Vortioxetine in inflammatory pain models: mechanism of action, effect on cognitive abilities and redox status of cardiomyocytes

[K. Nastić]

104 str.

Farmacija - Farmakologija / Pharmacy - Pharmacology

Bol je kompleksno, multidimenzionalno iskustvo koje oblikuju biološki, psihološki i socijalni faktori. Među najčešćim bolnim stanjima izdvajaju se inflamatorni bolovi, uključujući osteoartritis. Ciljevi ovog rada su bili ispitivanje efekata i mehanizama dejstva vortioksetina u modelima inflamatornog bola, kao i uticaja leka na kognitivne performanse, opštu dobrobit, redoks status i histološke promene kardiomiocita kod mužjaka i ženki pacova sa osteoartritisom. Efekti vortioksetina su ispitani u modelima akutnog inflamatornog trigeminalnog, visceralnog i somatskog bola, kao i u modelu osteoartritisa. Mehanizam dejstva vortioksetina u modelu trigeminalnog bola je ispitan primenom odgovarajućih receptorskih antagonista. U modelu osteoartritisa, praćen je uticaj leka na molekularne markere bolne preosetljivosti, parametre oksidativnog stresa u kolenu pacova, kognitivne performanse i opštu dobrobit životinja, kao i na parametre redoks statusa i histološke promene kardiomiocita. Vortioksetin je ostvario značajne efekte u svim ispitivanim modelima bola. U modelu trigeminalnog bola je pokazano učešće serotonergičkih 5-HT1B/1D, α2/β1 adrenergičkih, muskarinskih, α7 nikotinskih, kanabinoidnih CB1/CB2, adenozinskih A1 receptora. Vortioksetin je smanjio ekspresiju Ngf i nivo markera oksidativnog stresa u kolenu pacova oba pola; smanjio je ekspresiju iRNK za markere neuroinflamacije u spinalnim gangljima i kičmenoj moždini mužjaka, ali ne i ženki pacova. Dodatno, vortioksetin je poboljšao kognitivne performanse životinja sa osteoartritisom bez štetnog uticaja na opštu dobrobit životinja i redoks status i histološke promene kardiomiocita. Rezultati ukazuju da bi vortioksetin mogao biti efikasan u terapiji inflamatornih bolnih stanja, sa korisnim efektima na kognitivnu funkciju.

Pain is a complex, multidimensional experience shaped by biological, psychological, and social factors. Among the most prevalent pain conditions are inflammatory pain conditions, including osteoarthritis. The aim of this study was to investigate the effects and mechanisms of action of vortioxetine in models of inflammatory pain, as well as the drug’s impact on cognitive performance, general well-being, redox status, and histological changes in cardiomyocytes in male and female rats with osteoarthritis. Vortioxetine's effects were evaluated in models of acute inflammatory trigeminal, visceral, and somatic pain, as well as in a model of osteoarthritis. In the trigeminal pain model, its mechanism of action was assessed using selective receptor antagonists. In the osteoarthritis model, the drug’s influence was monitored on molecular markers of pain hypersensitivity, oxidative stress parameters in the rat knee, cognitive performance, general well-being, as well as on redox status and histological alterations in cardiomyocytes. Vortioxetine achieved significant effects in all pain models tested. In the trigeminal pain model, involvement of serotonergic 5-HT1B/1D, α2/β1-adrenergic, muscarinic, α7-nicotinic, cannabinoid CB1/CB2, and adenosine A1 receptors was demonstrated. Vortioxetine reduced Ngf expression and oxidative stress markers in the knees of both sexes; it also decreased mRNA expression of neuroinflammatory markers in the spinal ganglia and spinal cord of male, but not female rats. Additionally, vortioxetine improved cognitive performance in osteoarthritic animals without negative effects on general well-being, redox status, or cardiomyocyte histology. The results suggest that vortioxetine may be effective in treating inflammatory pain conditions, with beneficial effects on cognitive function.

vortioksetin, inflamatorni bol, osteoartritis, duloksetin, nervni faktor rasta, kognitivna disfunkcija, kardiovaskularna bezbednost, oksidativni stres, polno-specifične razlike

vortioxetine, inflammatory pain, osteoarthritis, duloxetine, nerve growth factor, cognitive dysfunction, cardiovascular safety, oxidative stress, sex-specific differences

615.214.011(043.3)

Tekst