New insights into endocannabinoid degradation and its therapeutic potential

M. Bari, N. Battista, F. Fezza, V. Gasperi, M. Maccarrone

Research output: Contribution to journalArticlepeer-review

Abstract

Endocannabinoids are amides, esters and ethers of long chain polyunsaturated fatty acids, which act as new lipidic mediators. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of (-)-Δ9-tetrahydrocannabinol (THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA and 2-AG at their receptors is limited by cellular uptake through an anandamide membrane transporter (AMT), followed by intracellular degradation. A fatty acid amide hydrolase (FAAH) is the main AEA hydrolase, whereas a monoacylglycerol lipase (MAGL) is critical in degrading 2-AG. Here, we will review growing evidence that demonstrates that these hydrolases are pivotal regulators of the endogenous levels of AEA and 2-AG in vivo, overall suggesting that specific inhibitors of AMT, FAAH or MAGL may serve as attractive therapeutic targets for the treatment of human disorders. Recently, the N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which synthesizes AEA from N-arachidonoylphosphatidylethanolamine (NArPE), and the diacylglycerol lipase (DAGL), which generates 2-AG from diacylglycerol (DAG) substrates, have been characterized. The role of these synthetic routes in maintaining the endocannabinoid tone in vivo will be discussed. Finally, the effects of inhibitors of endocannabinoid degradation in animal models of human disease will be reviewed, with an emphasis on their ongoing applications in anxiety, cancer and neurodegenerative disorders.

Original languageEnglish
Pages (from-to)257-268
Number of pages12
JournalMini-Reviews in Medicinal Chemistry
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 2006

Keywords

  • 2-arachidonoylglycerol
  • Anandamide
  • Fatty acid amide hydrolase
  • Human disease
  • Membrane transport
  • Therapy

ASJC Scopus subject areas

  • Chemistry(all)
  • Medicine (miscellaneous)
  • Pharmacology

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