title: Intrinsic up-regulation of 2-AG favors an area specific neuronal survival in different in vitro models of neuronal damage.
abstract: BACKGROUND
  The 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).
  
  
  RESULTS
  2-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.
  
  
  CONCLUSIONS
  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 thus represents a protective system for neurons that is involved in dendritic reorganisation.
authors.affiliation: Institut für Anatomie, Universität Leipzig, Leipzig, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Kallendrusch
authors.forename: Constance
authors.initials: C
authors.lastname: Hobusch
authors.forename: Angela
authors.initials: A
authors.lastname: Ehrlich
authors.forename: Marcin
authors.initials: M
authors.lastname: Nowicki
authors.forename: Simone
authors.initials: S
authors.lastname: Ziebell
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Marco
authors.initials: M
authors.lastname: Koch
authors.forename: Faramarz
authors.initials: F
authors.lastname: Dehghani
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D005989:Glycerides / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D008071:Lipoprotein Lipase / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008994:Monoacylglycerol Lipases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019580:Perforant Pathway / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; D016202:N-Methylaspartate; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D008071:Lipoprotein Lipase