piperidines and Ischemic-Attack--Transient

An emerging body of evidence supports a key role for the endocannabinoid system in numerous physiological and pathological mechanisms of the central nervous system. In the recent past, many experimental studies have examined the putative protective or toxic effects of drugs interacting with cannabinoid receptors or have measured the brain levels of endocannabinoids in in vitro and in vivo models of cerebral ischemia. The results of these studies have been rather conflicting in supporting either a beneficial or a detrimental role for the endocannabinoid system in post-ischemic neuronal death, in that cannabinoid receptor agonists and antagonists have both been demonstrated to produce either protective or toxic responses in ischemia, depending on a number of factors. Among these, the dose of the administered drug and the specific endocannabinoid that accumulates in each particular model appear to be of particular importance. Other mechanisms that have been put forward to explain these discrepant results are the effects of cannabinoid receptor activation on the modulation of excitatory and inhibitory transmission, the vasodilatory and hypothermic effects of cannabinoids, and their activation of cytoprotective signaling pathways. Alternative mechanisms that appear to be independent from cannabinoid receptor activation have also been suggested. Endocannabinoids probably participate in the mechanisms that are triggered by the initial ischemic stimulus and lead to delayed neuronal death. However, further information is needed before pharmacological modulation of the endocannabinoid system may prove useful for therapeutic intervention in stroke and related ischemic syndromes.

Topics: Animals; Brain Injuries; Brain Ischemia; Cannabinoid Receptor Modulators; Cell Death; Disease Models, Animal; Endocannabinoids; Humans; Ischemic Attack, Transient; Isoenzymes; Neurons; Nitric Oxide Synthase; Piperidines; Pyrazoles; Rimonabant

There are difficulties in accurately defining patients with vascular dementia (VaD) and, therefore, little is known about the characteristics of this population.. To examine the population characteristics in patients with VaD enrolled in two randomized, double-blind, placebo-controlled, 24-week clinical trials of the efficacy and tolerability of the acetylcholinesterase inhibitor donepezil.. Enrolled patients had probable or possible VaD, classified according to NINDS-AIREN criteria. Patients were excluded if they had a diagnosis of Alzheimer's disease or dementia caused by other conditions not associated with the cardiovascular system.. A total of 1,219 patients, 73% with probable VaD and 27% with possible VaD, were enrolled. Patients had a mean Hachinski score of 9.7, with memory impairment the most prominent feature of their dementia. Sixty-eight percent of patients had a history of at least one stroke and 28% of patients had a history of transient ischemic attack before dementia. In the 99% of patients who had abnormal computer-assisted tomography or magnetic resonance imaging scans, cortical and subcortical infarcts were among the lesions observed, with significant white-matter lesions also present in some patients. Seventy-three percent of patients had experienced an abrupt onset of cognitive symptoms. Vascular risk factors were prominent and included hypertension (70%), smoking (62%), and hypercholesterolemia (39%).. The patients enrolled in these trials had probable or possible VaD; these patients exhibited a history of cerebrovascular disease and a broad range of comorbid cardiovascular conditions. The large number of patients enrolled will permit a thorough examination of the efficacy and tolerability of donepezil in VaD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Humans; Indans; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Population Surveillance; Psychometrics; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome

Platelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events.. Lotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [alphaIIb/beta3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease.. The efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia.

Topics: Administration, Oral; Adolescent; Arterial Occlusive Diseases; Benzodiazepines; Double-Blind Method; Drug Evaluation; Female; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Myocardial Ischemia; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Research Design; Secondary Prevention; Stroke

Opioid agonists have been implicated in neuroprotection from hypoxic injury through regulating mitogen-activated protein kinases and cytokines. We determined the effects of remifentanil in focal brain ischemia and reperfusion (I/R) injury. Mechanisms linked to mitogen-activated protein kinases, including extracellular signaling-regulated kinase (ERK) 1/2, p38 kinases, and c-Jun N-terminal kinase (JNK), and various cytokines were also examined.. Male Sprague-Dawley rats were subjected to an I/R insult consisting of 90 minutes' middle cerebral artery occlusion (MCAO) followed by reperfusion under general anesthesia. Neurological deficit scores and infarct volume were determined after 24 hours of reperfusion. Remifentanil (5 μg/kg/min) was given alone or combined with naltrindole (δ-opioid receptor antagonist; 1 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (μ-opioid receptor antagonist; 1 mg/kg), or 5'-guanidinonaltrindole (κ-opioid receptor antagonist; 1 mg/kg). Opioid antagonists were administered 20 minutes before MCAO. Remifentanil infusion was started 10 minutes before MCAO and continued throughout. The control group was without drugs. The expression levels of ERK1/2, p38, and JNK, and also those of tumor necrosis factor-α (TNF-α) and interleukin-6, were determined after 1, 3, and 24 hours of reperfusion.. Remifentanil significantly improved the functional outcome and reduced the infarct volumes (69.0±24.3 mm(3) vs. 108.9±24.8 mm(3)), which were not affected by D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) or 5'-guanidinonaltrindole, but were abolished by naltrindole. The I/R insult enhanced the phosphorylation of ERK 1/2 and the expression of TNF-α, which were significantly reduced by remifentanil. Neither the phosphorylation of p38 and JNK nor the production of interleukin-6 was altered throughout the experiment.. Remifentanil may be neuroprotective against focal I/R injury, possibly through the activation of δ-opioid receptors and attenuation of ERK 1/2 activity and TNF-α production, in the rat brain.

Topics: Anesthetics, Intravenous; Animals; Blood Pressure; Blotting, Western; Carbon Dioxide; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Interleukin-6; Ischemic Attack, Transient; Male; Mitogen-Activated Protein Kinases; Naltrexone; Narcotic Antagonists; Nervous System Diseases; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Reperfusion Injury; Tumor Necrosis Factor-alpha

Our previous study demonstrated that pretreatment with electroacupuncture (EA) elicited protective effects against transient cerebral ischemia through cannabinoid receptor type 1 receptor (CB1R). In the present study, we investigated whether or not the extracellular signal regulated-kinase 1/2 (ERK1/2) pathway was involved in the ischemic tolerance induced by EA pretreatment through CB1R. At 24h after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion for 120min in rats. The neurological scores and infarct volumes were evaluated at 24h after reperfusion. The expression of p-ERK1/2 in the brains was also investigated in the presence or absence of CB1R antagonist AM251. EA pretreatment reduced infarct volumes and improved neurological outcome at 24h after reperfusion, and the beneficial effects were abolished by U0126. The blockade of CB1R by AM251 reversed the up-regulation of p-ERK1/2 expression induced by EA pretreatment. Our findings suggest that the ERK1/2 pathway might be involved in EA pretreatment-induced cerebral ischemic tolerance via cannabinoid CB1 receptor in rats.

Topics: Animals; Behavior, Animal; Blotting, Western; Brain Ischemia; Butadienes; Electroacupuncture; Enzyme Activation; Enzyme Inhibitors; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neuroprotective Agents; Nitriles; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Reperfusion Injury; Signal Transduction; Up-Regulation

Cerebral ischemia/reperfusion injury is characterized by the development of inflammatory response, in which vascular macrophages and endogenous microglia are involved. Recent studies showed marked induction of hematopoietic prostaglandin D synthase (HPGDS) after ischemic/reperfusion injury and its localization in microglia, but the molecular mechanism(s) of HPGDS actions in cerebral ischemia is not clear. To clarify the role of HPGDS in cerebral ischemia, C57BL/6 mice and bone marrow chimera mice with cerebral ischemia/reperfusion injury were treated with (4-benzhydryloxy-(1) {3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a specific inhibitor of HPGDS. The bone marrow chimera mice exhibit expression of enhanced green fluorescent protein (EGFP) in bone marrow/blood-derived monocytes/macrophages. Mice were subjected to ischemia/reperfusion and either treated with HQL-79 (n=44) or vehicle (n=44). Brain sections prepared at 72 h and 7 days after reperfusion were analyzed for neuronal nuclei (NeuN), HPGDS, ionized calcium-binding adapter molecule 1 (Iba1), inducible NO synthase (iNOS), nitrotyrosine, nuclear factor kappa B (NF-kB) and cyclooxygenase-2 (COX-2). The mortality rate (80%) and infarct size were larger in HQL-79- than vehicle-treated mice (58.7+/-8.5 versus 45.2+/-4.9 mm(3); mean+/-SEM, P<0.0001) at 7 days after reperfusion. HQL-79 reduced NeuN expression in the transition area and Iba1 expression (P<0.0001) in the ischemic peri- and penumbra area, but increased COX-2 (P<0.05) and NF-kB expression (P<0.05) in ischemic penumbra and increased formation of nitrotyrosine (P<0.0001) and iNOS (P<0.0001) in the ischemic core area at 72 h and 7 days after reperfusion. In EGFP chimera mice, HQL-79 increased the migration of Iba1/EGFP-positive bone marrow-derived monocytes/macrophages, and simultaneously upregulated iNOS expression in the ischemic core area (P<0.0001), but increased intrinsic microglia/macrophages in ischemic peri-area and penumbra (P<0.0001) at 72 h and 7 days after reperfusion, suggesting involvement of monocytes/macrophages in HQL-79-induced expansion of ischemic injury. Our results demonstrated that the neuroprotective effects of HPGDS in our model are mediated by suppression of activation and infiltration of inflammatory cells.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Bone Marrow Transplantation; Brain; Chemotaxis, Leukocyte; Disease Models, Animal; Encephalitis; Enzyme Inhibitors; Green Fluorescent Proteins; Hypoxia-Ischemia, Brain; Intramolecular Oxidoreductases; Ischemic Attack, Transient; Isomerases; Lipocalins; Macrophages; Male; Mice; Mice, Inbred C57BL; Microglia; Nerve Tissue Proteins; Neuroprotective Agents; Nitric Oxide Synthase Type II; Piperidines; Reperfusion Injury; Transplantation Chimera

Experimental evidence suggests that reactive free radicals are generated during brain ischemia. We investigated the effect of a novel brain penetrant, low molecular weight, non-peptidyl carbon, oxygen- and nitrogen-centered radical scavenger, IAC, on infarct volume and sensory-motor performance in a rat transient middle cerebral artery occlusion model (tMCAO). Rats received 90 min tMCAO and treated with i.p. or i.v. injections of vehicle or IAC following tMCAO. Sensory-motor performance was evaluated by neuroscore tests (NS). Cerebral infarct volume was evaluated at 72 h after tMCAO. Rats treated with IAC i.p. (1 or 6 h after the onset of tMCAO) or i.v. (1 h after the onset of tMCAO) showed significant improvement in NS during the 3 or 21 day follow-up period when compared to vehicle treated rats. Cerebral infarct volumes were significantly decreased compared to vehicle in rats receiving IAC i.p. 1 h or 6 h after occlusion, approximately 30.5% decrease compared to vehicle, or i.v. 1 h after the onset of tMCAO, 48.6% decrease compared to vehicle. These results demonstrate that IAC has neuroprotective properties with a wide therapeutic window following tMCAO in rats. IAC could therefore be a candidate for the treatment of stroke.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cerebral Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Esters; Ischemic Attack, Transient; Male; Neuroprotective Agents; Piperidines; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Time Factors

We have previously demonstrated that pretreatment with selective kappa-opioid agonist BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine], provides ischemic neuroprotection following transient focal ischemia in rats. The present study was undertaken to a) define "therapeutic opportunity" for ischemic neuroprotection with BRL 52537, and b) determine if BRL 52537 attenuates ischemia-evoked efflux of dopamine and its metabolites in the striatum in vivo following transient focal ischemia.. Using the intraluminal filament technique, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO). In a blinded, randomized fashion, rats were treated with saline (vehicle) or 1 mg/Kg/hr BRL 52537 infusion for 22 hours, initiated at onset, 2, 4, or 6 hours of reperfusion (Rep). In a separate set of experiments utilizing in vivo microdialysis, extracellular levels of dopamine and its metabolites were determined in the striatum during 2 hours of MCAO and 3 hours of reperfusion.. Infarct volume (% of contralateral structure; mean +/-SEM) in cortex was significantly attenuated when BRL 52537 was administered at reperfusion (22+/-6%), 2 hours (21+/-6%), and 4 hours (18+/-5%) compared with controls (39+/-5%). In striatum, infarct volume was significantly attenuated when BRL 52537 was administered at reperfusion (38+/-9%), 2 hours (40+/-8%), 4 hours (50+/-8%), and 6 hours (46+/-9%) as compared with controls (70+/-4%). A 6- to 8-fold increase in dopamine in microdialysates occurred within 40 minutes of MCAO. Pretreatment with BRL 52537 did not alter microdialysate levels of dopamine or its metabolites in the striatum during MCAO and early reperfusion, as compared with saline controls.. These data demonstrate that BRL 52537 provides robust ischemic neurprotection with a long therapeutic opportunity (at least 6 hours) without altering ischemia-evoked efflux of dopamine (DA) and its metabolites in striatum during ischemia and early reperfusion.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Corpus Striatum; Dopamine; Ischemic Attack, Transient; Microdialysis; Neuroprotective Agents; Piperidines; Pyrrolidines; Random Allocation; Rats; Rats, Wistar; Receptors, Opioid, kappa; Reperfusion Injury

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

Kappa-opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl) methylpiperidine], on infarct volume and nitric oxide production after transient focal ischemia in the rat.. With the use of the intraluminal filament technique, halothane-anesthetized male Wistar rats (weight, 250 to 300 g) were subjected to 2 hours of focal cerebral ischemia confirmed by Doppler flowmetry. In a blinded randomized fashion, rats were treated with intravenous saline or 1 mg/kg per hour BRL 52537 infusion, initiated 15 minutes before occlusion and maintained until 2 hours of reperfusion. In a second experiment, rats were treated during reperfusion with saline or 1 mg/kg per hour BRL 52537, initiated at onset of reperfusion and continued for 22 hours. In a final experiment, in vivo striatal nitric oxide production was estimated via microdialysis by quantification of citrulline recovery after labeled arginine infusion in striatum of intravenous BRL 52537- or saline-treated rats.. In rats treated with BRL 52537 during ischemia and early reperfusion, infarct volume was significantly attenuated in cortex (16+/-6% versus 40+/-7% of ipsilateral cortex in saline group) and in caudoputamen (30+/-8% versus 66+/-6% of ipsilateral caudoputamen in saline group). Infarct volume was also reduced by treatment administered only during reperfusion in cortex (19+/-8% in BRL 52537 group [n=10] versus 38+/-6% in saline group) and in caudoputamen (35+/-9% versus 66+/-4% in saline group). BRL 52537 treatment markedly attenuated NO production in ischemic striatum compared with saline-treated controls.. These data demonstrate that (1) the selective KOR agonist BRL 52537 provides significant neuroprotection from focal cerebral ischemia when given as a pretreatment or as a posttreatment and (2) attenuation of ischemia-evoked nitric oxide production in vivo may represent one mechanism of ischemic neuroprotection.

Topics: Animals; Arginine; Cerebral Infarction; Citrulline; Corpus Striatum; Disease Models, Animal; Ischemic Attack, Transient; Male; Microdialysis; Neuroprotective Agents; Nitric Oxide; Piperidines; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Treatment Outcome

Kappa-opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetrol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1). saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2). saline 15 min before reperfusion followed by BRL 52537 (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, 3). saline 15 min before reperfusion followed by nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mgx kg(-1)x h(-1)) and nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% +/- 4.3%; caudoputamen [CP], 23.8% +/- 6.7%) (mean +/- SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% +/- 4.9%; CP, 53.3% +/- 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% +/- 5.3%; CP, 40.9% +/- 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke.. The neuroprotective effect of selective kappa-opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Cranial Nerves; Functional Laterality; Gait; Hemodynamics; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Middle Cerebral Artery; Muscle Tonus; Naltrexone; Neuroprotective Agents; Pain; Piperidines; Putamen; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Weight Loss

Cyclin-dependent kinases (CDKs) are commonly known to regulate cell proliferation. However, previous reports suggest that in cultured postmitotic neurons, activation of CDKs is a signal for death rather than cell division. We determined whether CDK activation occurs in mature adult neurons during focal stroke in vivo and whether this signal was required for neuronal death after reperfusion injury. Cdk4/cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke. Deregulated levels of E2F1, a transcription factor regulated by pRb, are also observed. Administration of a CDK inhibitor blocks pRb phosphorylation and the increase in E2F1 levels and dramatically reduces neuronal death by 80%. These results indicate that CDKs are an important therapeutic target for the treatment of reperfusion injury after ischemia.

Topics: Animals; Apoptosis; Brain; Carrier Proteins; Cell Cycle Proteins; Cerebrovascular Circulation; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; Enzyme Inhibitors; Flavonoids; Ischemic Attack, Transient; Male; Neurons; Piperidines; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Retinoblastoma-Binding Protein 1; Transcription Factor DP1; Transcription Factors

In the present studies, we have examined the effects of two new Ca(2+) channel blockers, LY042826 (N-[2-[(2-methylphenyl)(phenyl)methoxy]ethyl]-1-butanamine hydrochloride) and LY393615 (N-[[5, 5-bis(4-fluorophenyl)tetrahydro-2-furanyl]methyl]-1-butanamine hydrochloride) in the gerbil model of global and the endothelin-1 rat model of focal cerebral ischaemia in vivo. Results indicated that both LY042826 (P<0.01) and LY393615 (P<0.001) provided significant protection against ischaemia-induced hippocampal damage in global cerebral ischaemia when dosed at 15 mg/kg i.p. 30 min before and 2 h 30 min after occlusion. In further studies, LY042826 (P<0.05) and LY393615 (P<0.01) were also protective when administered at 15 mg/kg i.p. immediately after and 3 h post-occlusion. Both compounds also provided a significant reduction in the infarct volume following endothelin-1 middle cerebral artery occlusion in the rat when administered at 15 mg/kg i.p. immediately (P<0.05) after occlusion. This protection was similar to that observed with the NMDA receptor antagonist (5R,10S)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine), MK-801 in this model. In conclusion and as a result of the present studies, we report that the novel Ca(2+) channel blockers, LY042826 and LY393615 protect against ischaemia-induced brain injury in gerbils and rats. The compounds were neuroprotective when administered post-occlusion and may therefore be useful anti-ischaemic agents.

Topics: Animals; Biphenyl Compounds; Butylamines; Calcium Channel Blockers; Cell Count; Dizocilpine Maleate; Endothelin-1; Furans; Gerbillinae; Guanidines; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Neuroprotective Agents; Piperidines

Poly(ADP-ribose) polymerase (PARP) is thought to play a physio-logical role in maintaining genomic integrity and in the repair of DNA strand breaks. However, the activation of PARP by free radical-damaged DNA plays a pivotal role in mediating ischemia-reperfusion injury. The excessive activation of PARP causes a rapid depletion of intracellular energy leading to cell death. The present study examined the effect of post-ischemic pharmacological inhibition of PARP in a rat focal cerebral ischemia model. In Long-Evans rats, focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid artery (CCA) occlusion for 90 min. A PARP inhibitor, 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ; IC50=1 microM/l) was injected i.p. 30 min after the onset of MCA occlusion (control: 10, 20, 40 and 80 mg/kg; n=7 each). Twenty-four hours later, the total infarct volume was measured. Regional blood flow in the right parietal cortex decreased to approximately 20% of the baseline following MCA occlusion in all groups. PARP inhibition lead to a significant decrease in damaged volume in all treated groups with the largest reduction in the 40 mg/kg group (111.5+/-24. 8 mm3, mean+/-SD, p<0.01), compared to the control group (193.5+/-28. 6 mm3). We also found there was a significant increase of poly(ADP-ribose) immunoreactivity in the ischemic region, as compared to the contralateral side, with DPQ treatment diminishing poly(ADP-ribose) production. These findings indicate that DPQ exerts its neuroprotective effects in vivo by PARP inhibition and that PARP inhibitors may be effective for treating ischemic stroke, even when the treatment is initiated after the onset of ischemia.

Topics: Animals; Arterial Occlusive Diseases; Cerebral Infarction; Cerebrovascular Circulation; Enzyme Inhibitors; Immunohistochemistry; Ischemic Attack, Transient; Isoquinolines; Male; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Long-Evans

NS521 (1-(1-butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine) belongs to a group of novel benzimidazolones, which exhibit neurotrophic-like activities. In vitro, NS521 rescued neuronal PC12 cells from death induced by serum and nerve growth factor deprivation. The survival effect of NS521 appeared to reflect a delay of the apoptotic process, because the extent of DNA fragmentation was attenuated transiently by NS521. NS521 did not preserve the neurites of the rescued cells, which, otherwise, appeared to be healthy and were able to regenerate when serum and nerve growth factor were added back to the culture. In vivo, NS521 provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. A neuroprotective effect of NS521 in the peripheral nervous system also was observed in rats after transection of the sciatic nerve, where daily treatment with NS521 was found to inhibit retrograde degeneration of the transected nerve. The neuroprotective effect of NS521 is unlikely to be mediated through neurotrophin receptors, such as TrkA, because NS521 did not induce phosphorylation of the 44- and 42-kDa isoforms of mitogen-activated protein kinases (ERK1/2) in PC12 cells.

Topics: Animals; Benzimidazoles; Calcium-Calmodulin-Dependent Protein Kinases; Cell Survival; Culture Media; DNA Fragmentation; Gerbillinae; Ischemic Attack, Transient; Male; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Neurons; Neuroprotective Agents; PC12 Cells; Phosphorylation; Piperidines; Rats; Rats, Wistar

A series of novel arylpiperidines (4a-d) which have highly potent blocking effects for both neuronal Na+ and T-type Ca2+ channels with extremely low affinity for dopamine D2 receptors were synthesized. Among these compounds, 1-(2-hydroxy-3-phenoxy)propyl-4-(4-phenoxyphenyl)-piperidine hydrochloride (4c; SUN N5030) exhibited remarkable neuroprotective activity in a transient middle cerebral artery occlusion (MCAO) model.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Calcium Channels, T-Type; Epilepsy, Reflex; Ischemic Attack, Transient; Mice; Mice, Inbred DBA; Neuroprotective Agents; Phenyl Ethers; Piperidines; Sodium Channel Blockers

Carotid endarterectomy (CEA) and coronary artery bypass grafting (CABG) as a combined procedure is occurring with increasing frequency. CEA-CABG incurs the morbidity of both procedures, and considerations for this procedure include anesthetic techniques that provide hemodynamic stability and prompt emergence from anesthesia. We present, to our knowledge, the first reported use in a combined CEA-CABG of the novel opioid remifentanil as a component of the anesthetic technique to achieve these goals. Remifentanil allows for early neurologic evaluation without sacrificing the hemodynamic stability of traditional, high-dose opioid techniques.

Topics: Analgesics, Opioid; Anesthesia Recovery Period; Anesthetics, Intravenous; Blood Pressure; Carotid Stenosis; Coronary Artery Bypass; Coronary Disease; Endarterectomy, Carotid; Heart Rate; Humans; Infusions, Intravenous; Injections, Intravenous; Intubation, Intratracheal; Ischemic Attack, Transient; Male; Middle Aged; Morphine; Neurologic Examination; Piperidines; Propofol; Remifentanil

While it has been widely reported that the vasospasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ET(A) receptor and by nonselective ET receptor antagonists, ie, antagonists of both the ET(A) and ET(B) receptors, there are no reports on the possible attenuation of the spasm by selective ET(B) receptor antagonists. The purpose of this study was to investigate whether (1) ET(B) receptor antagonists prevent and reverse SAH-induced spasm and (2) attenuation of the spasm results from blockade of smooth muscle ET(B) (ET(B2)) receptor-mediated constriction and/or endothelial ET(B) (ET(B1)) receptor-mediated ET-1-induced ET-1 release.. SAH-induced spasm of the rabbit basilar artery was induced with the use of a double hemorrhage model. In vivo effects of agents on the spasm were determined by angiography after their intracisternal infusion (10 microL/h) by mini osmotic pump. In situ effects of agents on the spasm were determined by direct measurement of vessel diameter after their suffusion in a cranial window.. SAH constricted the basilar artery by 30%. Intracisternal infusion with 10 micromol/L BQ788, an ET(B1/B2) receptor antagonist, reduced the spasm to 10%. To investigate whether BQ788 prevented the spasm by blockade of ET(B1) receptor-mediated ET-1-induced ET-1 release, as opposed to ET(B2) receptor-mediated constriction, we tested whether ET(B1) receptor blockade also prevented the spasm. Indeed, intracisternal infusion with 10 micromol/L RES-701-1, a selective ET(B1) receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1 micromol/L BQ788 reversed the spasm by 40%, and 1 micromol/L RES-701-1 reversed the spasm by 50%. However, both BQ788 and RES-701-1 enhanced by 40% to 50% the 3 nmol/L ET-1-induced constriction elicited in spastic vessels previously relaxed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor.. These results demonstrate that ET(B) receptor antagonists prevent and reverse SAH-induced cerebral vasospasm in an animal model. The likely mechanism underlying the attenuation of the spasm is blockade of ET(B1) receptor-mediated ET-1-induced ET-1 release of newly synthesized ET-1. These studies provide rationale for the therapeutic use of ET(B1) receptor antagonists to relieve the vasospasm following SAH, as well as other pathophysiological conditions involving possible ET-1-induced ET-1 release.

Topics: Animals; Basilar Artery; Endothelin Receptor Antagonists; Endothelin-1; Injections, Intraventricular; Ischemic Attack, Transient; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Rabbits; Receptor, Endothelin B; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilation

Focal cerebral lesions in the rat brain induced by photothrombosis cause hyperexcitability of the surrounding brain. This can be demonstrated in brain slices taken from animals several days after lesioning, by analysis of field potential responses to paired-pulse stimulation. We now investigated whether and how these remote effects of a cortical lesion can be modified pharmacologically. Application of the NMDA receptor antagonist, MK-801 ((+)-5-methyl-10, 11-dihydro-5H-dibnzo[a,d]cyclohepten-5,10-imine), was shown to block induction of immediate early genes and activation of astrocytes as evidenced by glial fibrillary acidic protein (GFAP) staining in the photothrombosis model. However, MK-801 did not affect the hyperexcitability that had been demonstrated by field potential recordings in brain slices. In another series of experiments, lubeluzole ((+)-(S)-4-(2-benzothiazolylmethylamino)-alpha-[(3,4-difluoroph enoxy) methyl]-1-piperidineethanol), which inhibits the glutamate-activated nitric oxide pathway as evidenced by down-regulation of intracellular cyclic GMP, was given immediately after induction of the insult. This reduced hyperexcitability as investigated 7 days later. In the light of these data one can suggest that a nitric oxide-cyclic GMP-related mechanism may be responsible for functional alterations in the surround of photothrombotic brain lesions.

Topics: Animals; Cerebral Cortex; Dermatitis, Phototoxic; Disease Models, Animal; Dizocilpine Maleate; Electrophysiology; Evoked Potentials; Excitatory Amino Acid Antagonists; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Male; Neuroprotective Agents; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Thiazoles

Topics: Animals; Arterial Occlusive Diseases; Cerebral Arteries; Excitatory Amino Acid Antagonists; Immunohistochemistry; Interneurons; Ischemic Attack, Transient; Male; Mice; Parietal Lobe; Parvalbumins; Piperidines

Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.

Topics: Adenosine Triphosphate; Animals; Benzamides; Brain; Cells, Cultured; Cerebral Cortex; Cerebrovascular Circulation; DNA Damage; Enzyme Activation; Enzyme Inhibitors; Hemodynamics; Immunity, Innate; Ischemic Attack, Transient; Isoquinolines; Mice; Mice, Knockout; N-Methylaspartate; NAD; Neurons; Neurotoxins; Nitrates; Nitric Oxide; Piperidines; Poly(ADP-ribose) Polymerases

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

Recently, an important role of platelet-activating factor (PAF), an inflammation mediator, has been demonstrated in the genesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). In the current study, the authors examined whether intravenous administration of the novel PAF antagonist, E5880, can prevent vasospasm following SAH in rabbits. A vasospasm model was produced in three groups of rabbits using two subarachnoid injections of autologous arterial blood, followed by intravenous administration of distilled water (control), a low dose of E5880 (0.1 mg/kg in distilled water), or a high dose of E5880 (0.5 mg/kg in distilled water). Neurological deterioration was largely prevented in the rabbits that received E5880. Basilar artery constriction was also reduced by both doses of E5880. Histological examination at autopsy predominantly showed ischemic changes in the brain. Animals in each E5880-treated group exhibited ischemic changes less frequently than those in the control group. Plasma thromboxane B2 concentrations were reduced in rabbits treated with E5880. Platelet-activating factor was immunolocalized in the intima and media of the basilar artery in the control group. The PAF immunoreactivity demonstrated in the basilar artery was decreased in the E5880 groups in a dose-dependent manner. Thus, this study provides evidence that PAF may play a role in the pathogenesis of vasospasm after SAH and that intravenous administration of E5880 is a promising approach in preventing vasospasm.

Topics: Animals; Female; Ischemic Attack, Transient; Piperidines; Pyridinium Compounds; Rabbits; Subarachnoid Hemorrhage; Thromboxane B2

Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke.. Patch-clamp electrophysiology and intracellular Ca2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound.. In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36 +/- 8% and 89 +/- 4% after 5 and 20 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50 +/- 2.5% after N-methyl-D-aspartate/glycine stimulation (P < .01). KCl depolarization-induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased (P < .05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced (P < .05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% (P < .01). No blood pressure effects were observed with the therapeutic dose of the compound.. These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.

Topics: Animals; Blood Pressure; Calcium; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Cerebellum; Cerebral Infarction; Disease Models, Animal; Glycine; Hippocampus; Ischemic Attack, Transient; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Neurons; Neuroprotective Agents; Patch-Clamp Techniques; Piperidines; Potassium Chloride; Rats; Rats, Inbred F344; Rats, Inbred Strains; Rats, Sprague-Dawley

The selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) and the selective N-methyl-D-aspartate (NMDA) receptor antagonists MK 801 and ifenprodil were administered to Mongolian gerbils following a 5 min period of bilateral carotid artery occlusion. NBQX when given 4, 6 or 24 h after ischaemia gave a reduced loss of hippocampal CA1 neurones compared to control animals receiving vehicle only. Dizocilipine (MK 801) (1-10 mg/kg i.p.) and ifenprodil (a total of 45 mg/kg i.p.) gave no protection. The peak levels of NBQX obtained in the cerebrospinal fluid of gerbils receiving the neuroprotective dose (3 x 30 mg/kg i.p.) was 1 microM. In gerbil cortex slices, this concentration had no effect on NMDA-evoked depolarization, but had a moderate effect on kainate and gave a total blockade of AMPA depolarizations. It is concluded that antagonists of non-NMDA glutamate receptor subtypes, possibly AMPA, may be a useful therapeutic approach for cerebral ischaemia-related brain damage following global ischaemia.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Gerbillinae; Hippocampus; Ibotenic Acid; Ischemic Attack, Transient; Kinetics; Male; Neurons; Piperidines; Quinoxalines; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate

Serotonin released from platelets has been suggested as one substance causing the vasospasm following subarachnoid hemorrhage. We studied whether such serotonin is able to constrict pial vessels.. We studied the uptake of serotonin in pial perivascular nerves by immunohistochemistry. We measured the contractile response in rat basilar artery after in vitro incubation with serotonin and during electrical field stimulation of perivascular nerves following experimental subarachnoid hemorrhage.. After incubation with serotonin, electrical field stimulation caused a tetrodotoxin- and ketanserin-blockable contractile response. We observed no such response in vessels from rats treated with 6-hydroxydopamine or after blockade of serotonin uptake. After subarachnoid hemorrhage, a pronounced network of serotonin-immunoreactive nerve fibers was demonstrated in the vessel wall. In vessels from control rats, no serotonin fibers were seen, and in vessels from 6-hydroxydopamine-treated animals with subarachnoid hemorrhage only a few such fibers were seen. Electrical field stimulation of the basilar artery from rats tested 2 or 16 hours (but not 10 minutes or 24 hours) after subarachnoid hemorrhage showed contractile responses that were prevented by tetrodotoxin, ketanserin, and prior 6-hydroxydopamine treatment.. Our study demonstrates a capacity of the perivascular sympathetic nerves to take up serotonin both in vitro and during the early phase of subarachnoid hemorrhage. Such uptake may help to remove excess serotonin from the subarachnoid space. Only if serotonin is subsequently released upon nerve activation may minor smooth muscle contraction develop.

Topics: Animals; Basilar Artery; Electric Stimulation; Ischemic Attack, Transient; Ketanserin; Male; Oxidopamine; Paroxetine; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Subarachnoid Hemorrhage; Sympathetic Nervous System; Tetrodotoxin; Vasoconstriction

The effects of the 5-HT2 receptor antagonists pirenperone, cinanserin and ritanserin on impairment of working memory in an animal model of cerebral ischemia were investigated, using a three-panel runway task. A 5-min period of ischemia caused a significant increase in the number of errors (attempts to pass through two incorrect panels of the 3 panel gates at 4 choice points). Pirenperone at 0.32 and 1.0 mg/kg, cinanserin 10 mg/kg and ritanserin 3.2 mg/kg administered i.p. immediately after blood flow reperfusion significantly reduced the increase in errors expected to occur 24 h after the 5 min of ischemia. These results suggest that the blockade of 5-HT2 receptors prevents the impairment of working memory following transient forebrain ischemia.

Topics: Animals; Cinanserin; Ischemic Attack, Transient; Male; Memory; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists

Pharmacological inhibition of cell excitation during focal ischemia was studied in the rat middle cerebral artery occlusion model. The potent and selective N-methyl-D-aspartate antagonist CGS 19755, administered 5 minutes prior to or 5 minutes following permanent middle cerebral artery occlusion, caused a substantial decrease in infarct size, which was associated with reduction of postischemic cerebral glucose hypermetabolism. These data support a role for excitation-induced hypermetabolism in the pathogenesis of infarction following focal cerebrovascular occlusion.

Topics: Animals; Deoxy Sugars; Deoxyglucose; Energy Metabolism; Ischemic Attack, Transient; Male; Pipecolic Acids; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

We evaluated several doses of cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS-19755), a potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight-arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium-calmodulin binding. High-dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS-19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium-calmodulin binding. We conclude that CGS-19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia.

Topics: Animals; Calcium; Calmodulin; Dose-Response Relationship, Drug; Ischemic Attack, Transient; Male; Pipecolic Acids; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

The measurement of cortical omega 3 (peripheral-type benzodiazepine binding) site densities provides an accurate index for the detection and quantification of ischaemic brain lesions following middle cerebral artery occlusion (MCAO) in mice. Here, we have used this marker to assess the neuroprotective activity of potential anti-ischaemic drugs belonging to several chemical classes. In untreated mice, the mean infarcted volume measured 96 h after unilateral coagulation of the middle cerebral artery was 27.9 +/- 4.3 mm3 (17.5% of the hemisphere volume) and omega 3 site densities (measured by incubation with 3H-PK 11195) were increased by 107.3 +/- 4.8% (cortical homogenates) or by 81% (coronal brain sections). The administration of the anti-ischaemic agent SL 82.0715 (10 mg/kg i.p.), 5 min, 6 h and 18 h after the occlusion and then twice daily until sacrifice evoked a decrease of similar magnitude (ca. 60-70%) in the volume of the infarction and in the proliferation of omega 3 sites. The constant tissue sparing effect of SL 82.0715 allowed the examination of the window of therapeutic opportunity. A significant diminution of cortical omega 3 sites was still noted when the first administration was delayed until 3 h post-occlusion. Moreover, the protective effect of SL 82.0715 was enhanced by repeated treatment for the first 36 h but not thereafter. Based on the histological, autoradiographic and homogenate binding results obtained with SL 82.0715, we studied the protective effects of several competitive and non-competitive NMDA receptor antagonists. When administered according to the above-described standard protocol, these drugs reduced omega 3 site levels in cortical homogenates from MCAO mice in a dose-dependent manner. The dose preventing by 50% the increase in omega 3 site levels (in mg/kg i.p.) and the maximal inhibition were respectively: MK-801 (0.2, 93%); TCP (1.6, 66%); kynurenate (260, 58%); ifenprodil (7.0, 58%); SL 82.0715 (1.1, 72%); CGS 19755 (46% at 10 mg/kg); dextromethorphan (46% at 30 mg/kg). In contrast, agents acting preferentially upon sigma (sigma) opiate receptors ((+)-3PPP, 1-10 mg/kg i.p. and haloperidol, 0.3-3 mg/kg i.p.) did not provide a significant protection. In general, calcium channel blockers (nimodipine, flunarizine, verapamil, perhexiline, diltiazem) were devoid of a clear neuroprotective potential when administered at non-toxic doses after the coagulation of the middle cerebral artery. Diltiazem (3 and 10 mg/kg i.p.) provi

Topics: Animals; Calcium Channel Blockers; Cell Survival; Cyclandelate; Ischemic Attack, Transient; Male; Mice; Molecular Structure; N-Methylaspartate; Piperidines; Platelet Activating Factor; Receptors, GABA-A; Receptors, Opioid; Receptors, sigma; Vincamine

We studied the protective effects of pentobarbital, vinpocetine, flunarizine, and ifenprodil on delayed neuronal death using Mongolian gerbils. The animals were allowed to survive for 7 days after 5 min of cerebral ischemia induced by bilateral occlusion of the common carotid arteries. Hippocampal cell loss was quantified histologically 7 days following ischemia. Intraperitoneal application of pentobarbital (40 mg/kg) 30 min and vinpocetine (50 and 100 mg/kg) 10 min before ischemia significantly reduced neuronal cell loss in the CA1 sector. However, the intraperitoneal administration of flunarizine (10 and 30 mg/kg) and ifenprodil (10 and 30 mg/kg) 15 min before ischemia was not protective. The results suggest that pentobarbital and vinpocetine prevent ischemic neuronal damage, but not flunarizine and ifenprodil. These findings are of interest in relation to the mechanism of delayed neuronal death.

Topics: Animals; Cell Survival; Flunarizine; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Pentobarbital; Piperidines; Vinca Alkaloids

Transient brain ischemia results in a selective destruction of cell bodies within the hippocampus and cortex. This cellular destruction appears to be mediated through a release of endogenous exictatory amino acids following the ischemic episode, since the neurotoxic effects of ischemia can be attenuated by compounds that have antagonist activity at N-methyl-D-aspartate (NMDA) receptors. In the present study, the protective effects of a novel NMDA receptor antagonist, CGS 19755, were further evaluated by using quantitative autoradiography to characterize adenosine A1, NMDA, PCP, and benzodiazepine receptors in ischemic gerbil brain. Bilateral carotid artery occlusion (20 minutes) resulted in marked decreases (30-60%) in adenosine A1, NMDA, and PCP, but not benzodiazepine, receptors in gerbil forebrain. Postischemic treatment with CGS 19755 was found to completely block the ischemia-induced decreases in brain adenosine and NMDA receptors. [3H]TCP binding in ischemic gerbil brain was also elevated by CGS 19755 treatment; significant differences remained, however, between the CGS 19755-treated and control gerbils. These results indicate that transient brain ischemia produces significant and selective alterations in gerbil forebrain receptor systems. The observed decreases in radioligand binding are probably reflective of an ischemia-induced destruction of forebrain structures. However, there is some evidence that transient ischemia can also cause long-term changes in the affinity of some receptor systems. The postischemic efficacy of CGS 19755 appears to be due to its ability to block the neurotoxic effects of transient ischemia.

Topics: Adenosine; Animals; Autoradiography; Female; Flunitrazepam; Gerbillinae; Image Processing, Computer-Assisted; Ischemic Attack, Transient; Pipecolic Acids; Piperazines; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine

N-Methyl-D-aspartate (NMDA) antagonists reduce ischemic brain damage and associated hypermotility. Two potent, selective and competitive NMDA antagonists, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) and 4-(3-phosphonopropyl)-2-piperazine-carboxylic acid (CPP), were characterized in the gerbil ischemia model with respect to dose-response and time course effects. Both drugs were effective in reducing ischemia-induced hippocampal brain damage as well as hypermotility. In this model, CGS 19755 was more potent than CPP, and had protective effects when given after longer delays between ischemia and drug administration.

Topics: Animals; Aspartic Acid; Brain; Female; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Motor Activity; N-Methylaspartate; Neurons; Pipecolic Acids; Piperazines; Piperidines

In an experimental cat model the leptomeningeal vasculature was studied by a vital microscopic brain window technique. The brain window was connected to a thermostat-regulated pool of Elliot's solution. By air-drying (10 min) of the arachnoid mesothelium access for drugs, applied into the pool, was established to the adventitia of the leptomeningeal vasculature. Application of 5-hydroxytryptamine (5-HT) (10(-6)-10(-4) M) caused dose-dependent contractile responses (morphometry of outer vessel diameter) of both arteries and veins of three different sizes (large, 200-300 microns; medium, 50-150 microns; small, 30-50 microns). A well-reproducible contractile response was obtained at challenge with 5-HT (10(-4) M) from the various vascular beds with most pronounced effects on the arterial side. If the animals were pretreated with peripheral blockade of serotonergic (5-HT2) receptors (ketanserin 0.3 mg/kg i.v.), challenge with 5-HT (10(-4) M) elicited no significant vascular responses on either the arterial or venous sides. Vital microscopy further visualized capillary beds after ketanserin pretreatment that were not seen under control conditions.

Topics: Animals; Cats; Cerebrovascular Circulation; Ischemic Attack, Transient; Ketanserin; Muscle Contraction; Muscle, Smooth, Vascular; Piperidines; Serotonin; Serotonin Antagonists

Peri-aneurysmal CSF was obtained at operation from 13 patients with subarachnoid haemorrhage from ruptured intracranial aneurysms. The 5-hydroxytryptamine antagonist ketanserin inhibited contractions of isolated human intracranial arteries, elicited by this CSF. The presence of 5-HT in CSF was confirmed by high performance liquid chromatography. The use of ketanserin in the therapy of postoperative cerebral vasospasm is discussed.

Topics: Adult; Aged; Animals; Female; Humans; Hydroxyindoleacetic Acid; Intracranial Aneurysm; Intraoperative Complications; Ischemic Attack, Transient; Ketanserin; Male; Middle Aged; Piperidines; Postoperative Complications; Rats; Rupture, Spontaneous; Serotonin; Serotonin Antagonists; Subarachnoid Hemorrhage; Vasoconstriction

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Adult; Age Factors; Amino Alcohols; Craniocerebral Trauma; Deafness; Electrooculography; Humans; Injections, Intravenous; Ischemic Attack, Transient; Piperidines; Prognosis; Tinnitus; Vertigo; Vestibular Function Tests

Topics: Amides; Clopamide; Diuretics; Ergoloid Mesylates; Humans; Hypertension; Ischemic Attack, Transient; Piperidines