The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages

• Published in: Brain research Vol. 1283; pp. 148 - 154
• Main Authors: Tolón, Rosa María, Núñez, Estefanía, Pazos, María Ruth, Benito, Cristina, Castillo, Ana Isabel, Martínez-Orgado, José Antonio, Romero, Julián
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 04.08.2009
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - drug effects; Amyloid beta-Peptides - metabolism; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Bornanes - pharmacology; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Cannabinoids - pharmacology; Cannabinoids - therapeutic use; Cell Line, Tumor; Dose-Response Relationship, Drug; Encephalitis - drug therapy; Encephalitis - physiopathology; Encephalitis - prevention & control; Gliosis - drug therapy; Gliosis - physiopathology; Gliosis - prevention & control; Humans; Indoles - pharmacology; Indoles - therapeutic use; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Neurology; Neuropharmacology; Phagocytosis - drug effects; Phagocytosis - physiology; Pharmacology. Drug treatments; Plaque, Amyloid - drug effects; Plaque, Amyloid - metabolism; Psychodysleptics: hallucinogen; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; Amyloid; Cannabinoid; Phagocytosis; Macrophage; Cb2-receptor; Human; Exeresis; β Amyloid protein; Activation; CB2 cannabinoid receptor; In vitro
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.05.098

Abstract The endocannabinoid system is a promising therapeutic target in a wide variety of diseases. However, the non-desirable psychotropic effects of natural and synthetic cannabinoids have largely counteracted their clinical usefulness. These effects are mostly mediated by cannabinoid receptors of the CB1 type, that exhibit a wide distribution in neuronal elements of the CNS. Thus, the presence of other elements of this system in the CNS, such as CB2 receptors, may open new possibilities for the development of cannabinoid-based therapies. These receptors are almost absent from the CNS in normal conditions but are up-regulated in glial cells under chronic neuroinflammatory stimuli, as has been described in Alzheimer's disease. To understand the functional role of these receptors, we tested their role in the process of beta-amyloid removal, that is currently considered as one of the most promising experimental approaches for the treatment of this disease. Our results show that a CB2 agonist (JWH-015) is capable of inducing the removal of native beta-amyloid removal from human frozen tissue sections as well as of synthetic pathogenic peptide by a human macrophage cell line (THP-1). Remarkably, this effect was achieved at low doses (maximum effect at 10 nM) and was specific for this type of cells, as U373MG astrocytoma cells did not respond to the treatment. The effect was CB2 -mediated, at least partially, as the selective CB2 antagonist SR144528 prevented the JWH-015-induced plaque removal in situ . These data corroborate the possible therapeutic interest of CB2 cannabinoid specific chemicals in the treatment of Alzheimer's disease.