Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

“…Thus, we hypothesized that changes in phosphorylation of residues at the FGF14 C-tail could affect the interaction with Nav channels. Our previous research has shown that GSK–3, a multifunctional kinase important for neuronal survival, cellular signaling, and stress response (Jope et al, 2007; Jope & Roh, 2006; Wu et al, 2013; Chen et al, 2011; Kim & Snider, 2011) and dysregulated in a number of AD and psychiatric disorders (Emamian, 2012; Jope et al, 2007; Jope & Roh, 2006; Liu et al, 2013; Budni et al, 2012; Scala et al, 2015; Maqbool et al, 2016; Morris & Berk, 2016; Provensi et al, 2016; Avila et al, 2010) affecting cognition, including depression and bipolar disorder (Gould et al, 2004; Koros & Dorner-Ciossek, 2007; Omata et al, 2011), critically modifies the interaction, assembly, localization, and activity of FGF14 and Nav channels (Hsu et al, 2015; James et al, 2015; Shavkunov et al, 2013). Furthermore, we observed that the C-tail of FGF14 contains a consensus GSK–3 phosphorylation motif ( S/T )XXX(S/T), the first residue in this sequence corresponding to S226.…”

“…Through direct monomeric binding to the Nav channel C-terminal tail, FGF14 forms a complex with the channel that is required for proper gating, expression and trafficking of the channel to the AIS as well as the control of neuronal excitability (Ali et al, 2014, 2016; Alshammari et al, 2016a; Laezza et al, 2007, 2009; Lou et al, 2005; Wang et al, 2000, 2002; Xiao et al, 2007; Goetz et al, 2009). Using the bioluminescence-based luciferase complementation assay (LCA) (Michnick et al, 2010; Remy & Michnick, 2006; Shavkunov et al, 2012; Villalobos et al, 2007, 2008), a PPI assay that quantitatively measures the complementation of reconstituted FGF14 and Nav1.6 channel complexes, we previously identified glycogen synthase kinase 3 (GSK–3), a multifunctional kinase dysregulated in Alzheimer's, depression and schizophrenia (Emamian, 2012; Jope et al, 2007; Jope & Roh, 2006; Liu et al, 2013; Budni et al, 2012; Scala et al, 2015; Maqbool et al, 2016; Morris & Berk, 2016; Provensi et al, 2016; Avila et al, 2010), as a key modulator of the FGF14:Nav1.6 complex. Inhibition of GSK–3 reduces the assembly of the FGF14:Nav channel complex, modifies FGF14-dependent regulation of Na + currents, and induces dissociation and subcellular redistribution of the native FGF14:Nav channel complex (Shavkunov et al, 2013).…”

Therapeutics of Neurotransmitters in Alzheimer’s Disease

“…It is currently in clinical trials and completed phase II trials in schizophrenia patients (NCT00690274). While pitolisant reduces cognitive deficits in schizophrenia, it would be interesting to study these effects in AD patients based on the recent findings of H3R antagonist, i.e., ABT-239, where it reverted the reduced pSer9GSK-3β hippocampal expression in AβPP-overexpressing Tg2576 mice [177, 193, 194]. WakixR is marketed for pitolisant and has been approved by the European Medical Agency in November 2015 for narcolepsy [192].…”

“…The effect of the ABT-239 and donepezil was evaluated in the object recognition test and on the levels of GSK-3β phosphorylation. Their results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects [194]. However, all these findings are in the primitive stage, so there is a need to search for H3R antagonists to treat the AD patients in an early stage as the histamine plays a crucial role in oxidative stress and inflammation, and there is also a need to the check the efficacy and tolerability of novel H3R antagonists [195] including pitolisant [191] in AD mouse models and patients.…”

Carbonic anhydrase activation enhances object recognition memory in mice through phosphorylation of the extracellular signal-regulated kinase in the cortex and the hippocampus

“…Object recognition is a one-trial task, and does not involve the learning of any rule, being entirely based on the spontaneous exploratory behavior of rodents toward objects. The detailed procedure has been published previously (Provensi et al, 2016). In brief, mice were placed in a white polyvinylchloride box (70 Â 60 cm and 30 cm high) with a grid floor that is easily cleaned, and illuminated by a 75-W lamp suspended 50 cm above the box.…”