Kronik öngörülemeyen hafif stres fare modelinde TRPM2 inhibisyonunun tedavi etkinliğinin araştirilmasi

Although the current pharmacological approach to the treatment of depression, which is the leading cause of disability worldwide, is largely based on the monoamine theory, in recent years calcium channel inhibitors have also been shown to have serious antidepressant effects. The antidepressive behavior of mice knocking out the calcium-permeable transient receptor potential melastain 2 (TRPM2) channel, which can be activated by oxidative stress, plays a role in the etiopathogenesis of the disease, has made these channels an excellent target for the treatment of depression. The current study aimed to explain the possible antidepressant effects and possible neuronal mechanisms of 8-Br-ADPR, a TRPM2 ion channel specific inhibitor, in the depression model induced by chronic unpredictable mild stress (CDHS) in mice. For this purpose, a total of 50 BALBC male mice, 10 animals in each group, were used as control, sham (8-Br-ADPR), KÖHS, KÖHS+Fluoxetine (20 mg/kg dose) (positive control) and KÖHS+8-Br ADPR (3mg/kg). kg/day) were divided into 5 groups. KCD was created by randomly exposing mice to 2-3 daily stress factors for 5 weeks. Fluoxetine and 8-Br-ADPR were administered to the treatment groups for the last 15 days of the experiment. Total brain levels of dopamine, serotonin, BDNF and GDNF molecules were measured by ELISA. TRPM2 and neuronal signaling pathways were analyzed by qRT-PCR. While CES exposure in mice did not cause a change in serotonin levels, it significantly reduced dopamine levels. Exposure of mice to CES caused significant down-regulations in the GDNF/GFR1α, BDNF/TRK signaling pathways and up-regulations in the TRPM2, PARP1, PARG pathways in the prefrontal cortex and total brain. 8-Br-ADPR (3 mg/kg) and Fluoxetine (20 mg/kg) of mice significantly ameliorated all behavioral and biochemical changes induced by KCD. However, Flu and 8-Br-ADPR had no detectable effect on the serotonergic system. These results suggest that 8-Br-ADPR produces an antidepressant-like effect in CDHS-induced mice, possibly at least in part by restoring dopamine, GDNF, BDNF, TRPM2 signaling pathways.