It is known that microglial

It is known that microglial function and morphology are closely related [20], but no studies have addressed whether neuroinflammation induced by alcohol might modify microglial salbutamol sulfate sale (i.e. morphology, neuroimmunochemical phenotype) through an eCB-dependent mechanism. Since this alcohol-induced microglial modification might also affect memory and cognition, this is a relevant issue when thinking on potential therapeutics utilities of ECS-related drugs. Here, we investigated this potential therapeutic utility by analyzing the pharmacological effects of the repeated administration (5 days) of the NAEs hydrolyzing enzyme FAAH inhibitor URB597 (0.3 mg/kg), compared to OEA (10 mg/kg), AEA (10 mg/kg), ACEA (3 mg/kg) and JWH133 (0.2 mg/kg), in a rat model of subchronic (2 weeks) voluntary oral ethanol exposure. Microglia phenotyping (IBA-1, iNOS), morphometric parameters (fractal dimension, lacunarity, roughness, cell area, cell perimeter, density, among others), glial recruitment (chemokine receptors CX3CR1, CCR2, CCR4, CXCR4) and mRNA levels of cytokines related to innate immune TLR4 signaling (TNFα, IL-1β, IL-6) and chemotactic cytokines (fractalkine/CX3CL1, MCP-1/CCL2, SDF-1α/CXCL12, eotaxin-1/CCL11) were analyzed in the hippocampus of ethanol-exposed rats. Regarding behavior associated with hippocampal functioning, short and long-term visual recognition memory was also assessed.
Materials and methods
Results
Discussion In the present study, we show that the FAAH inhibitor URB597 induced the most consistent changes in morphology (fractal analysis), phenotyping related to innate immune TLR4 system (TLR4, TNFα, IL-6) and glial recruitment through chemokines (SDF-1α/CXCL12, MCP-1/CCL2) and chemokine receptors (CX3CR1, CCR2 and CCR4) in hippocampal microglia of rats exposed to ethanol. These effects of FAAH inhibition were clearly different from those observed after the administration of other natural or synthetic cannabinoids with differential sensitivity for CB1 or CB2 receptors (AEA, ACEA, JWH133), and different from those induced by the non-cannabinoid N-acylethanolamide OEA binding to PPARα receptors. These effects on microglial activity are likely associated with an improvement of object recognition memory despite ethanol exposure. To our knowledge, this is the first study that evaluates the influence of cannabinoids and ethanol on microglial phenotyping, morphology and hippocampal-dependent memory.
Disclosure
Author contributions
Acknowledgements
Introduction The endocannabinoid system is represented by a group of neuromodulatory lipids and of their receptors that are involved in a variety of physiological and pathological conditions. Each endocannabinoid belongs to a larger class of lipids termed N-acyl-ethanolamines (NAEs) and monoacylglycerols (MAGs), respectively, where the members differ in the length and unsaturation degree of their acyl chains [1]. In particular, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), represent polyunsaturated derivatives with potential biological activities as for example in the nervous system where they act as retrograde messengers [2]. These endocannabinoids are not stored in vesicles and mediate intercellular signals from postsynaptic neurons back to presynaptic terminals where they inhibit the neurotransmitter release [3]. Endogenous ligands of cannabinoid receptors are involved as transmitters in a large collection of physiological and pathological conditions including pain perception, feeding, emotional state, and reward behaviors [1], [4]. The modulation of their levels appears to be of noteworthy therapeutic importance in a variety of human disorders, ranging from neurological, affective and neuropsychiatric disorders and different types of chronic pain to gastrointestinal and hepatic diseases, allergic and inflammatory disorders, cancer and osteoporosis. A barrier to the development of cannabinoid medications has been the psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors that is the principal cannabinoid receptor in the central nervous system (CNS) and is broadly distributed throughout the brain and at lower levels in peripheral tissues. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist or employ of selective CB2 receptor agonists.