Federica Pessina1, Raffaele Capasso2, Francesca Borrelli2, Teresa Aveta3, Lorena Buono4, Giuseppe Valacchi5, Paolo Fiorenzani1, Vincenzo Di Marzo3, Pierangelo Orlando4, Angelo A Izzo6. 1. Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy. 2. Department of Pharmacy, University of Naples Federico II, Naples, Italy; Institute of Protein Biochemistry, National Research Council, Naples, Italy; National Institute of Optics, National Research Council, Pozzuoli, Italy; Endocannabinoid Research Group. 3. Institute of Protein Biochemistry, National Research Council, Naples, Italy; Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy; National Institute of Optics, National Research Council, Pozzuoli, Italy; Endocannabinoid Research Group. 4. Institute of Protein Biochemistry, National Research Council, Naples, Italy; National Institute of Optics, National Research Council, Pozzuoli, Italy; Endocannabinoid Research Group. 5. Department of Life Science and Biotechnologies, University of Ferrara, Ferrara, Italy. 6. Department of Pharmacy, University of Naples Federico II, Naples, Italy; Institute of Protein Biochemistry, National Research Council, Naples, Italy; National Institute of Optics, National Research Council, Pozzuoli, Italy; Endocannabinoid Research Group. Electronic address: aaizzo@unina.it.
Abstract
PURPOSE: PEA is an endogenous mediator released together with the endocannabinoid anandamide from membrane phospholipids. It is a plant derived compound with analgesic and anti-inflammatory properties. We verified whether the pathophysiology of experimental cystitis involves changes in the levels of PEA and of some of its targets, ie CB1 and CB2 receptors, and PPARα. We also determined whether exogenously administered PEA could be proposed as a preventive measure for cystitis. MATERIALS AND METHODS: Cystitis was induced by cyclophosphamide in female rats. Nociceptive responses, voiding episodes, gross damage, myeloperoxidase activity, bladder weight, bladder PEA and endocannabinoid levels (measured by liquid chromatography-mass spectrometry) and the expression of PEA targets (measured by quantitative reverse transcriptase-polymerase chain reaction) were recorded. RESULTS: Cyclophosphamide induced pain behavior, bladder inflammation and voiding dysfunction associated with increased bladder levels of PEA, up-regulation of CB1 receptor mRNA expression, down-regulation of PPARα mRNA and no change in CB2 receptor mRNA expression. Exogenously administered, ultramicronized PEA attenuated pain behavior, voids and bladder gross damage. The CB1 antagonist rimonabant and the PPARα antagonist GW6471 counteracted the beneficial effect of PEA on gross damage. Also, GW6471 further decreased voiding episodes in rats treated with PEA. CONCLUSIONS: The current study provides strong evidence for a protective role of PEA as well as an alteration in bladder levels of PEA and of some of its targets in cyclophosphamide induced cystitis.
PURPOSE: PEA is an endogenous mediator released together with the endocannabinoidanandamide from membrane phospholipids. It is a plant derived compound with analgesic and anti-inflammatory properties. We verified whether the pathophysiology of experimental cystitis involves changes in the levels of PEA and of some of its targets, ie CB1 and CB2 receptors, and PPARα. We also determined whether exogenously administered PEA could be proposed as a preventive measure for cystitis. MATERIALS AND METHODS:Cystitis was induced by cyclophosphamide in female rats. Nociceptive responses, voiding episodes, gross damage, myeloperoxidase activity, bladder weight, bladder PEA and endocannabinoid levels (measured by liquid chromatography-mass spectrometry) and the expression of PEA targets (measured by quantitative reverse transcriptase-polymerase chain reaction) were recorded. RESULTS:Cyclophosphamide induced pain behavior, bladder inflammation and voiding dysfunction associated with increased bladder levels of PEA, up-regulation of CB1 receptor mRNA expression, down-regulation of PPARα mRNA and no change in CB2 receptor mRNA expression. Exogenously administered, ultramicronized PEA attenuated pain behavior, voids and bladder gross damage. The CB1 antagonist rimonabant and the PPARα antagonist GW6471 counteracted the beneficial effect of PEA on gross damage. Also, GW6471 further decreased voiding episodes in rats treated with PEA. CONCLUSIONS: The current study provides strong evidence for a protective role of PEA as well as an alteration in bladder levels of PEA and of some of its targets in cyclophosphamide induced cystitis.