Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide

Jonsson, Kent-Olov; Vandevoorde, Séverine; Lambert, Didier M.; Tiger, Gunnar; Fowler, Christopher J.

doi:10.1038/sj.bjp.0704199

Cited by 147 publications

(127 citation statements)

References 54 publications

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“…Note that [ 3 H]-PEA hydrolysis was optimal at pH 8 (Fig 4a), which is reminiscent of the pH dependence described for FAAH, and minimal at pH 5 (Fig 3a and 4a), the optimal pH for NAAA activity (Ueda et al 1999;Ueda et al 1995). Both PEA and AEA competed for [ 3 H]-PEA hydrolysis with IC 50 values of 1.1 μM and 0.4 μM, respectively, which again is reminiscent of FAAH (Jonsson et al 2001) (Fig. 4b).…”

Section: Resultsmentioning

confidence: 96%

Microglia produce and hydrolyze palmitoylethanolamide

Muccioli

Stella

2008

Neuropharmacology

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Microglial cell activation and migration play an important role in neuroinflammation propagation. While it is known that the lipid transmitter palmitoylethanolamide (PEA) regulates microglial migration by interacting with a cannabinoid-like receptor, the production and inactivation of this lipid by microglia has never been addressed directly. Here we show that the mouse microglial cell line BV-2 produces and hydrolyzes PEA. The carbamate compound URB602 inhibits PEA hydrolysis in BV-2 cell homogenates and increases PEA levels in intact cells, whereas the FAAH inhibitor URB597 and serine-hydrolase inhibitor MAFP do not affect PEA levels in intact cells. This unique pharmacological profile of inhibitors on PEA hydrolysis suggests the involvement of a previously undescribed enzyme that degrades PEA. This enzyme expressed by microglia constitutes a promising target for controlling the propagation of neuroinflammation.

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Section: Resultsmentioning

confidence: 96%

Microglia produce and hydrolyze palmitoylethanolamide

Muccioli

Stella

2008

Neuropharmacology

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“…This effect was inhibited by capsazepine, indicating that it was mediated by an endovanilloid(s) binding to the capsaicin-binding domain of TRPV1. Although we did not measure the anandamide content of bladders after PIA application, the finding that PIA inhibits the anandamide-hydrolyzing enzyme FAAH (Jonsson et al, 2001) suggests that that endovanilloid was anandamide. In agreement with the assumed role of anandamide in the development of inflammatory bladder hyperreflexia and the inhibitory action of PIA on FAAH, PIA also increased the activity of two of four inflamed bladders.…”

Section: Discussionmentioning

confidence: 99%

Anandamide-Evoked Activation of Vanilloid Receptor 1 Contributes to the Development of Bladder Hyperreflexia and Nociceptive Transmission to Spinal Dorsal Horn Neurons in Cystitis

Dinis¹,

Charrua²,

Avelino³

et al. 2004

J. Neurosci.

183

132

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The role of anandamide in the development of inflammatory hyperalgesia and visceral hyperreflexia was studied in the rat urinary bladder. Animals were given intraperitoneal cyclophosphamide injection, which evokes painful hemorrhagic cystitis accompanied by increased bladder reflex activity. These results suggest that anandamide, through activating TRPV1, contributes to the development of hyperreflexia and hyperalgesia during cystitis.

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“…Although perhaps not a direct agonist of cannabinoid receptors (Lambert et al, 1999), being a structural analogue of anandamide, OEA has cannabimimetic effects by competing with anandamide for the endocannabinoid-metabolizing enzyme, fatty acid amide hydrolase (Jonsson et al, 2001) and can be considered an ECL. OEA has recently been shown to be the endogenous ligand of an 'orphan' receptor GPR119, which appears to be localized primarily to gut-associated organs, with some CNS expression (Overton et al, 2006).…”

Section: Functional Targets Of Endocannabinoidsmentioning

confidence: 99%

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Sun

Alexander

Garle

et al. 2007

British Journal of Pharmacology

205

172

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Background and purpose: Although CB 1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPARa and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. Experimental approach: Assays of PPARa occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPARa activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPARa gene-disrupted mice. Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPARa ligand binding domain and to increase PPARa-driven transcriptional activity. The high affinity synthetic CB 1/2 cannabinoid agonist WIN 55212-2 bound to PPARa equipotently with the PPARa agonist fenofibrate, and stimulated PPARa-mediated gene transcription. The phytocannabinoid D 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPARa-null mice. OEA treatment also led to increased expression of the NFkB-inhibitory protein, IkB, in mouse cerebral cortex, while expression of the NFkB-regulated protein COX-2 was inhibited. Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARa and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

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Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide

Cited by 147 publications

References 54 publications

Microglia produce and hydrolyze palmitoylethanolamide

Microglia produce and hydrolyze palmitoylethanolamide

Anandamide-Evoked Activation of Vanilloid Receptor 1 Contributes to the Development of Bladder Hyperreflexia and Nociceptive Transmission to Spinal Dorsal Horn Neurons in Cystitis

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

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