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

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

doi:10.1186/1742-2094-9-8

Abstract

BackgroundAlzheimer'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.MethodsWe 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).ResultsNovel 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.ConclusionsIn summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

Highlights

Alzheimer’s disease (AD) brain shows an ongoing inflammatory condition and non-steroidal antiinflammatories diminish the risk of suffering the neurologic disease
Effect of cannabinoid oral treatment on cognitive impairment and glucose uptake by positron emission tomography (PET) In a previous work we assessed the effects of cannabinoids following intraventricular administration concomitant to Ab injection for 7 days to rats [12]
In this work we have chosen to administer cannabinoids in the drinking water to investigate their effects in the genetic model of AD

Summary

Introduction

Alzheimer’s disease (AD) brain shows an ongoing inflammatory condition and non-steroidal antiinflammatories diminish the risk of suffering the neurologic disease. The cognitive impairment is associated with the degeneration of particular subsets of neurons in regions involved in learning and memory processes In addition another invariant feature of AD is neuroinflammation, an important component in the disease led to the discovery that prolonged treatment with non-steroidal antiinflammatories (NSAIDS) had beneficial effects for AD. Several prospective works have shown that this kind of treatment markedly reduced the risk of suffering the neurologic condition, delayed its onset, ameliorated the symptomatic severity and slowed cognitive decline [3,4,5] Their administration to already demented patients may be ineffective, suggesting the importance of early administration or, alternatively, the existence of additional targets of NSAIDs, besides cycloxygenase inhibition. Other compounds with antiinflammatory activity may be disease modifying drugs, which may delay onset or slow its progression, in contrast with the present AD palliative treatment

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