Abstract
BackgroundThe endocannabinoid 2-arachidonoyl glycerol (2-AG) acts as a retrograde messenger and modulates synaptic signaling e. g. in the hippocampus. 2-AG also exerts neuroprotective effects under pathological situations. To better understand the mechanism beyond physiological signaling we used Organotypic Entorhino-Hippocampal Slice Cultures (OHSC) and investigated the temporal regulation of 2-AG in different cell subsets during excitotoxic lesion and dendritic lesion of long range projections in the enthorhinal cortex (EC), dentate gyrus (DG) and the cornu ammonis region 1 (CA1).Results2-AG levels were elevated 24 h after excitotoxic lesion in CA1 and DG (but not EC) and 24 h after perforant pathway transection (PPT) in the DG only. After PPT diacylglycerol lipase alpha (DAGL) protein, the synthesizing enzyme of 2-AG was decreased when Dagl mRNA expression and 2-AG levels were enhanced. In contrast to DAGL, the 2-AG hydrolyzing enzyme monoacylglycerol lipase (MAGL) showed no alterations in total protein and mRNA expression after PPT in OHSC. MAGL immunoreaction underwent a redistribution after PPT and excitotoxic lesion since MAGL IR disappeared in astrocytes of lesioned OHSC. DAGL and MAGL immunoreactions were not detectable in microglia at all investigated time points. Thus, induction of the neuroprotective endocannabinoid 2-AG might be generally accomplished by down-regulation of MAGL in astrocytes after neuronal lesions.ConclusionIncrease in 2-AG levels during secondary neuronal damage reflects a general neuroprotective mechanism since it occurred independently in both different lesion models. This intrinsic up-regulation of 2-AG is synergistically controlled by DAGL and MAGL in neurons and astrocytes and thus represents a protective system for neurons that is involved in dendritic reorganisation.
Highlights
The endocannabinoid system was shown to be involved in processes of neurodegeneration
We here compared the induction of the 2-arachidonoyl glycerol (2-AG) regulatory machinery in an in vitro model of Organotypic Hippocampal Slice Cultures (OHSC) and investigated the temporal changes in 2-AG levels and its main enzymes diacylglycerol lipase alpha (DAGL) and monoacylglycerol lipase (MAGL) after 1) long-range projection damage as it occurs in stroke by transection of the perforant pathway and 2) excitotoxic lesion as a central mechanism of neuronal damage by application of NMDA
Co-localization of DAGL IR with GFAP IR in astrocytes and isolectin B4 (IB4) positive microglial cells was hardly detectable in control Organotypic Entorhino-Hippocampal Slice Cultures (OHSC) and no change was found in OHSC after perforant pathway transection (PPT) until 12 hpl
Summary
Increase in 2-AG levels during secondary neuronal damage reflects a general neuroprotective mechanism since it occurred independently in both different lesion models. This intrinsic up-regulation of 2-AG is synergistically controlled by DAGL and MAGL in neurons and astrocytes and represents a protective system for neurons that is involved in dendritic reorganisation
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