T-type calcium channel enhancer SAK3 promotes dopamine and serotonin releases in the hippocampus in naive and amyloid precursor protein knock-in mice.

PLoS One 2018

Wang S, Yabuki Y, Matsuo K

Abstract

  1. PLoS One. 2018 Dec 20;13(12):e0206986. doi: 10.1371/journal.pone.0206986. eCollection 2018.

T-type calcium channel enhancer SAK3 promotes dopamine and serotonin releases in the hippocampus in naive and amyloid precursor protein knock-in mice.

Wang S(1), Yabuki Y(1), Matsuo K(1), Xu J(1), Izumi H(1), Sakimura K(2), Saito T(3), Saido TC(3), Fukunaga K(1).

Author information: (1)Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. (2)Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan. (3)Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.

Erratum in PLoS One. 2019 Jan 25;14(1):e0211590. doi: 10.1371/journal.pone.0211590.

Expression of concern in PLoS One. 2023 Jan 11;18(1):e0280120. doi: 10.1371/journal.pone.0280120.

T-type calcium channels in the brain mediate the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel therapeutic candidate, 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), for Alzheimer’s disease (AD). The cognitive improvement by SAK3 is closely associated with enhanced acetylcholine (ACh) release in the hippocampus. Since monoamines such as dopamine (DA), noradrenaline (NA), and serotonin (5-HT) are also involved in hippocampus-dependent learning and psychomotor behaviors in mice, we investigated the effects of SAK3 on these monoamine releases in the mouse brain. Oral administration of SAK3 (0.5 mg/kg, p.o.) significantly promoted DA and 5-HT releases in the naive mouse hippocampal CA1 region but not in the medial prefrontal cortex (mPFC), while SAK3 did not affect NA release in either brain region. The T-type calcium channel-specific inhibitor, NNC 55-0396 (1 μM) significantly antagonized SAK3-enhanced DA and 5-HT releases in the hippocampus. Interestingly, the α7 nicoti

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