were mainly induced by dl-NBP, an active compound converted from its precursor, dl-PHPB. In conclusion, dl-PHPB can reduce infarct volume and improve neurobehavioral deficits in a rat model of transient MCAO. Those effects may partially be due to an increase in CBF by the active metabolite (dl-NBP) of dl-PHPB. Therefore, our results suggest that dl-PHPB may be useful for treatment of ischemia stroke.

Topics: Animals; Benzoates; Benzofurans; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Neuroprotective Agents; Pentanes; Prodrugs; Rats; Rats, Sprague-Dawley

The role of endocannabinoid signaling in the response of the brain to injury is tantalizing but not clear. In this study, transient middle cerebral artery occlusion (MCAo) was used to produce ischemia/reperfusion injury. Brain content of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol were determined during MCAo. Whole brain AEA content was significantly increased after 30, 60 and 120 min MCAo compared with sham-operated brain. The increase in AEA was localized to the ischemic hemisphere after 30 min MCAo, but at 60 and 120 min, was also increased in the contralateral hemisphere. 2-Arachidonoylglycerol content was unaffected by MCAo. In a second set of studies, injury was assessed 24 h after 2 h MCAo. Rats administered a single dose (3 mg/kg) of the cannabinoid receptor type 1 (CB1) receptor antagonist SR141716 prior to MCAo exhibited a 50% reduction in infarct volume and a 40% improvement in neurological function compared with vehicle control. A second CB1 receptor antagonist, LY320135 (6 mg/kg), also significantly improved neurological function. The CB1 receptor agonist, WIN 55212-2 (0.1-1 mg/kg) did not affect either infarct volume or neurological score.

Topics: Animals; Arachidonic Acids; Benzofurans; Benzoxazines; Blood Pressure; Brain Chemistry; Brain Infarction; Chromatography, Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Hemodynamics; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Mass Spectrometry; Morpholines; Naphthalenes; Neurologic Examination; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Reperfusion Injury; Rimonabant; Tetrazolium Salts; Time Factors

To investigate the effects of 3-n-butylphthalide (NBP) on apoptosis induced by transient focal cerebral ischemia in rats, compare the action potency of s-(-)-, r-(+)- and (+/-)-NBP, and clarify the enantiomer that played a main role.. DNA fragmentation was detected by the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assay and gel electrophoresis. The expression of cytochrome c and caspase-3 protein was observed by Western blot analysis and immunohistochemistry. Middle cerebral artery was occluded for 2 h.. Significant DNA fragmentation was detected at 24 h after reperfusion. This response was inhibited by s-(-)-NBP (5, 10 mg/kg i.p.). s-(-)-NBP 10 mg/kg almost completely inhibited DNA fragmentation, whereas r-(+)- NBP 10 mg/kg showed less effect. (+/-)-NBP (20 mg/kg) showed an inhibitory effect between that of s-(-)-NBP (10 mg/kg) and r-(+)-NBP (10 mg/kg). During the apoptotic process, cytochrome c was released into the cytosol and caspase-3 was activated. This effect was markedly inhibited by s-(-)-NBP, and the action potency of r-(+)- and (+/-)-NBP on the changes of cytochrome c and caspase-3 protein was similar to that on DNA fragmentation.. NBP, especially its s-(-)-enantiomer, could potently reduce the release of cytochrome c, decrease the activation of caspase-3, and inhibit DNA fragmentation after transient focal cerebral ischemia. Our findings on the beneficial effects of NBP on cerebral ischemia-induced apoptosis might have important implications for the study and treatment of ischemic cerebrovascular diseases.

Topics: Animals; Apoptosis; Benzofurans; Caspase 3; Caspases; Cytochromes c; DNA Fragmentation; Drugs, Chinese Herbal; Ischemic Attack, Transient; Male; Neuroprotective Agents; Rats; Rats, Wistar; Stereoisomerism

The aim of the present study was designed to explore the effect of (+/-) -3-n-butylphthalide (NBP) on ATPase, anti-oxidant enzymes activities and lipid peroxidation of mitochondria and cerebral cortex in rats subjected to 24 hours of reperfusion following 2 hours of cerebral ischemia (tMCAO).. Activities of SOD (Superoxide Dismutase), GSH-Px (glutathione Peroxidase,) and CAT (Catalase), and MDA level of mitochondria or cortex were measured by using biochemical methods in tMCAO rats.. (1) The activities of mitochondrial Na+K(+)-ATPase, Ca(2+)-ATPase and Mg2+ ATPase were found to decrease significantly in the vehicle group (ischemia + saline). Pre-treatment with NBP (5, 10, 20 mg/kg, i.p.) 10 min before tMCAO markedly enhanced the activities of Na+K(+)-ATPase and Ca(2+)-ATPase, compared with vehicle group. (2) The activities of SOD and mitochondrial GSH-Px were decreased and MDA level increased in vehicle groups as compared with that in sham group (non-ischemia + saline). NBP (20 mg/kg, i.p.) significantly enhanced total mitochondrial SOD activity, and also enhanced cerebral cortex total SOD activity (in 5, 10, 20 mg/kg groups). However, it had no obvious effect on CuZn-SOD activity. NBP (20 mg/kg i.p.) markedly increased mitochondrial (but not in cerebral cortex) GSH-Px activity; NBP 10, 20 mg/kg markedly decreased mitochondrial MDA level compared with that in vehicle group (P < 0.05). (3) The action of raceme NBP on the increase of the activities of ATPase and antioxidative enzymes seemed to be beneficial than that of (-) -NBP or (+) NBP.. The results suggest that NBP improves energy pump and subsides oxidative injury which may contribute to its anti-neuronal apoptotic effect.

Topics: Adenosine Triphosphatases; Animals; Benzofurans; Cerebral Cortex; Drugs, Chinese Herbal; Glutathione Peroxidase; Ischemic Attack, Transient; Lipid Peroxidation; Male; Mitochondria; Neuroprotective Agents; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase

The objective of this work was to study the protective effects of salvianolic acid B (Sal B) on the dysfunctions of learning and memory induced by transient cerebral ischemia in mice. The mechanisms of its actions also were researched both in vivo and in vitro. The model of dysfunction of learning and memory induced by transient cerebral ischemia in mice was used. One trail passive avoidance tests were used to evaluate the learning and memory functions and experiments in vitro were employed to observe the antioxidative effects of Sal B. Cerebral transient ischemia would impair the function of memory in mice. In step down test. the error number and latency were 2.63 and 120.5 in control group and were 1.35 and 234.4 respectively in sham operated group (p < 0.05). In Sal B treated groups, the error number was less and latency was longer significantly than those of control group. Meanwhile. 3 and 10 mgkg(-1) of Sal B iv. reduced the malondialdehyde contents in cortex, hippocampus and striatum of cerebral transient ischemia rat ion vivo. Sal B 10--100 nmol L(-1) also inhibited lipid-peroxidation and scavenged free hydroxyl radicals in vitro. As conclusion. Sal B ameliorated learning and memory dysfunctions induced by cerebral transient ischemia. Its actions might be related to its antioxidant activity.

Topics: Animals; Antioxidants; Avoidance Learning; Benzofurans; Brain; Free Radical Scavengers; Hydroxyl Radical; Ischemic Attack, Transient; Learning; Lipid Peroxidation; Male; Malondialdehyde; Memory; Mice; Rats; Rats, Wistar

To study the protective effect of dl-3-n-butylphthalide (NBP) on blood-brain barrier (BBB) damage induced by reperfusion following focal cerebral ischemia.. Focal cerebral ischemia in rats was performed by inserting a nylon suture into intracranial segment of internal carotid artery to block the origin of middle cerebral artery and reperfusion by withdrawing the nylon suture. Permeability of BBB was determined by extravasation of the protein-bound Evans blue dye to cerebral cortex and further evaluated by immunohistochemical or electronmicroscopic method.. Reperfusion for 3 h following focal cerebral ischemia for 3 h produced BBB damage which exhibited the increase in extravasation in cerebral cortex, elevation of the expression of immunoglobulin (IgG), and pore formation in endothelial cell membrane of capillary in cerebral cortex. NBP (5-20 mg.kg-1) decreased the extravasation in a dose-dependent manner. The expression of IgG in cerebral cortex was decreased and the ultrastructure damage of capillaries was alleviated after treatment with NBP. NBP 20 mg.kg-1 also alleviated brain edema caused by 3-h reperfusion following 3-h middle cerebral artery occlusion (MCAO).. NBP has protective effect on BBB damage induced by reperfusion after MCAO.

Topics: Animals; Benzofurans; Blood-Brain Barrier; Capillaries; Capillary Permeability; Cerebral Cortex; Immunoglobulin G; Ischemic Attack, Transient; Male; Microscopy, Electron; Neuroprotective Agents; Rats; Rats, Wistar; Reperfusion Injury

To study the effect of dl-3-n-butylphthalide (NBP) on regional cerebral blood flow (rCBF) in forcal cerebral ischemia rats.. In chloral hydrate-anesthetized rat, the proximal portion of right middle cerebral artery (RMCA) was occluded, and H2 needle electrode was implanted in right striatum. rCBF was monitored in striatum using hydrogen clearance method.. Ten min after RMCA occlusion (RMCAO), NBP (5, 10, 20 mg.kg-1 i.p.) markedly increased rCBF to striatum (P < 0.01). When NBP was given i.p. 40 min after RMCAO, the increasing effect on rCBF was also observed (P < 0.05). However, when NBP was injected i.p. 60 min after RMCAO, the increasing effect of NBP on rCBF was not found. In NBP-pretreated (i.p. 40 min before RMCAO) group, rCBF in striatum measured at different time points of 30, 60, 90, 120, 150, and 180 min after RMCAO were increased by 97%, 107%, 136%, 211%, 173%, and 317%, respectively, compared with the percentages of vehicle group. The potency of the effect of Nim (0.5 mg.kg-1 i.p.) was similar to that of NBP (10 mg.kg-1 i.p.).. NBP pre-treatment or post-treatment markedly enhanced the rCBF to striatum in RMCAO rats.

Topics: Animals; Benzofurans; Cerebrovascular Circulation; Corpus Striatum; Drugs, Chinese Herbal; Ischemic Attack, Transient; Male; Neuroprotective Agents; Nimodipine; Rats; Rats, Wistar; Vasodilator Agents

Transient cerebral ischemia may cause striking changes in gene expression in rat brain. The induction of heat shock protein 70 (hsp70) mRNA is considered to be an important marker of cerebral ischemia injury, and c-fos may upregulate the expression of other genes related to the secondary injuries. dl-3-n-Butylphthaline(NBP) had been shown to have good anti-cerebral ischemic effect. Using the in situ hybridization and Northern blot technique, the effect of NBP on the expression of hsp70 mRNA and c-fos in transient middle cerebral artery occlusion (MCAo) rat caused by intraluminal thread was studied, and found that the expression of hsp70 mRNA was at the lesioned site at 1 h of reperfusion. It increased gradually with the duration of reperfusion time and peaked at 12 h at the lesioned site. With NBP treatment(i.p. 10 mg.kg-1 10 min before ischemia or 20 mg.kg-1 after ischemia), the expression of hsp70 mRNA attenuated significantly. For c-fos, the expression appeared at 0.5 h of reperfusion, peaked at 3 h, and decreased at 6 h. NBP pretreatment (10 mg.kg-1 10 min before ischemia) also decreased the c-fos expression. The same results were obtained with Northern blot technique. Since NBP had been shown to have good anti-cerebral ischemic effects, the attenuating effect on gene expression seemed to be the secondary effect after the alleviation of tissue injury.

Topics: Animals; Benzofurans; HSP70 Heat-Shock Proteins; Ischemic Attack, Transient; Male; Neuroprotective Agents; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; RNA, Messenger; Stereoisomerism

To study the effects of dl-3-n-butylphthalide (NBP) on the changes of thromboxane B2 (TXB2) and 6-keto-PGF1 alpha (6-keto-PGF1 alpha) contents in hippocampus, striatum, and cerebral cortex of rats subjected to focal cerebral ischemia followed by reperfusion.. Focal cerebral ischemia was induced by inserting a nylon suture into intracranial segment of internal carotid artery from external carotid artery and blockade of the origin of middle cerebral artery. For reperfusion, the suture was pulled out to restore the blood flow to the ischemic brain. Determination of TXB2 and 6-keto-PGF1 alpha was performed by RIA method.. Reperfusion following focal cerebral ischemia resulted in increases in TXB2 at 5 min and 6-keto-PGF1 alpha at 30 min and a decrease in the ratio of epoprostenol (PGI2)/thromboxane A2 (TXA2) (6-keto-PGF1 alpha/TXB2) at 5 min in hippocampus, striatum, and cerebral cortex. NBP 10 mg.kg-1 reduced the content of TXB2 without decreasing effect on 6-keto-PGF1 alpha. NBP 20 mg.kg-1 reduced both TXB2 and 6-keto-PGF1 alpha in lesser extent than aspirin (Asp, 20 mg.kg-1). NBP 20 or 10 mg.kg-1 elevated the ratio of PGI2/TXA2 after reperfusion, but Asp 20 mg.kg-1 did not increase the ratio except in striatum at 5 min after reperfusion.. NBP increases the ratio of PGI2/TXA2 which may have beneficial effects on the impaired microcirculation in postischemic brain tissues.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Benzofurans; Brain; Ischemic Attack, Transient; Neuroprotective Agents; Rats; Reperfusion Injury; Thromboxane B2

Restoration of blood flow after an ischaemic event generates the formation of oxygen radicals which could augment brain damage. The authors studied the effects of different doses (50, 100, 200 mg/kg/i.p.) of a new antioxidant, IRFI-016, [2(2,3-dihydro-5-acetoxy-4,6,7-trimethylbenzofuranyl) acetic acid] on brain damage in the Mongolian gerbil induced by 5 min of bilateral carotid occlusion (BCO) followed by reperfusion. Post-ischaemic brain malondialdehyde (MDA) levels and locomotor activity at different times and delayed neuronal death of hippocampal CA1 area on the fourth day after occlusion were evaluated. During reperfusion, after BCO, enhancement of brain MDA occurs (37.5%, 62.5% and 100% at 15, 30 and 60 min of reperfusion, respectively). Brain MDA postischaemic increases were reduced at 15 min of reperfusion to 15.4% and 44.4% by IRFI-016, 100 and 200 mg/kg, respectively. After 30 min of reperfusion brain MDA was reduced to 31.25% and 53.13% by IRFI-016 100 and 200 mg/kg, respectively. Hyperactivity and delayed neuronal death of CA1 were significantly reduced in postischaemic gerbils treated with the highest doses of IRFI-016. Results indicate that pretreatment with the antioxidant IRFI-016 improves in a dose-dependent manner brain damage induced by ischaemia and reperfusion in the gerbil.

Topics: Animals; Antioxidants; Benzofurans; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Gerbillinae; Ischemic Attack, Transient; Locomotion; Male; Reperfusion; Vitamin E

Mongolian gerbils were subjected to transient forebrain ischaemia by occluding both common carotid arteries for 7 min. Subcutaneous administration of either the kappa-opioid receptor agonist enadoline (CI-977; 1 mg kg-1), or the non-competitive NMDA receptor antagonist dizocilpine (MK-801; 3 mg kg-1), at induction of ischaemia prevented neurodegeneration of CA1-CA2 pyramidal neurones in the dorsal hippocampus. It was shown by continuously monitoring intrahippocampal temperature that brain temperature drops by approximately 4 degrees C during ischaemia, when rectal temperature is maintained normothermic. Enadoline at no time point tested affected brain temperature, whereas dizocilpine statistically lowered brain temperature following ischaemia. These findings suggest that enadoline affords neuroprotection in the absence of any hypothermic episode, whilst in the case of dizocilpine, the small transient hypothermia observed following ischaemia may act synergistically or additively with the drug to yield neuroprotection.

Topics: Animals; Benzofurans; Body Temperature; Brain; Dizocilpine Maleate; Female; Gerbillinae; Ischemic Attack, Transient; Models, Biological; Pyrrolidines

The effects of the kappa-1 opioid receptor agonist (5R)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-4- benzofuranacetamide monohydrochloride (CI-977) upon ischemic brain damage have been examined in 15 halothane-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery (MCA), and the animals killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotactic planes. Pretreatment with CI-977 (0.3 mg/kg i.v. followed by continuous infusion at 0.15 mg/kg/h until death), initiated 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 2345 +/- 675 mm3 of the cerebral hemisphere in vehicle-treated cats to 1569 +/- 370 mm3 in CI-977-treated cats; P < 0.01). These data indicate that the kappa-1 opioid agonist CI-977 is neuroprotective in a model of focal cerebral ischemia in a gyrencephalic species where key systemic variables have been assessed throughout the entire post-ischemic period.

Topics: Animals; Benzofurans; Blood Glucose; Blood Pressure; Body Temperature; Brain; Cats; Cerebral Arteries; Hematocrit; Histocytochemistry; Ischemic Attack, Transient; Pyrrolidines; Receptors, Opioid, kappa

The effect of a novel, highly potent and selective kappa-opioid receptor agonist CI-977 upon ischaemic brain damage and brain swelling has been examined in a rat model of focal cerebral ischaemia. Focal ischaemia was produced by the permanent occlusion of the left middle cerebral artery (MCA) during a brief period of halothane anaesthesia. The animals were sacrificed 24 h after MCA occlusion and the amount of ischaemic brain damage and swelling was assessed in coronal sections at 8 predetermined stereotactic planes. Treatment with CI-977 (0.03, 0.3 or 3 mg/kg), initiated 30 min prior to MCA occlusion (and at multiple times thereafter) produced dose-dependent reductions in the volumes of infarction and of brain swelling, with the most marked reductions being noted with CI-977 (0.3 mg/kg) in both infarction (reduced by 38% from controls; P less than 0.02) and swelling (reduced by 31%; P less than 0.002). There was an excellent correlation between the volume of brain swelling and ischaemic damage which was similar with saline-treated and CI-977-treated animals (overall correlation coefficient r = 0.896). These results indicate that CI-977 is effective in reducing infarction in a model of focal cerebral ischaemia, and that the reduction in brain swelling occurs in parallel with the reduction in ischaemic damage.

Topics: Animals; Benzofurans; Brain Edema; Cerebral Infarction; Disease Models, Animal; Ischemic Attack, Transient; Male; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Topics: Amiodarone; Arrhythmias, Cardiac; Benzofurans; Dose-Response Relationship, Drug; Humans; Ischemic Attack, Transient; Thyroid Gland