title: Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration.
abstract: Endogenous cannabinoid receptor ligands (endocannabinoids) may rescue neurons from glutamate excitotoxicity. As these substances also accumulate in cultured immature neurons following neuronal damage, elevated endocannabinoid concentrations may be interpreted as a putative neuroprotective response. However, it is not known how glutamatergic insults affect in vivo endocannabinoid homeostasis, i.e. N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as other constituents of their lipid families, N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs), respectively. Here we employed three in vivo neonatal rat models characterized by widespread neurodegeneration as a consequence of altered glutamatergic neurotransmission and assessed changes in endocannabinoid homeostasis. A 46-fold increase of cortical NAE concentrations (anandamide, 13-fold) was noted 24 h after intracerebral NMDA injection, while less severe insults triggered by mild concussive head trauma or NMDA receptor blockade produced a less pronounced NAE accumulation. By contrast, levels of 2-AG and other 2-MAGs were virtually unaffected by the insults employed, rendering it likely that key enzymes in biosynthetic pathways of the two different endocannabinoid structures are not equally associated to intracellular events that cause neuronal damage in vivo. Analysis of cannabinoid CB(1) receptor mRNA expression and binding capacity revealed that cortical subfields exhibited an up-regulation of these parameters following mild concussive head trauma and exposure to NMDA receptor blockade. This may suggest that mild to moderate brain injury may trigger elevated endocannabinoid activity via concomitant increase of anandamide levels, but not 2-AG, and CB(1) receptor density.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical Faculty, Complutense University, Madrid, Spain. hsh@dfh.dk
authors.forename: H H
authors.initials: HH
authors.lastname: Hansen
authors.forename: P C
authors.initials: PC
authors.lastname: Schmid
authors.forename: P
authors.initials: P
authors.lastname: Bittigau
authors.forename: I
authors.initials: I
authors.lastname: Lastres-Becker
authors.forename: F
authors.initials: F
authors.lastname: Berrendero
authors.forename: J
authors.initials: J
authors.lastname: Manzanares
authors.forename: C
authors.initials: C
authors.lastname: Ikonomidou
authors.forename: H H
authors.initials: HH
authors.lastname: Schmid
authors.forename: J J
authors.initials: JJ
authors.lastname: Fernández-Ruiz
authors.forename: H S
authors.initials: HS
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001924:Brain Concussion / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects; D006259:Craniocerebral Trauma / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D063388:Endocannabinoids; D004983:Ethanolamines / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009410:Nerve Degeneration / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C094503:glyceryl 2-arachidonate; C078814:anandamide