Role of 2-Arachidonoyl-Glycerol and CB1 Receptors in Orexin-A-Mediated Prevention of Oxygen-Glucose Deprivation-Induced Neuronal Injury.

Letizia Palomba,Giuseppe Battaglia,Valeria Bruno,Vincenzo Di Marzo,Andrea Motta,Fabiana Piscitelli,Federica Mastroiacovo,Roberta Imperatore,Luigia Cristino,Raffaele Capasso

doi:10.3390/cells9061507

Abstract

Orexin-A (OX-A) protects the brain against oxidative stress-mediated ischemic injury. Since the endocannabinoid 2-arachidonoylglycerol (2-AG) and cannabinoid type-1 (CB1) receptors were previously shown to mediate some of the effects of OX-A exerted through the orexin-1 receptor (OX-1R), we investigated the involvement of 2-AG in OX-A-induced neuroprotection following oxygen and glucose deprivation (OGD) in mouse cortical neurons. OGD-induced reactive oxygen species (ROS) accumulation and neuronal death were prevented by both OX-A and arachidonyl-2′-chloroethylamide (ACEA), a synthetic CB1 receptor agonist, in a manner sensitive to OX-1R and CB1 receptor antagonists, SB334867 and AM251. OX-A stimulated 2-AG biosynthesis in cortical neurons. In neurons isolated from monoacylglycerol lipase (MAGL, a 2-AG hydrolyzing enzyme) null mice, 10-fold higher 2-AG concentrations were found and OGD failed to induce ROS production and cell death, whereas AM251 restored these noxious effects. OX-A-induced neuroprotection was mediated by the phosphoinositide-3-kinase/Akt (PI3K/Akt) survival pathway since both OX-A and ACEA induced phosphorylation of Akt and prevented OGD-induced cytochrome c release from the mitochondria, in a manner counteracted by SB334867 or AM251. Administration of OX-A reduced infarct volume and elevated brain 2-AG levels in a mouse model of transient ischemia. These results suggest that 2-AG and CB1 receptor mediate OX-A prevention of ischemia-induced neuronal apoptosis.

Highlights

IntroductionOrexins (orexin-A and orexin-B; known as hypocretins-1 and -2) are neuropeptides that are widely distributed in the central nervous system and peripheral tissues
Orexins are neuropeptides that are widely distributed in the central nervous system and peripheral tissues
Since OX-A is protective against oxidative stress [8,24,25], we used oxygen and glucose deprivation (OGD)-induced injury, an in vitro model of cerebral ischemia/reperfusion, to determine if OX-A can offer neuroprotection by preventing

Summary

Introduction

Orexins (orexin-A and orexin-B; known as hypocretins-1 and -2) are neuropeptides that are widely distributed in the central nervous system and peripheral tissues. The anatomical architecture of orexin neurons and the wide distribution of orexin receptors appear to be essential for the multiple functions of these neuropeptides. Orexins play an important role in many physiological aspects of mammalian life, including the control of food intake and sleep–wake behavior [5,6], as well as, among many others, the protection of neurons against oxidative stress and ischemic brain injury [7,8,9]. Brain ischemia is a neurological disorder that occurs when a part of the brain is deprived of oxygen and glucose, with subsequent neuronal cell death mainly due to oxygen and glucose deprivation (OGD)-mediated oxidative stress [10]. Radical oxygen species (ROS) are generated to a small extent during ischemia, while a far greater production occurs after reintroduction of oxygen during reperfusion

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