Investigation of the antidepressant effects of some newly synthesized phenylpropionic acid derivatives in rats with chronic mild stress model

In this thesis study, 10 original 2-phenylpropionic acid derivative compounds (1a-1j) with chemical structure similar to ibuprofen were synthesized. The structures of the compounds were elucidated by 1H-NMR, 13C-NMR and mass spectroscopy methods, and their effects on cyclooxygenase (COX) enzymes were investigated in vitro and in silico. In order to investigate the antidepressant efficacy, a depression model with chronic unpredictable mild stress was induced in rats. Depression parameters of animals were determined by sucrose preference, modified forced swimming (MFST) and splash tests; motor activities were evaluated by activitymeter measurements. Body and adrenal gland weights of rats were recorded within the scope of the experimental protocol. The changes in serum ACTH and proinflammatory cytokine levels were determined using the ELISA method. Compounds 1a and 1b showed inhibitory effects on COX-1 and COX-2 enzymes, and molecular modeling studies also supported these findings. In vivo experiments showed that compounds 1a and 1b (50 mg.kg-1) significantly increased the reduced sucrose preferences, percent grooming times, body weights and motor activities of the stressed rats. These compounds decreased the increased immobility numbers of stressed rats and increased the reduced swimming numbers in MFST. In 1a and 1b administrated groups, augmented right and left adrenal gland weight values and serum ACTH, TNF-α and IL-1β levels of stressed rats returned to control levels. The results indicated that compounds 1a and 1b have antidepressant effects and this effect is mediated by the suppression of various inflammatory mechanisms that play a role in the pathogenesis of depression.