The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic–ischemic injury in fetal lambs

Alonso-Alconada, Daniel; Álvarez, Francisco J.; Álvarez, Antonia; Mielgo, Victoria; Goñi‐de‐Cerio, Felipe; Rey-Santano, M C; Caballero, A; Martı́nez-Orgado, José; Hilario, Enrique

doi:10.1016/j.brainres.2010.09.050

Cited by 28 publications

(32 citation statements)

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“…A growing body of evidence indicates that CBs modulate pathways involved in numerous harmful events (3,4) and show neuroprotective effects in different paradigms of hypoxicischemic brain injury (7,14,22). It is well known that ischemic brain tissue produces and accumulates both 2-AG and AEA, whose protective role has been highlighted either by their exogenous administration or by the inhibition of their metabolic enzymes (9,10,15). Thus, it is not surprising to consider endocannabinoids as endogenous protective molecules and, by extension, the endocannabinoid system as a potential target for new drugs that could improve ischemic injury.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the endocannabinoid system has been extensively evaluated as a possible target for the treatment of cerebral ischemia (7,9,10), trauma (11), and excitotoxicity (12,13). Enhanced levels of endocannabinoids have also been observed in the brain after an acute excitotoxic insult in newborn rats and exogenous administration of synthetic or endocannabinoids has shown neuroprotective effects both in vitro and in vivo (7,14,15).After activation of CB receptors, endocannabinoids are rapidly inactivated by reuptake and enzymatic hydrolysis, therefore limiting their potential protective effects. Termination of endocannabinoid signaling is carried out primarily by fatty acid amide hydrolase, which degrades AEA, and monoacylglycerol lipase (MAGL), which hydrolyzes 2-AG (1).…”

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Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic–ischemic brain injury in rats

et al. 2012

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Background:The endocannabinoids are emerging as nat ural brain protective substances that exert potentially benefi cial effects in several neurological disorders by virtue of their hypothermic, immunomodulatory, vascular, antioxidant, and antiapoptotic actions. This study was undertaken to assess whether preventing the deactivation of the endocannabi noid 2arachidonoylglycerol (2aG) with the monoacylglycerol lipase (MaGL) inhibitor URB602 can provide neuroprotective effects in hypoxia-ischemia (hI)induced brain injury. Methods: URB602 was administered into the right lateral ventricle 30 min before 7dayold pup rats were subjected to hI. The neuroprotective effect was evaluated on postnatal day (PN) 14 or at adulthood (PN80) using behavioral and histologi cal analyses. activated caspase3 expression and propidium iodide labeling were assessed as indexes of apoptotic and necrotic cell death, respectively. results: Pretreatment with URB602 reduced apoptotic and necrotic cell death, as well as the infarct volume measured at PN14. at adulthood, URB602treated hI animals performed better at the Tmaze and the Morris maze, and also showed a significant reduction of brain damage. conclusion: These results demonstrate that a pretreatment with URB602 significantly reduces brain damage and improves functional outcome, indicating that endocannabinoid degrading enzymes may represent an important target for neuroprotection in neonatal ischemic brain injury. i n the past decades, important advances have been made in cannabinoid (CB) research, with the endocannabinoids emerging as natural brain protective substances. These are part of a new intercellular communication network, called the endogenous CB system (1). The endocannabinoid system comprises the CB receptors (CB1, CB2, and non-CB1/CB2 receptors), the endocannabinoids N-arachidonylethanolamine (anandamide; AEA), 2-arachidonylglycerol (2-AG), and the enzymes responsible for endocannabinoid biosynthesis, transport, and degradation (1).Acting as retrograde messengers, endocannabinoids provide neuromodulatory functions in the brain, regulating processes such as motor activity, memory and learning, appetite, emesis, nociception, and the survival or death decision of neural cells after harmful insults (1,2). They exert potentially beneficial effects by virtue of their hypothermic, immunomodulatory, vascular, antioxidant, and antiapoptotic actions (3,4), which can generate a neuroprotective response after several neurological disorders.Following an ischemic brain injury, there is an increased production and accumulation of endocannabinoids in the brain (5,6), and upregulation of CB receptors (7,8). Activation of the endocannabinoid system has been extensively evaluated as a possible target for the treatment of cerebral ischemia (7,9,10), trauma (11), and excitotoxicity (12,13). Enhanced levels of endocannabinoids have also been observed in the brain after an acute excitotoxic insult in newborn rats and exogenous administration of synthetic or endocannabinoids has shown neuroprotect...

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Section: Discussionmentioning

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Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic–ischemic brain injury in rats

et al. 2012

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“…Recently, we have found that administration of the cannabinoid agonist WIN decreases brain injury in a lamb model of perinatal asphyxia [135] . In this study, we showed that WIN successfully prevented delayed cell death, as the number of TUNEL + cells in hypoxic-ischemic fetal lambs treated with the cannabinoid agonist was similar as that in non-asphyxiated pups.…”

Section: Therapeutic Potential Of Cannabinoid After Hypoxia-ischemiamentioning

confidence: 99%

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

2011

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Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. Because of the fact that there is still no specific treatment for perinatal brain lesions due to the complexity of neonatal hypoxic-ischemic pathophysiology, the search of new neuroprotective therapies is of great interest.In this regard, therapeutic possibilities of the endocannabinoid system have grown lately. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. Concerning perinatal asphyxia, the neuroprotective role of this endogenous system is emerging these years. The present review mainly focused on the current knowledge of the cannabinoids as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.

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“…Using a lamb model of perinatal asphyxia, we have previously reported that the reduction of the umbilical blood flow leads to brain damage [11,32] and that the administration of the cannabinoid agonist WIN 55,212-2 decreases brain injury reducing both delayed cell death and glial damage [33].…”

Section: Introductionmentioning

confidence: 99%

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

Alonso-Alconada

Álvarez

et al. 2011

Neurochem Res

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Perinatal hypoxia-ischemia has significant mortality and morbidity due to there is still no specific treatment as a consequence of the complexities of hypoxic-ischemic pathophysiology. The aim of this work was to evaluate the effects of the cannabinoid agonist WIN 55212-2 on apoptotic cell death and mitochondrial dysfunction after perinatal asphyxia in fetal lambs. Animals were assigned to: one SHAM group and two hypoxic-ischemic groups that received a dose of 0.01 μg/kg WIN 55,212-2 (HI + WIN) or not (HI + VEH) after 60 min of partial occlusion of the umbilical cord, and sacrificed 3 h later. Different brain regions were separated for morphological studies, and the same territories were dissociated and analyzed by flow cytometry to quantify apoptosis, to determine mitochondrial integrity and transmembrane potential and to analyze intracellular calcium levels. Our results showed that WIN 55,212-2 reduced apoptotic cell death in all regions studied through the maintenance of mitochondrial integrity and functionality.

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The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic–ischemic injury in fetal lambs

Cited by 28 publications

References 55 publications

Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic–ischemic brain injury in rats

Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic–ischemic brain injury in rats

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

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

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