Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults.
While endocannabinoid modulation of both GABAergic and glutamatergic synaptic transmission and plasticity has been extensively investigated, our understanding of the role of endocannabinoids in protecting neurons from harmful insults remains limited. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous ligand and a full agonist for cannabinoid receptors, exhibits anti-inflammatory and neuroprotective effects via a CB1 receptor (CB1R)-mediated mechanism. However, it is still not clear whether 2-AG is also able to protect neurons from β-amyloid (Aβ)-induced neurodegeneration. Here, we demonstrate that exogenous application of 2-AG significantly protected hippocampal neurons in culture against Aβ-induced neurodegeneration and apoptosis. This neuroprotective effect was blocked by SR141716 (SR-1), a selective CB1R antagonist, but not by SR144528 (SR-2), a selective CB2R antagonist, or capsazepine (CAP), a selective transient receptor potential cation channels, subfamily V, member 1 (TRPV1) receptor antagonist. To determine whether endogenous 2-AG is capable of protecting neurons from Aβ insults, hippocampal neurons in culture were treated with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), the enzyme hydrolyzing 2-AG. MAGL inhibition that elevates endogenous levels of 2-AG also significantly reduced Aβ-induced neurodegeneration and apoptosis. The 2-AG-produced neuroprotective effects appear to be mediated via CB1R-dependent suppression of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) phosphorylation and cyclooxygenase-2 (COX-2) expression. Our results suggest that elevation of endogenous 2-AG by inhibiting its hydrolysis has potential as a novel efficacious therapeutic approach for preventing, ameliorating or treating Alzheimer's disease.
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D018929:Cell Culture Techniques; D004347:Drug Interactions; D063388:Endocannabinoids; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy*; D010446:Peptide Fragments / Q000009:adverse effects*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D001095:Arachidonic Acids; D052117:Benzodioxoles; D001713:Biphenyl Compounds; D001892:Camphanes; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D010446:Peptide Fragments; D010880:Piperidines; D011720:Pyrazoles; C110630:SR 144528; C501835:URB602; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; C071423:capsazepine; D000077285:Rimonabant; D002211:Capsaicin
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