Impact of pharmacological inhibition of the soluble epoxy hydrolase enzyme on the activation of satellite glial cells in the trigeminal ganglion in a persistent model of rheumatoid arthritis in rats.

• Grant number: 23/12659-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2024
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Henrique Ballassini Abdalla
• Grantee: Maria Eliza Tofanin
• Host 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

Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by pain and swelling due to infiltration of immune cells into the joint. Immune cells, such as neutrophils and lymphocytes, can be activated, producing inflammatory cytokines, leading to continuous inflammatory and degenerative reactions. As a synovial joint, the temporomandibular joint (TMJ) can be affected by RA. In this scenario, new targets and specific therapies are needed to improve the effectiveness of conventional treatments and reduce associated side effects. Epoxy-eicosatrienoic acids (EETs) are endogenous signaling molecules that play an essential role in reducing inflammation and pain; however, they are readily metabolized by soluble epoxide hydrolase (sEH), generating less bioactive and pro-inflammatory acids. Thus, sEH inhibitors are considered an attractive therapeutic target, capable of increasing the bioavailability of endogenous EETs. TPPU (N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea), is a potent inhibitor of soluble epoxy hydrolase, reducing the hydrolysis of EETs and their consequent inactivation. Therefore, we intend to evaluate the impact of pharmacological inhibition of sEH in a persistent model of albumin-induced arthritis in the TMJ. Furthermore, we will investigate the influence of sEH inhibition on the activation of glial satellite cells located in the trigeminal ganglion of rats, on the expression of Toll-like receptors 2 and 4, and the gene expression of the mediators TNF±, IL-1², IL-6, IL-10, IL-4, IL-13, and TGF-². For this, arthritis in the TMJ of Wistar rats will be induced by methylated bovine albumin (mBSA) diluted in Freud's complete solution. Intra-articular injections of mBSA (10 mg/ATM/week) for three weeks resulted in persistent inflammatory hypernociception. The nociceptive evaluation of TPPU and its potential analgesic effect will be evaluated through the analysis of the nociceptive behavioral response induced by subthreshold formalin in the TMJ of rats. Immediately after quantification of nociceptive behaviors, the animals will be killed by deepening anesthesia, and the trigeminal ganglion will be removed to evaluate the activation of glial satellite cells, expression of TLR 2 and 4 receptors, and the expression of inflammatory mediators. This study is expected to contribute to the understanding of the pathophysiology of the nociceptive response of RA in the orofacial region, as well as the search for new pharmacological therapies.