Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0917798 (cerebral ischemia)
17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Marijuana and related drugs (cannabinoids) have been proposed as treatments for a widening spectrum of medical disorders. R(+)-[2, 3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate (R(+)-WIN 55212-2), a synthetic cannabinoid agonist, decreased hippocampal neuronal loss after transient global cerebral ischemia and reduced infarct volume after permanent focal cerebral ischemia induced by middle cerebral artery occlusion in rats. The less active enantiomer S(-)-WIN 55212-3 was ineffective, and the protective effect of R(+)-WIN 55212-2 was blocked by the specific central cannabinoid (CB1) cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide-hydrochloride. R(+)-WIN 55212-2 also protected cultured cerebral cortical neurons from in vitro hypoxia and glucose deprivation, but in contrast to the receptor-mediated neuroprotection observed in vivo, this in vitro effect was not stereoselective and was insensitive to CB1 and CB2 receptor antagonists. Cannabinoids may have therapeutic potential in disorders resulting from cerebral ischemia, including stroke, and may protect neurons from injury through a variety of mechanisms.
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PMID:Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. 1019 16

The endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonylglycerol increased cell viability in cerebral cortical neuron cultures subjected to 8 h of hypoxia and glucose deprivation. This effect was observed at nanomolar concentrations, was reproduced by a non-hydrolyzable analog of anandamide, and was unaltered by CB1 or CB2 cannabinoid receptor antagonists. Like synthetic cannabinoids, endocannabinoids can protect neurons from hypoxic injury, and may represent endogenous neuroprotective molecules in cerebral ischemia.
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PMID:Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. 1065 17

Cannabinoids protect cortical neurons from ischemic injury by interacting with CB1 receptors. Because a variety of neuroprotective genes are induced in cerebral ischemia, we examined the effect of experimental stroke, produced by 20 minutes of middle cerebral artery occlusion in rats, on CB1 receptor expression. Western blotting and immunohistochemistry showed that CB1 expression on neurons was increased in the arterial boundary zone of the cortical mantle, beginning by 2 hours and persisting for 72 hours or more after ischemia These findings are consistent with a neuroprotective role for endogenous cannabinoid signaling pathways and with a potential therapeutic role in stroke for drugs that activate CB1 receptors.
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PMID:CB1 cannabinoid receptor induction in experimental stroke. 1093 79

(-)-(R)-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) is a new high-affinity cannabinoid receptor subtype 1 (CB1 receptor) ligand (K(i) = 0.46-1.85 nM; rat brain, human cortex, or recombinant human CB1 receptor), structurally unrelated to any cannabinoid receptor ligand known so far. BAY 38-7271 was characterized as a CB1 receptor agonist in 5-[gamma(35)S]-thiophosphate triethylammonium salt binding assays using rat or human CB1 receptors. In the rat hypothermia assay, BAY 38-7271 induced a dose-dependent reduction in body temperature (minimal effective dose = 6 microg/kg, i.v.); whereas in rats trained to discriminate the CB1/CB2 receptor agonist (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.03 mg/kg, i.p.) from vehicle, BAY 38-7271 induced complete generalization (3 microg/kg, i.v.). In both in vivo models, a specific CB1 receptor-mediated mechanism was confirmed by demonstrating that the effects of CP 55,940 and BAY 38-7271 were blocked by pretreatment with the selective CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride. In the rat traumatic brain injury model, BAY 38-7271 demonstrated highly potent and efficient neuroprotective properties when administered as a 4-h infusion immediately after induction of subdural hematoma (70% infarct volume reduction at 100 ng/kg/h). Even when applied with a 3-h delay, a significant neuroprotective efficacy could be observed (59% infarct volume reduction at 300 ng/kg/h). The neuroprotective potential of BAY 38-7271 was confirmed in a rat model of focal cerebral ischemia induced by permanent occlusion of the middle cerebral artery. It is concluded that the CB1/CB2 receptor agonist BAY 38-7271 shows pronounced neuroprotective properties that do not result from drug-induced hypothermia and that occur in a dose range devoid of typical cannabinoid-like side effects.
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PMID:Characterization of the diarylether sulfonylester (-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties. 1206 38

Endogenous cannabinoid signaling pathways have been implicated in protection of the brain from hypoxia, ischemia, and trauma, but the mechanism for these protective effects is uncertain. We found that in CB1 cannabinoid receptor knock-out mice, mortality from permanent focal cerebral ischemia was increased, infarct size and neurological deficits after transient focal cerebral ischemia were more severe, cerebral blood flow in the ischemic penumbra during reperfusion was reduced, and NMDA neurotoxicity was increased compared with wild-type littermates. These findings indicate that endogenous cannabinoid signaling pathways protect mice from ischemic stroke by a mechanism that involves CB1 receptors, and suggest that both blood vessels and neurons may be targets of this protective effect.
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PMID:Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. 1242 32

Focal cerebral ischemia (FCI) induces rapid neuronal death in the ischemic core, which gradually expands toward the penumbra, partly as the result of a neuroinflammatory response. It is known that propagation of neuroinflammation involves microglial cells, the resident macrophages of the brain, which are highly motile when activated by specific signals. However, the signals that increase microglial cell motility in response to FCI remain mostly elusive. Here, we tested the hypothesis that endocannabinoids mediate neuroinflammation propagation by increasing microglial cell motility. We found that, in mouse cerebral cortex, FCI greatly increases palmitoylethanolamide (PEA), only moderately increases anandamide [arachidonylethanolamide (AEA)], and does not affect 2-arachidonoylglycerol levels. We also found that PEA potentiates AEA-induced microglial cell migration, without affecting other steps of microglial activation, such as proliferation, particle engulfment, and nitric oxide production. This potentiation of microglial cell migration by PEA involves reduction in cAMP levels. In line with this, we provide evidence that PEA acts through Gi/o-coupled receptors. Interestingly, these receptors engaged by PEA are pharmacologically distinct from CB1 and CB2 cannabinoid receptors, as well as from the WIN and abn-CBD (abnormal-cannabidiol) receptors, two recently identified cannabinoid receptors. Our results show that PEA and AEA increase after FCI and synergistically enhance microglial cell motility. Because such a response could participate in the propagation of the FCI-induced neuroinflammation within the CNS, and because PEA is likely to act through its own receptor, a better understanding of the receptor engaged by PEA may help guide the search for improved therapies against neuroinflammation.
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PMID:Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. 1294 5

Traumatic brain injury (TBI) is the most common cause of mortality and morbidity in adults under 40 years of age in industrialized countries. Worldwide the incidence is increasing, about 9.5 million people are hospitalized per year due to TBI, and the death rate is estimated to be more than one million people per year. Recently BAY 38-7271 has been characterized as a structurally novel, selective and highly potent cannabinoid CB1/CB2 receptor agonist in vitro and in vivo with pronounced neuroprotective efficacy in a rat traumatic brain injury model, showing a therapeutic window of at least 5 h. Furthermore, neuroprotective efficacy was also found in models of transient and permanent occlusion of the middle cerebral artery and brain edema models as well. In this article we review the in vitro and in vivo pharmacology of BAY 38-7271, the results from acute and subacute toxicity studies, pharmacokinetics and drug metabolism in animals and healthy male volunteers. In phase I studies BAY 38-7271 was safe and well tolerated when administered by i.v. infusion for either 1 or 24 h. As the doses of BAY 38-7271 in animals needed for maximal neuroprotective efficacy were significantly lower than those inducing typical cannabinoid-like side effects, it is to be expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI or cerebral ischemia.
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PMID:BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury. 1464 28

CB1 cannabinoid receptors (CB1Rs) are involved in protecting the brain from ischemia and related disorders. However, the underlying protective mechanisms are incompletely understood. We investigated the effect of CB1R activation on oxidative injury, which has been implicated in neuronal death after cerebral ischemia and neurodegenerative disorders, in mouse cortical neuron cultures. The CB1R agonist Win 55212-2 [R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate] reduced neuronal death, measured by lactate dehydrogenase release, in cultures treated with 50 microM FeCl2, and its protective effect was attenuated by the CB1R antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-cichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The endocannabinoid anandamide reproduced the effect of Win 55212-2, as did the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Neuronal injury was more severe after in vitro or in vivo administration of FeCl2 to CB1R-knockout compared with wild-type mice. Win 55212-2 reduced the formation of reactive oxidative species in cortical neuron cultures treated with FeCl2, consistent with an antioxidant action. Pertussis toxin reduced CB1R-mediated protection, which points to a protective mechanism that involves signaling through G(i/o) proteins. Since CB1R-activated G protein signaling inhibits protein kinase A but activates phosphatidylinositol 3-kinase (PI3K), we tested the involvement of these pathways in CB1R-mediated neuroprotection. Dibutyryl-cyclic adenosine monophosphate (dbcAMP) blocked protection by Win 55212-2, whereas the PI3K inhibitor wortmannin did not, and the effect of dbcAMP was inhibited by the protein kinase A inhibitor H89 [N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide] (> or =10 nM). CB1R-induced, SR141716A-, pertussis toxin-, and dbcAMP-sensitive protection was also observed for two other oxidative insults, exposure to H2O2 or buthionine sulfoximine. Therefore, receptor-stimulated inhibition of protein kinase A seems to be required for the neuroprotective effect of CB1R activation against oxidative neuronal injury.
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PMID:Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury. 1562 18

Recently, a potential neuroprotective effect of rimonabant, independent of the CB1 receptor interaction, has been proposed. In the present study, the role of transient receptor potential channel vanilloid subfamily member 1, named VR1, on neuroprotective effect of rimonabant, on global cerebral ischemia in gerbils, was investigated. Rimonabant (0.05-3 mg kg-1), given i.p. 5 min after recirculation, dose dependently antagonized the ischemia-induced decrease in electroencephalographic (EEG) total spectral power and restored relative frequency band distribution 7 days after ischemia. Rimonabant (0.125-0.5 mg kg-1) fully prevented ischemia-induced hyperlocomotion 1 day after ischemia and memory impairment evaluated in a passive avoidance task, 3 days after ischemia. At 7 days after ischemia, the survival of pyramidal cells, in the CA1 subfield, was respectively 91 and 96%, in the animals given rimonabant 0.25 and 0.5 mg kg-1, compared to the vehicle group. Higher doses were not protective. The protection induced by rimonabant followed a bell-shaped curve, the maximal active doses being 0.25 and 0.5 mg kg-1. Capsazepine (0.01 mg kg-1), a selective VR1 vanilloid receptor antagonist, completely reversed rimonabant-induced neuroprotective effects against EEG flattening, memory impairment and CA1 hippocampal neuronal loss. These findings suggest that VR1 vanilloid receptors are involved in rimonabant's neuroprotection even if other mechanisms can contribute to this effect.
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PMID:Vanilloid VR1 receptor is involved in rimonabant-induced neuroprotection. 1644 89

Whether cannabinoids act as neuroprotectants or, on the contrary, even worsen neuronal damage after cerebral ischemia is currently under discussion. We have previously shown that treatment with the cannabinoid (CB1) receptor antagonist SR141716A reduces infarct volume by approximately 40% after experimental stroke. Since it is suggested that SR141716A may exert neuroprotection besides its cannabinoid receptor-blocking effect, we addressed the question whether SR141716A may act via modulation of postischemic ligand binding to excitatory NMDA and/or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. For this purpose, rats (n = 12) were treated with either intravenous saline (control) or CB1 receptor antagonist SR141716A (1 mg/kg) 30 min after permanent middle cerebral artery occlusion. Five hours after ischemia, quantitative receptor autoradiography was performed using [(3)H]CP 55,940, [(3)H]MK-801, and [(3)H]AMPA for labeling of CB1, NMDA, and AMPA receptors, respectively. Ligand binding was analyzed within the infarct core, cortical penumbra, and corresponding areas of the contralateral hemisphere and compared to that of sham-operated rats (n = 5). Both in ischemic controls and SR141716A-treated rats [(3)H]CP 55,940 ligand binding was not specifically regulated in the cortical penumbra or contralateral cortex. Importantly, reduced infarct volumes in SR141716A-treated rats were associated with maintained [(3)H]MK-801 binding to excitotoxic NMDA receptors in the penumbra, compared to a decrease in the control group. In summary, our data suggest that SR141716A may possess additional intrinsic neuroprotective properties independent of receptor-coupled pathways or due to action as a partial agonist.
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PMID:Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra. 1687 4


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