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Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways.
Cell Death Differ. 2004 Oct; 11(10):1121-32.CD

Abstract

Anandamide (arachidonoylethanolamide or AEA) is an endocannabinoid that acts at vanilloid (VR1) as well as at cannabinoid (CB1/CB2) and NMDA receptors. Here, we show that AEA, in a dose-dependent manner, causes cell death in cultured rat cortical neurons and cerebellar granule cells. Inhibition of CB1, CB2, VR1 or NMDA receptors by selective antagonists did not reduce AEA neurotoxicity. Anandamide-induced neuronal cell loss was associated with increased intracellular Ca(2+), nuclear condensation and fragmentation, decreases in mitochondrial membrane potential, translocation of cytochrome c, and upregulation of caspase-3-like activity. However, caspase-3, caspase-8 or caspase-9 inhibitors, or blockade of protein synthesis by cycloheximide did not alter anandamide-related cell death. Moreover, AEA caused cell death in caspase-3-deficient MCF-7 cell line and showed similar cytotoxic effects in caspase-9 dominant-negative, caspase-8 dominant-negative or mock-transfected SH-SY5Y neuroblastoma cells. Anandamide upregulated calpain activity in cortical neurons, as revealed by alpha-spectrin cleavage, which was attenuated by the calpain inhibitor calpastatin. Calpain inhibition significantly limited anandamide-induced neuronal loss and associated cytochrome c release. These data indicate that AEA neurotoxicity appears not to be mediated by CB1, CB2, VR1 or NMDA receptors and suggest that calpain activation, rather than intrinsic or extrinsic caspase pathways, may play a critical role in anandamide-induced cell death.

Authors+Show Affiliations

Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15375383

Citation

Movsesyan, V A., et al. "Anandamide-induced Cell Death in Primary Neuronal Cultures: Role of Calpain and Caspase Pathways." Cell Death and Differentiation, vol. 11, no. 10, 2004, pp. 1121-32.
Movsesyan VA, Stoica BA, Yakovlev AG, et al. Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways. Cell Death Differ. 2004;11(10):1121-32.
Movsesyan, V. A., Stoica, B. A., Yakovlev, A. G., Knoblach, S. M., Lea, P. M., Cernak, I., Vink, R., & Faden, A. I. (2004). Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways. Cell Death and Differentiation, 11(10), 1121-32.
Movsesyan VA, et al. Anandamide-induced Cell Death in Primary Neuronal Cultures: Role of Calpain and Caspase Pathways. Cell Death Differ. 2004;11(10):1121-32. PubMed PMID: 15375383.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anandamide-induced cell death in primary neuronal cultures: role of calpain and caspase pathways. AU - Movsesyan,V A, AU - Stoica,B A, AU - Yakovlev,A G, AU - Knoblach,S M, AU - Lea,P M,4th AU - Cernak,I, AU - Vink,R, AU - Faden,A I, PY - 2004/9/18/pubmed PY - 2005/10/21/medline PY - 2004/9/18/entrez SP - 1121 EP - 32 JF - Cell death and differentiation JO - Cell Death Differ VL - 11 IS - 10 N2 - Anandamide (arachidonoylethanolamide or AEA) is an endocannabinoid that acts at vanilloid (VR1) as well as at cannabinoid (CB1/CB2) and NMDA receptors. Here, we show that AEA, in a dose-dependent manner, causes cell death in cultured rat cortical neurons and cerebellar granule cells. Inhibition of CB1, CB2, VR1 or NMDA receptors by selective antagonists did not reduce AEA neurotoxicity. Anandamide-induced neuronal cell loss was associated with increased intracellular Ca(2+), nuclear condensation and fragmentation, decreases in mitochondrial membrane potential, translocation of cytochrome c, and upregulation of caspase-3-like activity. However, caspase-3, caspase-8 or caspase-9 inhibitors, or blockade of protein synthesis by cycloheximide did not alter anandamide-related cell death. Moreover, AEA caused cell death in caspase-3-deficient MCF-7 cell line and showed similar cytotoxic effects in caspase-9 dominant-negative, caspase-8 dominant-negative or mock-transfected SH-SY5Y neuroblastoma cells. Anandamide upregulated calpain activity in cortical neurons, as revealed by alpha-spectrin cleavage, which was attenuated by the calpain inhibitor calpastatin. Calpain inhibition significantly limited anandamide-induced neuronal loss and associated cytochrome c release. These data indicate that AEA neurotoxicity appears not to be mediated by CB1, CB2, VR1 or NMDA receptors and suggest that calpain activation, rather than intrinsic or extrinsic caspase pathways, may play a critical role in anandamide-induced cell death. SN - 1350-9047 UR - https://www.unboundmedicine.com/medline/citation/15375383/Anandamide_induced_cell_death_in_primary_neuronal_cultures:_role_of_calpain_and_caspase_pathways_ L2 - https://doi.org/10.1038/sj.cdd.4401442 DB - PRIME DP - Unbound Medicine ER -