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Evaluation of the peripheral antinociceptive effect of the soluble Epoxy Hydrolase inhibitor, TPPU, on formalin-induced hypernociception in the temporomandibular joint of rats

Grant number: 18/05575-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): July 01, 2018
Effective date (End): June 30, 2019
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Juliana Trindade Clemente Napimoga
Grantee:Victor Luís Pieroni
Home Institution: Centro de Pesquisas Odontológicas São Leopoldo Mandic. Faculdade São Leopoldo Mandic (SLMANDIC). Sociedade Regional de Ensino e Saúde S/S Ltda (SRES). Campinas , SP, Brazil

Abstract

Epoxy-eicosatrienoic acids (EETs) are molecules of intracellular lipid signaling that have important biological activities, such as vasodilation, anti-inflammation and analgesic effects. However, EETs have a very short half-life since they are rapidly hydrolyzed by the soluble epoxy hydrolase enzyme (sEH), reducing their bioavailability. Thus, the inhibitors of the sEH enzyme arouse great interest for therapeutic use. Recently, the research group of Dr. Bruce D. Hammock (UC - Davis, USA) developed and patented a sEH inhibitor, named 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea (TPPU), which presented potential analgesic and anti-inflammatory effects. However, the mechanisms of action related to these effects still need to be studied. Since EETs have a potent anti-inflammatory effect mediated by the activation of peroxisome proliferator-activated receptor gamma (PPAR-³), we hypothesized that TPPU enhances the expression of EETs, which is mediated by the activation of the PPAR-³ expressed in TMJ, exhibits a potent anti-inflammatory effect. In this study we will use the formalin-induced inflammatory hypernociception model in TMJ to evaluate: (1) the peripheral antinociceptive effect of TPPU on formalin-induced inflammatory hypernociception in TMJ of rats; (2) Evaluate whether the TPPU-induced antinociceptive effect on ATM is mediated by PPAR-³ receptor activation; (3) to investigate the effect of TPPU on the alteration of M1 and M2 macrophages phenotyping in TMJ. The development of this project will contribute to the elucidation of the mechanisms involved in the peripheral antinociceptive effect induced by TPPU in TMJ, allowing the development of more efficient pharmacological targets for the control of painful conditions of inflammatory origin.