T-type calcium channel enhancer SAK3 produces anti-depressant-like effects by promoting adult hippocampal neurogenesis in olfactory bulbectomized mice
T-type calcium channel enhancer SAK3 produces anti-depressant-like effects by promoting adult hippocampal neurogenesis in olfactory bulbectomized mice
复制标题
T型钙通道增强剂SAK3通过促进嗅球切除小鼠成年海马神经发生产生抗抑郁样作用
DOI：
10.1016/j.jphs.2018.07.006
复制
发表时间：
2018
影响因子：
3.5
通讯作者：
Fukunaga Kohji
中科院分区：
文献类型：
--
作者：
Xu Jing;Yabuki Yasushi;Yu Mengze;Fukunaga Kohji
t型钙通道参与癫痫、疼痛和睡眠的病理生理。最近，我们开发了一种新的螺咪唑吡啶化合物SAK3（乙基8′-甲基-2′，4-二氧基-2-（哌啶-1-基）-2′h -螺[环戊烷-1,3′-咪唑[1,2-a]吡啶]-2-烯-3-羧酸盐），它能增强t型钙通道电流，改善嗅球去化（OBX）小鼠的记忆缺陷。在这里，我们证明了SAK3在OBX小鼠中的抗抑郁作用。慢性给药（0.5或1.0 mg/kg, p.o）改善OBX小鼠的抑郁样行为。慢性给药（0.5或1.0 mg/kg, p.o）可显著恢复OBX给药后4周海马齿状回（DG）的成体神经发生损伤。此外，SAK3 （0.5 mg/kg, p.o.）促进naïve DG新生细胞的增殖和存活。此外，SAK3给药（0.5 mg/kg, p.o）可拮抗钙/钙调素依赖性蛋白激酶II （CaMKII）和CaMKIV磷酸化水平的降低，从而挽救OBX DG中cAMP反应元件结合蛋白(CREB)/脑源性神经营养因子（BDNF）信号传导水平的降低。t型钙通道选择性阻滞剂NNC 55-0396 （12.5 mg/kg, i.p）完全阻断了SAK3的作用。总之，这些结果表明，SAK3通过刺激海马中的t型钙通道促进成人神经发生，从而改善抑郁样行为。
T-type calcium channels are involved in the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel spiroimidazopyridine compound, SAK3 (ethyl 8′-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3′-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate), which enhances T-type calcium channel currents and improves memory deficits in olfactory bulbectomized (OBX) mice. Here, we demonstrated the anti-depressant effects of SAK3 in OBX mice. Chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.) improved depressive-like behaviors in OBX mice. The impaired adult neurogenesis in the hippocampal dentate gyrus (DG) that occurred 4 weeks after OBX administration was significantly restored by chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.). Additionally, SAK3 (0.5 mg/kg, p.o.) promoted the proliferation and survival of newborn cells in the naïve DG. Moreover, SAK3 administration (0.5 mg/kg, p.o.) antagonized the reduction of calcium/calmodulin-dependent protein kinase II (CaMKII) and CaMKIV phosphorylation levels, thereby rescuing the decreased levels of cAMP response element-binding protein (CREB)/brain derived neurotrophic factor (BDNF) signaling in the OBX DG. The effects of SAK3 were completely blocked by the T-type calcium channel selective blocker NNC 55-0396 (12.5 mg/kg, i.p.). Altogether, these results suggest that SAK3 improves depressive-like behaviors by promoting adult neurogenesis via T-type calcium channel stimulation in the hippocampus.