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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

Jing Xu, Yasushi Yabuki, Mengze Yu, Kohji Fukunaga

J Pharmacol Sci. 2018 Aug;137(4):333-341.

PMID: 30196018

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1256269870	SAK3		1256269-87-0	Price

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