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Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels.
J Neurosci 2009; 29(7):2053-63JN

Abstract

Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca(2+) homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca(2+) regulation is bidirectional, depending on the excitability of cells. Under physiological K(+)/Ca(2+) levels, CBD caused a subtle rise in [Ca(2+)](i), whereas CBD reduced [Ca(2+)](i) and prevented Ca(2+) oscillations under high-excitability conditions (high K(+) or exposure to the K(+) channel antagonist 4AP). Regulation of [Ca(2+)](i) was not primarily mediated by interactions with ryanodine or IP(3) receptors of the endoplasmic reticulum. Instead, dual-calcium imaging experiments with a cytosolic (fura-2 AM) and a mitochondrial (Rhod-FF, AM) fluorophore implied that mitochondria act as sinks and sources for CBD's [Ca(2+)](i) regulation. Application of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and the mitochondrial Na(+)/Ca(2+) exchange inhibitor, CGP 37157, but not the mitochondrial permeability transition pore inhibitor cyclosporin A, prevented subsequent CBD-induced Ca(2+) responses. In established human neuroblastoma cell lines (SH-SY5Y) treated with mitochondrial toxins, CBD (0.1 and 1 microm) was neuroprotective against the uncoupler FCCP (53% protection), and modestly protective against hydrogen peroxide- (16%) and oligomycin- (15%) mediated cell death, a pattern also confirmed in cultured hippocampal neurons. Thus, under pathological conditions involving mitochondrial dysfunction and Ca(2+) dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca(2+) homeostasis.

Authors+Show Affiliations

School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19228959

Citation

Ryan, Duncan, et al. "Cannabidiol Targets Mitochondria to Regulate Intracellular Ca2+ Levels." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 29, no. 7, 2009, pp. 2053-63.
Ryan D, Drysdale AJ, Lafourcade C, et al. Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci. 2009;29(7):2053-63.
Ryan, D., Drysdale, A. J., Lafourcade, C., Pertwee, R. G., & Platt, B. (2009). Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 29(7), pp. 2053-63. doi:10.1523/JNEUROSCI.4212-08.2009.
Ryan D, et al. Cannabidiol Targets Mitochondria to Regulate Intracellular Ca2+ Levels. J Neurosci. 2009 Feb 18;29(7):2053-63. PubMed PMID: 19228959.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. AU - Ryan,Duncan, AU - Drysdale,Alison J, AU - Lafourcade,Carlos, AU - Pertwee,Roger G, AU - Platt,Bettina, PY - 2009/2/21/entrez PY - 2009/2/21/pubmed PY - 2009/4/17/medline SP - 2053 EP - 63 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 29 IS - 7 N2 - Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca(2+) homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca(2+) regulation is bidirectional, depending on the excitability of cells. Under physiological K(+)/Ca(2+) levels, CBD caused a subtle rise in [Ca(2+)](i), whereas CBD reduced [Ca(2+)](i) and prevented Ca(2+) oscillations under high-excitability conditions (high K(+) or exposure to the K(+) channel antagonist 4AP). Regulation of [Ca(2+)](i) was not primarily mediated by interactions with ryanodine or IP(3) receptors of the endoplasmic reticulum. Instead, dual-calcium imaging experiments with a cytosolic (fura-2 AM) and a mitochondrial (Rhod-FF, AM) fluorophore implied that mitochondria act as sinks and sources for CBD's [Ca(2+)](i) regulation. Application of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and the mitochondrial Na(+)/Ca(2+) exchange inhibitor, CGP 37157, but not the mitochondrial permeability transition pore inhibitor cyclosporin A, prevented subsequent CBD-induced Ca(2+) responses. In established human neuroblastoma cell lines (SH-SY5Y) treated with mitochondrial toxins, CBD (0.1 and 1 microm) was neuroprotective against the uncoupler FCCP (53% protection), and modestly protective against hydrogen peroxide- (16%) and oligomycin- (15%) mediated cell death, a pattern also confirmed in cultured hippocampal neurons. Thus, under pathological conditions involving mitochondrial dysfunction and Ca(2+) dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca(2+) homeostasis. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/19228959/abstract/Cannabidiol_targets_mitochondria_to_regulate_intracellular_Ca2+_levels_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=19228959 DB - PRIME DP - Unbound Medicine ER -