Os mecanismos fisiopatológicos envolvidos na fibromialgia diferem entre camundongos Swiss machos e fêmeas: 4-amino-3-(fenilselanil) benzenosulfonamida como uma estratégia terapêutica

Abstract

Fibromyalgia is a chronic painful condition that affects mainly women. Generally, it is accompanied by the development of comorbidities, including mood disorders, which impaired the quality of life of those patients. In addition, the pathophysiology of this disease remains poorly understood, making it difficult to develop a properly treatment. In view of this, preclinical studies would be expected for elucidate the mechanisms underlying fibromyalgia, as well as new effective and safe therapeutic strategies to treat this pathology. Therefore, the 1st stage of this study explored the mechanisms related to fibromyalgia, using the intermittent cold stress (ICS) model in Swiss mice, considering the sex specificities. The results demonstrated that the NMDA/ON/cGMPc signaling pathway and the serotonergic receptors may contribute to the development of nociceptive signs in mice of both sexes exposed to ICS. Nevertheless, this fibromyalgia model altered some markers of oxidative stress and inhibited the Na+ , K+ -ATPase activity in male mice, whereas an increase in the activity of this enzyme was observed in female mice. Thus, different signaling pathways may contribute to the development of fibromyalgia, regarding the particularities of sex. In the 2nd stage of this study, it was evaluated whether the sex differences affect the expression profile of microRNAs and their target genes in mice exposed to ICS, in order to identify possible pathophysiological markers for fibromyalgia. The results suggest that the decrease in miR-338-3p expression may have stimulated the TRPV1 expression in the plasma of male mice exposed to ICS. On the other side, the increase in miR-338-3p expression may have inhibited the TRPV1 expression in the plasma of female mice exposed to ICS. In the cerebral cortex, the increased expression of miR-115-5p may have inhibited the expression of BDNF in mice of both sexes exposed to ICS. Therefore, miR-155-5p and miR 338-3p alterations may participate in the pathophysiological processes involved in fibromyalgia. In the 3rd stage of this study, we investigated the pharmacological effects of the compound 4-amino-3-(phenylselanyl) benzenesulfonamide (4- APSB), a sulfonamide derivative containing selenium, in the ICS model. The results demonstrated that the 4-APSB treatment attenuated the nociceptive signs and the depressive-like phenotype in mice of both sexes exposed to ICS. Furthermore, the pharmacological action of 4-APSB in this experimental model might be associated to the modulation of the oxidative stress markers, the Na+ , K+ -ATPase activity and the expression of Nrf-2 and NFκB, signaling pathways related to oxidative stress and inflammation. The findings of this thesis reveal that sex impacts the neurobiological aspects related to fibromyalgia and, therefore, it should be considered for purposes of diagnosis and the development of more effective treatments.