INTRODUCTION: Pathomechanisms involved in the development of depression are mainly associated with the BDNF/TrkB/CREB signaling pathway. Therefore, affecting this pathway is an attractive target for antidepressant therapy and induction of hippocampal neurogenesis. 7,8-dihydroxyflavone (7,8-DHF) is a natural flavonoid that mimics the effects of BDNF. Recent advances showed that mTOR is activated by NV-5138, leading to an amelioration of depressive-like behavior in animals.

AIM(S): The aim of this study was to determine the effect of 7,8-DHF and 7,8-DHF+NV-5138 combination on neural tissue changes related to pathological behavioral symptoms in a chronic unpredictable stress (CUS)-induced model in rats.

METHOD(S): 12-week-old male Sprague Dawley rats were divided into 4 groups: control rats; rats exposed to stressors; CUS-rats that received 7,8-DHF or 7,8-DHF+NV-5138 combination. The rats were administered a single intraperitoneal dose of 7,8-DHF and mTOR activator (NV-5138), 24 hours before behavioural tests. We used forced swim test (FST) to detect behavioral changes. NO-synthase (NOS) activity, protein expression, and concentration of conjugated dienes (CD) were measured.

RESULTS: In FST, we found higher immobility in CUS group. CUS resulted in reduction of NOS activity and decrease in nNOS expression in the medial prefrontal cortex (mPFC). 7,8-DHF decreased immobility in FST and increased NOS activity in mPFC. 7,8-DHF+NV-5138 combination was effective in increasing BDNF and SOD expression in the hippocampus. The concentration of CD was increased after CUS, while 7,8-DHF and combination therapy reduced CD concentration.

CONCLUSIONS: Our results suggest that increased oxidative state in the brain and reduction of NO may play an important role in the pathophysiology of depression. Both 7,8-DHF and NV-5138 were shown to have antidepressant and antioxidant effects. Combination therapy was more effective than monotherapy.

FINANCIAL SUPPORT: The study was supported by grant: VEGA 2/0122/24