Ameliorated Neurogenesis Deficits in Dentate Gyrus May Underly the Pronounced Antidepressant Effect of TREK-1 Potassium Channel Blockade in Rats with Depressive-like Behavior.

Depression is considered to be the most common mental disorder and is probed by several studies that chronic mild stress contributes to depression, and fortunately, most antidepressants ameliorate depressive-like behavior accompanied with reversed hippocampal neurogenesis defects. In our present study, we confirmed that different antidepressants repaired the stress-induced neuronal and behavioral deficits by modulating adult hippocampal neurogenesis. Antidepressant treatment restored the adult hippocampal neurodegeneration, which was impaired by chronic unpredicted mild stress displaying decreased proliferation and neuronal differentiation but increased apoptosis of newly formed neurons in dentate gyrus. Notably, sucrose preference ratio significantly correlated with both neuronal differentiation proportion and newborn apoptosis proportion, suggesting a mechanistic relationship between neurogenesis and behavior. Indeed, the neotype TREK-1 potassium channel blocker expressed an earlier and pronounced antidepressant manifestation compared to the traditional selective serotonin-reuptake inhibitors fluoxetine. We therefore conclude that the administration of TREK-1 potassium channel antagonism can reverse the depressive deficits caused by chronic stress quickly via regulation of adult hippocampal neurogenesis.

Comparison of Therapeutic Effects of TREK1 Blockers and Fluoxetine on Chronic Unpredicted Mild Stress Sensitive Rats.

The animal model for depressive behavior due to chronic unpredicted mild stress (CUMS) is commonly used to evaluate antidepressant treatments. The CUMS model has faced some criticism because of the heterogeneity of behavioral effects. Spadin and SID1900 are TREK1 blockers with a quick antidepressant effect. However, to date, their effectiveness and the long-term therapeutic mechanisms are not known. We hypothesize that early intervention with TREK1 blockers can fully reverse depressive-like behaviors, that the chronic administration of TREK1 blockers has a more pronounced effect than the SSRI fluoxetine, and that its long-term therapeutic effects may be mediated by improvement of impaired neurogenesis. Furthermore, we optimized the use of the CUMS model for increased homogeneity by screening the rats after the CUMS induction procedure. Depressive-like behavior was assessed by a forced swimming test, sucrose preference, and open field tests. To evaluate neurogenesis, cell proliferation and newly generated cell apoptosis were measured in the hippocampal dentate gyrus. Of 32 rats that underwent the CUMS procedure, 26 rats that exhibited depressive-like behaviors were grouped as CUMS sensitive rats (CUMSS), while six that did not were grouped as CUMS resistant ones (CUMSR). The CUMSR rats exhibited minor neurogenesis impairments, while the CUMSS rats had a more pronounced effect. Treatment with TREK1 blockers could reverse depressive-like behaviors at least 1 week earlier than that of fluoxetine. Chronic administration of both the TREK1 blockers and fluoxetine could restore neurogenesis impairments. This study underlines the importance of model validation by determination of CUMS sensitivity. The TREK1 blockers were found to have an effect that was more rapid and more pronounced than that of fluoxetine. Therapeutic benefits after chronic administration were associated with a restoration of impaired neurogenesis.

The improvement effect of TREK-1 potassium channel blockade on the behavior of depression model rats / 中华行为医学与脑科学杂志

Objective To study the effect of TREK-1 potassium channel blocker on the behavior in rats with depression.Methods Forty-eight healthy adult male Sprague Dawley (SD) rats were divided into 6 groups as following:control + saline (CON group),control + fluoxetine (CON + FLU group),control + SID1900 (CON+SID group),CUMS + saline (CUMS group),CUMS + fluoxetine (CUMS+FLU group) and CUMS + SID1900 (CUMS+SID group) with 8 in each group.Isolated living conditions combining chronic unpredicted mild stress (CUMS) were used to establish depression model in rats.Four weeks after modeling,fluoxetine 10 mg· kg-1,SID1900 5.1 mg · kg-1 and 0.9％ sodium chloride were given by intraperitoneal injection respectively.Body weight and behavioral performance of rats in several experiment paradigms were measured after drug administration.The behavioral paradigms included sucrose preference test(SPT),open field test(OFT) and forced swimming test(FST).Results Drug administration had no significant effect on body weight and behavioral performance in non stress rats (P＞0.05),however,after chronic unpredicted mild stress the body weight,percentage of sucrose consumption,movement distances and rearing times in CUMS group were decreased dramatically contrast to CON group,but the immobility duration was increased significantly (all P＜0.001).After treatment with drug for 14 days,the sucrose consumption percentage(62.03± 6.99) ％) and rearing times (18.57 ± 6.37) in CUMS+SID group were increased contrast to C UMS group ((45.46± 15.54) ％,(5.83±3.06)),while the immobility time((123.57±26.73) s) was decreased compared with that in CUMS group((174.33±40.68) s).When drug administration for 28 days,the sucrose consumption percentage((79.64± 11.37) ％),the total distance as well as the rearing times ((13.18 ± 3.17) m,(19.33±3.33)) within OFT in CUMS+FLU group were increased in comparison with CUMS group((48.06± 17.10) ％,(4.45±3.69) m,(5.17± 2.99)),and the immobility duration ((97.83± 18.97) s) in CUMS+FLU group was shorter than that ((194.83±37.97) s) in CUMS group(P＜0.05).Notably,the immobility time in CUMS+SID group ((44.29± 14.30)s) was shortened obviously compared with that in CUMS+FLU group ((97.83± 18.97)s) (P＜0.01).Conclusion Blockade of TREK-1 potassium channel can ameliorate the depression-like behavior rapidly in rats.

TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling.

Current antidepressants often remain the inadequate efficacy for many depressive patients, which warrant the necessary endeavor to develop the new molecules and targets for treating depression. Recently, the two-pore domain potassium channel TREK1 has been implicated in mood regulation and TREK-1 antagonists could be the promising antidepressant. This study has screened a TREK1 blocker (SID1900) with a satisfactory blood-brain barrier permeation and bioavailability. Electrophysiological research has shown that SID1900 and the previously reported TREK1 blocker (spadin) efficiently blocked TREK-1 current in HEK293 cells and specifically blocked two-pore domain potassium channels in primary-cultured rat hippocampal neurons. SID1900 and spadin induced a significant antidepressant-like response in the rat model of chronic unpredictable mild stress (CUMS). Both two TREK1 blockers substantially increased the firing rate of 5-HT-ergic neurons in the dorsal raphe nuclei (DRN) and PFC of CUMS rats. SID1900 and spadin significantly up-regulated the expression of PKA-pCREB-BDNF signaling in DRN, hippocampus and PFC of CUMS rats, which were enhanced and reversed by a 5-HTR1A agonist (8-OH-DPAT) and antagonist (WAY100635) respectively. The present findings suggested that TREK1 channel blockers posses the substantial antidepressant-like effect and have the potential synergistic effect with 5-HT1A receptor activation through the common CREB-BDNF signal transduction.