The Cannabinoid WIN 55212-2 Mitigates Apoptosis and Mitochondrial Dysfunction After Hypoxia Ischemia

Alonso-Alconada, Daniel; Álvarez, Antonia; Álvarez, Francisco J.; Martı́nez-Orgado, José; Hilario, Enrique

doi:10.1007/s11064-011-0594-z

Cited by 16 publications

(16 citation statements)

References 83 publications

(106 reference statements)

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“…The reason for this unexpected result is not clear, but may be related to peculiarities of macrophage biology in the setting of systemic CB2 deficiency. Several other studies have shown anti-apoptotic effects of WIN55,212-2 in murine models of ischemia reperfusion injury via activation of CB2 [46, 47]. Alternatively, it is possible that WIN55,212-2 treatment resulted in CB2 receptor internalization [48], which would mimic CB2 deficiency in lesional macrophages and reduce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice

Rodgers

Fulmer

et al. 2015

J. Cardiol. Therap

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Purpose WIN55,212-2, a potent synthetic agonist of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), reduces atherosclerosis in apolipoprotein E (ApoE) null mice. Although pharmacologic evidence suggests the anti-atherosclerotic effects of WIN55,212-2 are mediated via CB2, this remains to be confirmed by genetic studies. Therefore, in this study, we investigated the effects of WIN55,212-2 on development of atherosclerosis in low-density lipoprotein receptor (Ldlr) null mice with and without homozygous deletion of the CB2 gene. Methods After 6 weeks on an atherogenic diet, groups of CB2+/+ and CB2−/− Ldlr-null mice received a daily intraperitoneal injection of WIN55,212-2 or vehicle. After two weeks, plasma lipid levels and atherosclerosis in the aortic root were quantified. Results Plasma cholesterol and triglyceride levels did not differ between CB2+/+ and CB2−/− mice and WIN55,212-2 had no effect on total cholesterol levels in either genotype. However, triglyceride levels in both CB2+/+ and CB2−/− mice were significantly lowered by WIN55,212-2. The size of aortic root lesions did not differ significantly between CB2+/+ and CB2−/− mice with or without WIN55,212-2 treatment. However, WIN55,212-2 treatment significantly lowered lesional macrophage accumulation in CB2+/+ mice, and lesional smooth muscle content in both CB2+/+ and CB2−/− mice. Lesional apoptosis was also greater in CB2+/+ mice compared to CB2−/−mice, and only reduced by WIN55,212-2 in CB2+/+ mice. Collagen content and elastin fiber fragmentation were unaffected by genotype or WIN55,212-2. Conclusions WIN55,212-2 treatment does not alter lesion size in Ldlr null-mice, but does modify lesion cellularity via CB2-dependent and CB2-independent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice

Rodgers

Fulmer

et al. 2015

J. Cardiol. Therap

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“…In newborn rats exposed to severe anoxia or to acute hypoxiaischemia [66,67], postinsult administration of WIN55212-2 afforded a strong neuroprotective effect, abolished by either CB 1 R or CB 2 R antagonists, too, as well as increasing neuronal and oligodendroglial cell proliferation in the subventricular zone 7 days after neonatal HI in rats [68]. In term fetal lambs exposed to HI damage by umbilical cord occlusion, postinsult administration of WIN55212-2 improved cerebral blood flow and reduced astrocytic, as well as apoptotic neuronal, death-those effects relying on the preservation of mitochondrial integrity and functionality [69]. These neuroprotective effects were also afforded with CBD, the major nonpsychoactive component of Cannabis sativa, again in animal models of newborn HI encephalopathy [70][71][72][73][74].…”

Section: Cannabinoids and Brain Damage In The Immature Brain: Neonatamentioning

confidence: 96%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

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“…Even though we have not observed a deleterious role of the use of 100% oxygen ventilation [5,9,10], we cannot rule out a possible harmful effect of this oxygen concentration, an issue observed in the piglet model causing oxidative stress and a dose-dependent oxidation of DNA [21], thus is currently not advised in the clinical situation. On the other hand, we used an ultra-low dose of WIN that, despite showing protective effects in different paradigms of hypoxic-ischemic brain injury [5,9,10], was not enough to activate CB2Rs and was considered to be involved in the antioxidant effects of CBs. WIN showed a higher preference towards CB1Rs (Ki values: 62.3 and 3.3 nM for the human cloned CB1 and CB2 receptors, respectively), whose activation can promote rather than inhibit oxidative stress [22,23].…”

Section: Discussionmentioning

confidence: 64%

“…WIN 55,212-2 (WIN) is a potent CB1R/CB2R mixed synthetic agonist with a slightly higher CB2R selectivity compared to other mixed agonists [8]. Our results suggest that the administration of WIN after perinatal asphyxia in fetal lambs reduced brain injury, decreasing both delayed cell death and glial damage [9], together with the maintenance of mitochondrial integrity and functionality [10].…”

Section: Introductionmentioning

confidence: 82%

Cannabinoid-mediated Modulation of Oxidative Stress and Early Inflammatory Response after Hypoxia–Ischemia

Alonso-Alconada

Álvarez

Goñi‐de‐Cerio

et al. 2020

IJMS

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In the process of neonatal encephalopathy, oxidative stress and neuroinflammation have a prominent role after perinatal asphyxia. With the exception of therapeutic hypothermia, no therapeutic interventions are available in the clinical setting to target either the oxidative stress or inflammation, despite the high prevalence of neurological sequelae of this devastating condition. The endocannabinoid system (ECS), recently recognized as a widespread neuromodulatory system, plays an important role in the development of the central nervous system (CNS). This study aims to evaluate the potential effect of the cannabinoid (CB) agonist WIN 55,212-2 (WIN) on reactive oxygen species (ROS) and early inflammatory cytokine production after hypoxia–ischemia (HI) in fetal lambs. Hypoxic–ischemic animals were subjected to 60 min of HI by partial occlusion of the umbilical cord. A group of lambs received a single dose of 0.01 μg/kg WIN, whereas non-asphyctic animals served as controls. WIN reduced the widespread and notorious increase in inflammatory markers tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 induced by HI, a modulatory effect not observed for oxidative stress. Our study suggests that treatment with a low dose of WIN can alter the profile of pro-inflammatory cytokines 3 h after HI.

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The Cannabinoid WIN 55212-2 Mitigates Apoptosis and Mitochondrial Dysfunction After Hypoxia Ischemia

Cited by 16 publications

References 83 publications

Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice

Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoid-mediated Modulation of Oxidative Stress and Early Inflammatory Response after Hypoxia–Ischemia

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