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

Ana María Martín-Moreno127, Begoña Brera12, Carlos Spuch238, Eva Carro23, Luis García-García4, Mercedes Delgado4, Miguel A Pozo45, Nadia G Innamorato26, Antonio Cuadrado26 and María L de Ceballos12*

Author Affiliations

1 Neurodenegeration Group, Dept. of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, Doctor Arce, 37, Madrid, 28002, Spain

2 Centre for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain

3 Neuroscience Group, Research Institute Hospital 12 de Octubre, Av. de Córdoba s/n Madrid, 28041, Spain

4 CAI de Cartografía Cerebral, Instituto Pluridisciplinar, UCM, Paseo Juan XXIII 1, Madrid, 28040, Spain

5 PET Technology Institute, Manuel Bartolomé Cossio 10, Madrid, 28040, Spain

6 Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols"UAM-CSIC, Facultad de Medicina, Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid, 28029, Spain

7 Current Address: MD Anderson Cancer Center, Arturo Soria 270, 28033 Madrid, Spain

8 Current Address: Department of Pathology and Neuropathology, University Hospital of Vigo (CHUVI), Vigo, Spain

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Journal of Neuroinflammation 2012, 9:8  doi:10.1186/1742-2094-9-8

Published: 16 January 2012

Abstract

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 18F-fluoro-deoxyglucose (18FDG) 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 18FDG 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.

Keywords:
Alzheimer's disease; β-amyloid peptide; cannabinoids; glial activation; interleukin 6; anti-inflammatories; tumor necrosis factor-α