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Neuropharmacology ; 117: 1-13, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28093211

ABSTRACT

T-type voltage-gated Ca2+ channels (T-VGCCs) function in the pathophysiology of epilepsy, pain and sleep. However, their role in cognitive function remains unclear. We previously reported that the cognitive enhancer ST101, which stimulates T-VGCCs in rat cortical slices, was a potential Alzheimer's disease therapeutic. Here, we introduce a more potent T-VGCC enhancer, SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo [1,2-a]pyridin]-2-ene-3-carboxylate), and characterize its pharmacological properties in brain. Based on whole cell patch-clamp analysis, SAK3 (0.01-10 nM) significantly enhanced Cav3.1 currents in neuro2A cells ectopically expressing Cav3.1. SAK3 (0.1-10 nM nM) also enhanced Cav3.3 but not Cav3.2 currents in the transfected cells. Notably, Cav3.1 and Cav3.3 T-VGCCs were localized in cholinergic neurve systems in hippocampus and in the medial septum. Indeed, acute oral administration of SAK3 (0.5 mg/kg, p.o.), but not ST101 (0.5 mg/kg, p.o.) significantly enhanced acetylcholine (ACh) release in the hippocampal CA1 region of naïve mice. Moreover, acute SAK3 (0.5 mg/kg, p.o.) administration significantly enhanced hippocampal ACh levels in olfactory-bulbectomized (OBX) mice, rescuing impaired memory-related behaviors. Treatment of OBX mice with the T-VGCC-specific blocker NNC 55-0396 (12.5 mg/kg, i.p.) antagonized both enhanced ACh release and memory improvements elicited by SAK3 administration. We also observed that SAK3-induced ACh releases were significantly blocked in the hippocampus from Cav3.1 knockout (KO) mice. These findings suggest overall that T-VGCCs play a key role in cognition by enhancing hippocampal ACh release and that the cognitive enhancer SAK3 could be a candidate therapeutic in Alzheimer's disease.


Subject(s)
Calcium Channels, T-Type/drug effects , Calcium Channels, T-Type/physiology , Imidazoles/pharmacology , Spiro Compounds/pharmacology , Acetylcholine/metabolism , Animals , Behavior, Animal/drug effects , Benzimidazoles , CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/physiology , Calcium Channels, T-Type/genetics , Cells, Cultured , Cholinergic Neurons/physiology , Cyclopropanes , Dose-Response Relationship, Drug , Imidazoles/antagonists & inhibitors , Indans/pharmacology , Male , Memory/drug effects , Mice , Mice, Knockout , Naphthalenes , Nootropic Agents/pharmacology , Olfactory Bulb/surgery , Septal Nuclei/physiology , Spiro Compounds/antagonists & inhibitors
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