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The FAAH inhibitor URB597 efficiently reduces tyrosine hydroxylase expression through CB₁- and FAAH-independent mechanisms.

Abstract

BACKGROUND

Anandamide and 2-arachidonoylglycerol are neuromodulatory lipids interacting with cannabinoid receptors, whose availability is regulated by the balance between 'on demand' generation and enzymatic degradation [by fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase]. Given the reported effects of anandamide on dopamine transmission, we investigated the influence of endocannabinoids and URB597, a well-known FAAH inhibitor, on the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis.

EXPERIMENTAL APPROACH

We investigated TH expression in N1E115 neuroblastoma using a reporter gene assay, as well as mRNA and protein quantifications. FAAH inhibition was confirmed by measuring radiolabelled substrate hydrolysis and endogenous endocannabinoids.

KEY RESULTS

Anandamide decreased TH promoter activity in N1E115 cells through CB₁ receptor activation. Unexpectedly, URB597 reduced TH expression (pEC₅₀ = 8.7 ± 0.2) through FAAH-independent mechanisms. Indeed, four structurally unrelated inhibitors of FAAH had no influence on TH expression, although all the inhibitors increased endocannabinoid levels. At variance with the endocannabinoid responses, the use of selective antagonists indicated that the URB597-mediated decrease in TH expression was not directed by the CB₁ receptor, but rather by abnormal-cannabidiol-sensitive receptors and PPARs. Further supporting the physiological relevance of these in vitro data, URB597 administration resulted in reduced TH mRNA levels in mice brain.

CONCLUSIONS

While confirming the implication of endocannabinoids on the modulation of TH, we provide strong evidence for additional physiologically relevant off-target effects of URB597. In light of the numerous preclinical studies involving URB597, particularly in anxiety and depression, the existence of non-CB₁ and non-FAAH mediated influences of URB597 on key enzymes of the catecholaminergic transmission system should be taken into account when interpreting the data.

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  • Authors+Show Affiliations

    ,

    Medicinal Chemistry Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Bruxelles, Belgium.

    ,

    Source

    British journal of pharmacology 169:4 2013 Jun pg 794-807

    MeSH

    Amidohydrolases
    Animals
    Animals, Outbred Strains
    Anti-Anxiety Agents
    Antidepressive Agents
    Benzamides
    Cannabidiol
    Cannabinoid Receptor Antagonists
    Carbamates
    Cell Line, Tumor
    Corpus Striatum
    Dopaminergic Neurons
    Endocannabinoids
    Enzyme Inhibitors
    Gene Expression Regulation, Enzymologic
    Genes, Reporter
    Hippocampus
    Mice
    Nerve Tissue Proteins
    Peroxisome Proliferator-Activated Receptors
    Promoter Regions, Genetic
    Receptor, Cannabinoid, CB1
    Tyrosine 3-Monooxygenase

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22970888

    Citation

    Bosier, Barbara, et al. "The FAAH Inhibitor URB597 Efficiently Reduces Tyrosine Hydroxylase Expression Through CB₁- and FAAH-independent Mechanisms." British Journal of Pharmacology, vol. 169, no. 4, 2013, pp. 794-807.
    Bosier B, Muccioli GG, Lambert DM. The FAAH inhibitor URB597 efficiently reduces tyrosine hydroxylase expression through CB₁- and FAAH-independent mechanisms. Br J Pharmacol. 2013;169(4):794-807.
    Bosier, B., Muccioli, G. G., & Lambert, D. M. (2013). The FAAH inhibitor URB597 efficiently reduces tyrosine hydroxylase expression through CB₁- and FAAH-independent mechanisms. British Journal of Pharmacology, 169(4), pp. 794-807. doi:10.1111/j.1476-5381.2012.02208.x.
    Bosier B, Muccioli GG, Lambert DM. The FAAH Inhibitor URB597 Efficiently Reduces Tyrosine Hydroxylase Expression Through CB₁- and FAAH-independent Mechanisms. Br J Pharmacol. 2013;169(4):794-807. PubMed PMID: 22970888.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - The FAAH inhibitor URB597 efficiently reduces tyrosine hydroxylase expression through CB₁- and FAAH-independent mechanisms. AU - Bosier,Barbara, AU - Muccioli,Giulio G, AU - Lambert,Didier M, PY - 2012/01/09/received PY - 2012/08/23/revised PY - 2012/09/03/accepted PY - 2012/9/14/entrez PY - 2012/9/14/pubmed PY - 2014/10/9/medline SP - 794 EP - 807 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 169 IS - 4 N2 - BACKGROUND: Anandamide and 2-arachidonoylglycerol are neuromodulatory lipids interacting with cannabinoid receptors, whose availability is regulated by the balance between 'on demand' generation and enzymatic degradation [by fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase]. Given the reported effects of anandamide on dopamine transmission, we investigated the influence of endocannabinoids and URB597, a well-known FAAH inhibitor, on the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. EXPERIMENTAL APPROACH: We investigated TH expression in N1E115 neuroblastoma using a reporter gene assay, as well as mRNA and protein quantifications. FAAH inhibition was confirmed by measuring radiolabelled substrate hydrolysis and endogenous endocannabinoids. KEY RESULTS: Anandamide decreased TH promoter activity in N1E115 cells through CB₁ receptor activation. Unexpectedly, URB597 reduced TH expression (pEC₅₀ = 8.7 ± 0.2) through FAAH-independent mechanisms. Indeed, four structurally unrelated inhibitors of FAAH had no influence on TH expression, although all the inhibitors increased endocannabinoid levels. At variance with the endocannabinoid responses, the use of selective antagonists indicated that the URB597-mediated decrease in TH expression was not directed by the CB₁ receptor, but rather by abnormal-cannabidiol-sensitive receptors and PPARs. Further supporting the physiological relevance of these in vitro data, URB597 administration resulted in reduced TH mRNA levels in mice brain. CONCLUSIONS: While confirming the implication of endocannabinoids on the modulation of TH, we provide strong evidence for additional physiologically relevant off-target effects of URB597. In light of the numerous preclinical studies involving URB597, particularly in anxiety and depression, the existence of non-CB₁ and non-FAAH mediated influences of URB597 on key enzymes of the catecholaminergic transmission system should be taken into account when interpreting the data. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/22970888/The_FAAH_inhibitor_URB597_efficiently_reduces_tyrosine_hydroxylase_expression_through_CB₁__and_FAAH_independent_mechanisms_ L2 - https://doi.org/10.1111/j.1476-5381.2012.02208.x DB - PRIME DP - Unbound Medicine ER -