Investigation of antidepressant-like efficiency of tangeretinand related mechanisms

Anadolu University, Graduate School of Health Sciences, January 2021 Supervisor: Prof. Dr. Özgür Devrim CAN In this thesis study, the antidepressant-like efficacy of tangeretin, a phytochemical found in citrus peels, was investigated by reliable and validated in vivo methods and some mechanisms underlying this effect have been elucidated by antagonism studies.The antidepressant-like efficacy of tangeretin (10, 20 ve 40 mg.kg-1, p.o.) was examined by tail suspension (TST) and modified forced swimming tests (MFST), while its effect on the motor coordination of experimental animals was evaluated using the Rota-rod method. The data obtained revealed that doses of 10 and 20 mg.kg-1 tangeretin decreased the immobility time of mice in TST and immobility number of mice in MFST compared to control animals not receiving tangeretin. These findings indicated that tangeretin showed an antidepressant-like efficacy comparable to the reference drug fluoxetine (30 mg.kg-1) when administered at doses of 10 and 20 mg.kg-1. Tangeretin, at the same doses, did not alter the climbing number of mice in MFST, but significantly increased their swimming number. The 40 mg.kg-1 dose of this flavonoid did not cause a statistically significant effect in either test. While α-methyl-para-tyrosine methyl ester pretreatment, which was carried out to elucidate the mechanism of action of tangeretin, did not change the antidepressant-like efficacy induced by 20 mg.kg-1 dose of this flavonoid; pretreatment of p-chlorophenylalanine methyl ester, NAN-190 and ketanserin reversed this activity. These findings indicated that tangeretin has an antidepressant-like activity mediated by the serotonergic system and pointed out that 5-HT1A and 5-HT2A/5- HT2C serotonergic receptor subtypes play roles in this effect. It is obvious that for tangeretin to be considered an antidepressant agent, the antidepressant-like efficacy demonstrated for the first time in this preclinical study must be confirmed by well- designed clinical studies conducted on depressed patients. Keywords: Tangeretin, Antidepressant-like effect, Tail suspension test, Modified forced swimming test, Rota-rod test.