Update on the Role of Cannabinoid Receptors after Ischemic Stroke (original) (raw)
Related papers
Cannabinoid receptors in acute and chronic complications of atherosclerosis
British Journal of Pharmacology, 2008
Atherosclerosis is a chronic inflammatory disease that is the primary cause of myocardial infarction and stroke, which occur after sudden thrombotic occlusion of an artery. A growing body of evidence suggests that cannabinoid signalling plays a fundamental role in atherosclerosis development and its clinical manifestations. Thus, CB 2 receptors are protective in myocardial ischaemia/reperfusion and implicated in the modulation of chemotaxis, which is crucial for the recruitment of leukocytes during inflammation. Delta-9-Tetrahydrocannabinol (THC)-mediated activation has been shown to inhibit atherosclerotic plaque progression in a CB 2 dependent manner. Although CB 1 and CB 2 expression has been reported on platelets, their involvement in thrombus formation is still controversial. While several reports suggest that CB 1 receptors may have a relevant role in neuroprotection after ischaemic stroke, recent studies show the protective effects in various forms of neuroprotection are not related to CB 1 stimulation, and a protective role of CB 1 blockade has also been reported. In addition, vascular and myocardial CB 1 receptors contribute to the modulation of blood pressure and heart rate. It is tempting to suggest that pharmacological modulation of the endocannabinoid system is a potential novel therapeutic strategy in the treatment of atherosclerosis. For these purposes, it is important to better understand the complex mechanisms of endocannabinoid signalling and potential consequences of its pharmacological modulation, as it may have both pro-and anti-atherosclerotic effects.
Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2009
Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB(2) receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB(2) receptors, by selective CB(2) agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB(2) receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In a...
Journal of Cerebral …, 2007
Cannabinoid CB 2 Receptor (CB 2 ) activation has been shown to have immunomodulatory properties without psychotropic effects. The hypothesis of this study is that selective CB 2 agonist treatment can attenuate cerebral ischemia/reperfusion injury. Selective CB 2 agonists (O-3853, O-1966) were administered intravenously 1 h before transient middle cerebral artery occlusion (MCAO) or 10 mins after reperfusion in male mice. Leukocyte/endothelial interactions were evaluated before MCAO, 1 h after MCAO, and 24 h after MCAO via a closed cranial window. Cerebral infarct volume and motor function were determined 24 h after MCAO. Administration of the selective CB 2 agonists significantly decreased cerebral infarction (30%) and improved motor function (P < 0.05) after 1 h MCAO followed by 23 h reperfusion in mice. Transient ischemia in untreated animals was associated with a significant increase in leukocyte rolling and adhesion on both venules and arterioles (P < 0.05), whereas the enhanced rolling and adhesion were attenuated by both selective CB 2 agonists administered either at 1 h before or after MCAO (P < 0.05). CB 2 activation is associated with a reduction in white blood cell rolling and adhesion along cerebral vascular endothelial cells, a reduction in infarct size, and improved motor function after transient focal ischemia.
Surprising outcomes in cannabinoid CB1/CB2 receptor double knockout mice in two models of ischemia
Life sciences, 2018
We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion. Focal cerebral infarcts were created using either photo induced permanent injury or transient middle cerebral artery occlusion. Infarct volume and motor function were evaluated in cannabinoid receptor 1/cannabinoid receptor 2 double knockout mice. The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia. Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited. Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion...
Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke
Stroke, 2016
Background and Purpose— Stroke is a leading cause of adult disability characterized by physical, cognitive, and emotional disturbances. Unfortunately, pharmacological options are scarce. The cannabinoid type-2 receptor (CB2R) is neuroprotective in acute experimental stroke by anti-inflammatory mechanisms. However, its role in chronic stroke is still unknown. Methods— Stroke was induced by permanent middle cerebral artery occlusion in mice; CB2R modulation was assessed by administering the CB2R agonist JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran) or the CB2R antagonist SR144528 ( N -[(1S)- endo -1,3,3-trimethylbicyclo-[2.2.1]-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) once daily from day 3 to the end of the experiment or by CB2R genetic deletion. Analysis of immunofluorescence-labeled brain sections, 5-bromo-2´-deoxyuridine (BrdU) staining, fluorescence-activated cell sorter analysis of ...
Journal of Neurochemistry, 2015
Brain ischemia produces neuronal cell death and the recruitment of pro-inflammatory cells. In turn, the search for neuroprotection against this type of insult has rendered results involving a beneficial role of endocannabinoid receptor agonists in the Central Nervous System. In this work, to further elucidate the mechanisms associated to this neuroprotective effect, focal brain ischemia was generated by middle cerebral artery occlusion (MCAo) in C57Bl/6 mice. Three, 24 and 48 h after MCAo, animals received CB1R agonist ACEA (1 mg/kg), CB1R antagonist AM251 (1 mg/kg) or vehicle. To assess motor activity, neural deficit scores and motor tests were performed 1 day before and 3, 7, 14, 21, and 28 days after MCAo. At 7 and 28 days post lesion, cytoskeleton structure, astroglial and microglial reaction, and alterations in synapsis were studied in the cerebral cortex. ACEA treatment reduced astrocytic reaction, neuronal death, and dendritic loss. In contrast, AM251 treatment increased these parameters. Motor tests showed a progressive deterioration in motor activity in ischemic animals, which only ACEA treatment was able to counteract. Our results suggest that CB1R may be involved in neuronal survival and in the regulation of neuroprotection during focal cerebral ischemia in mice.
Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases
Current medicinal chemistry, 2014
In the last decades, the cannabinoid system (comprising synthetic and endogenous cannabinoid agonists and antagonists, their receptors and degrading enzymes) has been shown to induce potent immunomodulatory activities in atherogenesis and acute ischemic complications. Different from the other cannabinoid receptors in which controversial results are reported, the selective activation of the cannabinoid receptor type 2 (CB2) has been shown to play antiinflammatory and protective actions within atherosclerotic vessels and downstream ischemic peripheral organs. CB2 is a transmembrane receptor that triggers protective intracellular pathways in cardiac, immune and vascular cells in both human and animal models of atherosclerosis. Considering basic research data, medications activating CB2 function in the circulation or peripheral target organs might be a promising approach against atherogenesis. This review updates evidence from preclinical studies on different CB2-triggered pathways in a...
Cannabinoid CB2 receptors in human brain inflammation.
British Journal of Pharmacology, 2007
The presence of functional cannabinoid CB 2 receptors in the CNS has provoked considerable controversy over the past few years. Formerly considered as an exclusively peripheral receptor, it is now accepted that it is also present in limited amounts and distinct locations in the brain of several animal species, including humans. Furthermore, the inducible nature of these receptors under neuroinflammatory conditions, in contrast to CB 1 , makes them attractive targets for the development of novel therapeutic approaches. In fact, the undesired psychoactive effects caused by CB 1 activation have largely limited the clinical use of cannabinoid-related compounds that act on these receptors. In this review some recent findings on the antiinflammatory properties of CB 2 receptors are presented, as well as new perspectives that have been obtained based on studies of human postmortem brain samples. In addition, various working hypotheses are also proposed and discussed.
Introduction: Recent studies demonstrated that cannabidiol had neuroprotective property. There is some evidence about effective role of cannabidiol in reduction of ischemic damages. It has been reported that infarct size is influenced by various factors after MCAO, including inflammatory factors. The aim of the present study was to evaluate the effect of cannabidiol on infarction volume and correlation of infarct size with tumor necrosis factor receptor 1 (TNFR1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) expression. Methods: Using stereotaxic surgery, guide cannula was implanted in the right lateral ventricle. Cannabidiol (50, 100, and 200 ng/rat) was injected through ntracerebroventricular (i.c.v.) route for 5 consecutive days . Then, the rats underwent 60 minutes of right middle cerebral artery occlusion (MCAO). After 24 h reperfusion, the infarct volume in total, cortex, piriform cortex-amygdala (Pir-Amy), and striatum areas of hemisphere were assessed. The expression of inflammatory factors such as TNFR1 and NF-кB in these regions were also studied. Results: The present results indicate that in the MCAO-induced cerebral ischemia, administration of cannabidiol (100 and 200 ng/rat) causes a significant reduction in infarction volume in comparison with the vehicle group. Also, there were significant correlations between decrease of regional infarct volume and TNFR1/NF-кB expression. Conclusion: The results of this study indicate that cannabidiol reduced cerebral infarction possibly through diminishing TNFR1/NF-кB-induced neurotoxicity in transient focal cerebral ischemia.