Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus

Abstract

The integrity of the hippocampal network depends on the coordination of excitatory and inhibitory signaling, which are under dynamic control by various regulatory influences such as the cholinergic systems. ZSET1446 (ST101; spiro[imidazo[1,2-a] pyridine-3,2-indan]-2(3H)-one) is a newly synthesized azaindolizinone derivative that significantly improves learning deficits in various types of Alzheimer disease (AD) models in rats. We examined the effect of ZSET1446 on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated regulation of synaptic transmission in hippocampal slices of rats. ZSET1446 significantly potentiated the facilitatory effect of nicotine and ACh on the frequency of spontaneous postsynaptic currents (sPSCs) recorded in CA1 pyramidal neurons with a maximum effect at 100 pM (tested range, 10 pM-1000 pM). The basal sPSC frequency without ACh was not affected. Such potentiation by ZSET1446 was observed in both the pharmacologic isolations of inhibitory and excitatory sPSCs and markedly reduced by blockade of either a7 or a4b2 nAChRs. ZSET1446 did not affect ACh-activated inward currents or depolarization of interneurons in the stratum radiatum and the lacunosum moleculare. These results indicate that ZSET1446 potentiates the nicotine-mediated enhancement of synaptic transmission in the hippocampal neurons without affecting nAChRs themselves, providing a novel possible mechanism of procognitive action that might improve learning deficits in clinical therapy.

Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection

“…Thus, a new therapeutic target that improves Ca 2+ intake in FTAAD patients with Myh11 lysine 1256 deletion could be more effective than a therapy targeting the elastin contractile unit. The T-type calcium channel activator, ZSET1446, has been studied for more than a decade [31][32][33] and has the potential to improve cognition, but it has not been administered to humans. If T-type calcium channel activation improves the contraction of the aorta and ultimately prevents or treats familial aortic dissection, this activator would represent a novel class of aortic dissection medication leading to the development of new drugs.…”

Cav3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance

“…Importantly, this phenomenon would further aggravate the functional disinhibition in the septohippocampal system, as described in our model (see also Figure 1 ). On the other hand, stimulation of T-Type VGCCs, e.g., via ST101 or SAK3, enhanced ACh-mediated GABA release in the rat hippocampus [ 254 ]. Furthermore, T-type VGCC activation can increase ACh release from cholinergic neurons and trigger enhanced cholinergic and/or glutamatergic transmission on postsynaptic cells.…”