Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun, Yan; Alexander, Stephen P.H.; Garle, Michael J.; Gibson, Claire L.; Hewitt, Katherine N.; Murphy, Seán; Kendall, David A.; Bennett, Andrew J.

doi:10.1038/sj.bjp.0707478

Cited by 204 publications

(184 citation statements)

References 50 publications

(58 reference statements)

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“…2) Ttype Ca 2+ channels have been suggested to be inhibited by both unsaturated long chain fatty acid amides, including some N--acylethanolamines, N-acyl-serotonins, and N-acyldopamines [49], and THC and CBD [50]. 3) peroxisome-proliferator activated receptor-α is activated by both anandamide congeners such as N-palmitoylethanolamine and N-oleoylethanolamine [51], which have in this nuclear receptor their preferred target, and some plant and synthetic cannabinoids [52]; instead, PPARγ is activated, at concentrations of 1-10 μM, by both CBD and anandamide or 2-AG [53,54].…”

Section: Other Ways Through Which Non-thc Plant Cannabinoids Influencmentioning

confidence: 99%

The Endocannabinoid System and its Modulation by Phytocannabinoids

2015

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The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ 9 -tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)-cannabinoid receptor type-1 (CB 1 R) and cannabinoid receptor type-2 (CB 2 R); their two most studied endogenous ligands, the "endocannabinoids" N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism. However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB 1 R and CB 2 R. Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with "endocannabinoid-like" mediators that may or may not interact with the same proteins as Δ 9 -tetrahydrocannabinol and other phytocannabinoids. In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors. Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets. Here, we review the whole world of ligands, receptors, and enzymes, a true "endocannabinoidome", discovered after the cloning of CB 1 R and CB 2 R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.

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Section: Other Ways Through Which Non-thc Plant Cannabinoids Influencmentioning

confidence: 99%

The Endocannabinoid System and its Modulation by Phytocannabinoids

2015

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“…-tetrahydrocannabinol (THC) (Devane et al 1992;Solinas et al 2008), has recently begun to receive attention as a potential endogenous PPAR-a ligand (O'Sullivan 2000;Mackie and Stella 2006;Sun et al 2007). OEA has primarily been studied as a satiety factor (Rodriguez de Fonseca et al 2001;Fu et al 2003) and PEA as an anti-inflammatory factor (Kuehl et al 1957;Calignano et al 1998;Jaggar et al 1998).…”

mentioning

confidence: 99%

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Mazzola¹,

Medalie²,

Scherma³

et al. 2009

Learn. Mem.

116

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Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB 1 -receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR-a) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-a agonist WY14643, and these enhancements were blocked by the PPAR-a antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-a, either directly by administering a PPAR-a agonist or indirectly by administering a FAAH inhibitor.Peroxisome proliferator-activated receptor-a (PPAR-a) is a ligandactivated transcriptional factor that regulates the expression of genes involved in lipid utilization, fatty acid oxidation, and inflammation (van Raalte et al. 2004;LoVerme et al. 2006). Immunolocalization studies of PPAR-a in the adult rat brain suggest that this nuclear receptor might have specific functions in regulating expression of genes involved in cholinergic neurotransmission and learning and memory processes (Moreno et al. 2004;Cimini et al. 2005). For example, there are high concentrations of PPAR-a receptors in the hippocampus and amygdala (Moreno et al. 2004). However, the potential involvement of PPAR-a in learning and memory processes has not been systematically investigated.Endogenous ligands for PPAR-a include the lipid mediators N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA). In addition, anandamide (N-arachidonoylethanolamine), which has primarily been studied as an endogenous ligand for G-proteincoupled cannabinoid CB 1 receptors that mediate the behavioral effects of cannabis and its active constituent D 9-tetrahydrocannabinol (THC) (Devane et al. 1992;Solinas et al. 2008), has recently begun to receive attention as a potential endogenous PPAR-a ligand (O'Sullivan 2000;Mackie and Stella 2006;Sun et al. 2007). OEA has primarily been studied as a satiety factor (Rodriguez de Fonseca et al. 2001;Fu et al. 2003) and PEA as an anti-inflammatory factor (Kuehl et al. 1957;Calignano et al. 1998;Jaggar et al. 1998). OEA and PEA are structurally similar to anandamide but do not bind to or activate cannabinoid CB 1 receptors. Anandamide, OEA, and PEA are all inactivated primarily by the intracellular serine enzyme, fatty acid amide hydrolase (FAAH) (Cravatt and Lichtman 2002;Fegley et al. 2005). Consequently, selective FAAH-inhibiting drugs such as cyclohexyl carbamic acid 39-carbamoyl-3-yl ester (URB597) increase endogenous levels of anandamide, OEA, and PEA in the brain (Fegley et al. 2005;Piomelli et al. 2006).In the present experiments, the effects of FAAH inhibition on learning and memory processes and the involvement of cannabinoid CB 1 receptors and PPAR-a nuclear receptors in those effects were studied using a passive-avoidance procedure in rats. FAAH inhibition was accomplished by administering U...

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“…Ligand binding to PPARs causes the recruitment of regulator proteins that bind to a third site on PPARs, and these are thought to modulate transactivation. PPAR target genes are primarily involved in 13 (C)…”

Section: P Eroxisomementioning

confidence: 99%

Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

O’Sullivan

2012

WIREs Membr Transp Signal

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Since 2002, evidence has been building that cannabinoids, including endocannabinoids and endocannabinoid-like compounds, phytocannabinoids and synthetic cannabinoid ligands, bind to and activate the different isoforms of the nuclear receptors, peroxisome proliferator-activated receptors (PPARs; α, β, and γ ). This has been shown through the use of reporter gene assays, binding studies, the use of antagonists and knockout animals. Increasing use of tools to assess a potential role for PPAR activation in underpinning the physiological effects of cannabinoids means that a picture is emerging of the relevance of PPAR activation by cannabinoids. There is now evidence that activation of PPARα and γ mediate some of the anti-inflammatory, analgesic, neuroprotective, and cardiovascular effects of cannabinoids, sometimes in combination with activation of the more traditional target sites of action such as CB 1 , CB 2 , and TRPV1. There is also a role for PPARα activation by cannabinoids in some of their central effects including memory acquisition, reward processing, food intake and body weight regulation. Activation of PPARγ plays a role in the apoptotic effects of cannabinoids. However, much further work is required to fully establish the profile of cannabinoid compounds at all isoforms of the PPAR family and the relevance of this in normal physiology and pathological situations.

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Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Cited by 204 publications

References 50 publications

The Endocannabinoid System and its Modulation by Phytocannabinoids

The Endocannabinoid System and its Modulation by Phytocannabinoids

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

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