Journal Article

Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

Pozo, Miguel A, Carro, Eva, Spuch, Carlos, Martín-Moreno, Ana María, Brera, Begoña, García-García, Luis, Cuadrado, Antonio, Delgado, Mercedes, Innamorato, Nadia G, de Ceballos, María L

2012

Overview

Background Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. Methods We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18 F-fluoro-deoxyglucose ( 18 FDG) uptake by positron emission tomography (PET). Results Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18 FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro . Conclusions In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

• Publisher: BioMed Central,BMC
• Subject: Administration, Oral / Alzheimer Disease - complications / Alzheimer Disease - genetics / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Amyloid beta-Protein Precursor - genetics / Analysis of Variance / Animals / anti-inflammatories / Benzoxazines - administration & dosage / Biomedical and Life Sciences / Biomedicine / cannabinoids / Cannabinoids - administration & dosage / Choroid Plexus - metabolism / Choroid Plexus - pathology / Cognition Disorders - diagnostic imaging / Cognition Disorders - etiology / Cognition Disorders - prevention & control / Corpus Striatum - drug effects / Corpus Striatum - metabolism / Cyclooxygenase 2 - genetics / Cyclooxygenase 2 - metabolism / Disease Models, Animal / Encephalitis - diagnostic imaging / Encephalitis - etiology / Encephalitis - prevention & control / Enzyme-Linked Immunosorbent Assay / Fluorodeoxyglucose F18 - metabolism / Gene Expression Regulation - drug effects / Gene Expression Regulation - genetics / glial activation / Glycogen Synthase Kinase 3 - metabolism / Glycogen Synthase Kinase 3 beta / Humans / Immunology / interleukin 6 / Mice / Mice, Transgenic / Microglia - drug effects / Microglia - pathology / Morpholines - administration & dosage / Naphthalenes - administration & dosage / Neurobiology / Neurology / Neurosciences / Positron-Emission Tomography / Receptor, Cannabinoid, CB2 - metabolism / RNA, Messenger - metabolism / Time Factors / tumor necrosis factor-α / β-amyloid peptide