Long-Term Monoacylglycerol Lipase Inhibitor Treatment Decelerates Pathological Changes in APP/PS1-21 Mice, but Behavioral Improvements Require Early-Stage Treatment Onset—Short Report

Rea Pihlaja,Annamari Torittu,Juha O Rinne,Anniina Snellman,Noora Lindgren,Merja Haaparanta-Solin

doi:10.4236/wjns.2018.82014

Abstract

The arachidonic acid (AA) pathway produces several essential proinflammatory eicosanoids. However, in many neurodegenerative diseases, e.g. Alzheimer’s disease (AD), this pathway is chronically hyperactivated. In brain, primarily monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to AA, which is further metabolized to generate many proinflammatory eicosanoids. MAGL inhibition, simultaneously reducing the level of eicosanoids and increasing those of neuroprotective endocannabinoids, has proved efficacious in some AD models, reducing neurotoxic β-amyloid (Aβ) levels and improving memory functions. Here, a MAGL inhibitor, JZL184 was chronically administered (16 mg/kg, i.p., 3 x/wk for 5 mo) for 1 - 1.5 mo and 7 - 8 mo old transgenic (TG) and wild-type (WT) APP/PS1-21 mice modelling cerebral amyloidosis. According to immunohistochemistry, JZL184 significantly increased the expression levels of cannabinoid receptor 1 in older WT and younger TG and WT mice, decreased cannabinoid receptor 2 and oligomeric Aβ in older and younger TG mice and decreased microglia-specific marker Iba1 in younger TG mice, compared to TG mice treated with vehicle only. However, in the Morris Water Maze test, spatial memory functions improved significantly only in younger TG and WT mice, compared to vehicle-treated littermates. These tentative results suggest that chronic, rather long-term MAGL inhibition can decelerate pathological changes in TG APP/PS1-21 mice but it improves memory functions only when administered at an early stage of the pathology

Highlights

Neuroinflammation plays a prominent role in many nervous system pathologies, contributing to the disease process itself, there probably are differences in certain features in the mediators of inflammation between these diseases [1] [2]
Old or young TG amyloid precursor protein Aβ (APP)/PS1-21 mice or their WT littermates were treated with JZL184 (16 mg/kg, i.p.) or vehicle, 3 x /week for 5 mo
Treatment with monoacylglycerol lipase (MAGL) inhibitor JZL184 evoked a positive effect on spatial memory functions in young but not in old TG APP/PS1-21 mice

Summary

Introduction

Neuroinflammation plays a prominent role in many nervous system pathologies, contributing to the disease process itself, there probably are differences in certain features in the mediators of inflammation between these diseases [1] [2]. During the progression of Alzheimer’s disease (AD), chronically hyperactivated microglia recruit increased numbers of reactive astrocytes and these cells enhance the inflammatory response, leading to the appearance of one of the typical pathological hallmarks of the disease; extracellular β-amyloid (Aβ) deposits [3]. The endocannabinoid system is involved in many physiological processes, including cognitive functions, memory and inflammation. This system consists of endogenous signalling lipids i.e. 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, which bind to and activate cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) [8]. Activation of CB1/CB2 receptors by synthetic agonists has been reported to reduce neuroinflammation and inhibit the production of Aβ as well as improving cognition in mouse model of AD [12]

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