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Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults.
Neuroscience 2011; 178:159-68N

Abstract

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.

Authors+Show Affiliations

Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21256197

Citation

Chen, X, et al. "Endocannabinoid 2-arachidonoylglycerol Protects Neurons Against Β-amyloid Insults." Neuroscience, vol. 178, 2011, pp. 159-68.
Chen X, Zhang J, Chen C. Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults. Neuroscience. 2011;178:159-68.
Chen, X., Zhang, J., & Chen, C. (2011). Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults. Neuroscience, 178, pp. 159-68. doi:10.1016/j.neuroscience.2011.01.024.
Chen X, Zhang J, Chen C. Endocannabinoid 2-arachidonoylglycerol Protects Neurons Against Β-amyloid Insults. Neuroscience. 2011 Mar 31;178:159-68. PubMed PMID: 21256197.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults. AU - Chen,X, AU - Zhang,J, AU - Chen,C, Y1 - 2011/01/19/ PY - 2010/10/01/received PY - 2011/01/06/revised PY - 2011/01/12/accepted PY - 2011/1/25/entrez PY - 2011/1/25/pubmed PY - 2011/6/28/medline SP - 159 EP - 68 JF - Neuroscience JO - Neuroscience VL - 178 N2 - 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. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/21256197/abstract/Endocannabinoid_2_arachidonoylglycerol_protects_neurons_against_β_amyloid_insults_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(11)00047-9 DB - PRIME DP - Unbound Medicine ER -