Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine‐binding site of N‐methyl‐D‐aspartate receptor

Abstract

Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high concentration of glycine (300 μM), sunifiram treatments failed to potentiate LTP in the CA1 region. Taken together, sunifiram stimulates the glycine-binding site of NMDAR with concomitant PKCα activation through Src kinase. Enhancement of PKCα activity triggers to potentiate hippocampal LTP through CaMKII activation.

Establishing Natural Nootropics: Recent Molecular Enhancement Influenced by Natural Nootropic

“…Sunifiram is observed to ameliorate the memory function and has less adverse effects [ 81 ]. A recent study reports the improvement of hippocampal LTP induced by sunifiram is mediated by the glycine-binding site of NMDA receptor [ 101 ], an attractive binding site for Alzheimer's disease drugs [ 102 ]. Thus, the reaction of sunifiram on the same binding site is suggested to ameliorate the impaired cognitive function of Alzheimer's disease patients [ 101 ].…”

CaMKII activity is essential for improvement of memory‐related behaviors by chronic rivastigmine treatment

“…Interestingly, sunifiram‐induced enhancement of hippocampal LTP is mediated by NMDAR‐dependent Src activation and in turn ERK (Moriguchi et al . ). In contrast, rivastigmine failed to stimulate tyrosine phosphorylation GluN2B (Tyr‐1472) and ERK.…”

“…We recently introduced nootropic drug sunifiram, which stimulates NMDAR through its activation of glycine biding site, thereby enhancing CaMKII activity and LTP in OBX mouse hippocampus (Moriguchi et al 2013). Interestingly, sunifiram-induced enhancement of hippocampal LTP is mediated by NMDAR-dependent Src activation and in turn ERK (Moriguchi et al 2013). In contrast, rivastigmine failed to stimulate tyrosine phosphorylation GluN2B (Tyr-1472) and ERK.…”

Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings

“…From these and other experiments, the authors concluded that these data indicate that Sunifiram ameliorates OBX-induced deficits of memory-related behaviors and impaired LTP in the hippocampal CA1 region via stimulation of glycine-binding site of N-methyl-D-aspartate receptor (NMDA-R). In the second paper 29 , the authors, to address the question whether Sunifiram affects (NMDAR)-dependent synaptic function in the hippocampal CA1 region, studied the effects of Sunifiram on NMDAR-dependent LTP confirming that Sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of NMDA receptor. At the moment, the relation of this result with our finding on AMPA receptors involvement is unclear.…”