Biology subjects

Hess, E.

Publications and source records attributed to Hess, E..

2 recordsLinked to original sources

bioRxiv2026

Quercetin and 6-Br_uercetin antioxidant properties and off target screening results advance glycosylated 6BrQ as a development candidate for Alzheimers disease

Quercetin is an abundant dietary flavonol with interesting in vitro properties that include substrate-selective positive allosteric modulation (PAM) of the activity of the receptor type protein tyrosine phosphatase D (PTPRD) and substantial antioxidant actions. Its in vivo activities include reducing incidence of Alzheimers disease (AD) and reducing AD neurofibrillary pathology in mouse models. Structure-activity studies have identified quercetin analogs with improved in vitro and in vivo properties, including the improved PTPRD PAM 6-bromoquercetin (6BrQ). However, there is no comparison of the antioxidant properties of 6BrQ to those of quercetin. There is no systematic screening for activities of quercetin or of 6BrQ using a panel of targets for most currently-used drugs. We now report that both quercetin and 6BrQ provide equivalent results in cyclic voltammetric and biochemical antioxidant assays. We also report that neither 10-7 M quercetin nor 6BrQ provides any significant (>50%) effects on any of the 104 assays in a Eurofins off-target screening panel. At 10-5 M, both quercetin and 6BrQ exert significant effects in assays for glycogen synthase kinase 3 (GSK3{beta}) as well as those for serotonin 5HT2B receptor, adenosine transport, adenosine A2A receptors, cyclooxygenases COX1 and COX2, phosphodiesterases PDE3A and 4D2 and PPAR gamma. These data extend prior characterization of quercetins biochemical effects, provide novel results for 6BrQ and support the likelihood that both quercetin and 6BrQ can a) directly inhibit GSK3, b) reduce GSK3 activities via enhancement of its dephosphorylation by PTPRD and c) display modest numbers of off target activities at high concentrations, several of which could conceivably contribute to anti-AD activities. These results advance bioavailable glycosylated prodrugs that can be metabolized to 6BrQ as developmental candidates for AD.

neuroscience↗

bioRxiv2020

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+ channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility

BackgroundImbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown. MethodsIn mice harboring a floxed version of the kcnj3 (Girk1) gene, we used a viral-cre approach to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic (PL) or infralimbic (IL) cortices. Additional studies used a novel model of chronic unpredictable stress (CUS) to determine the impact on PL GIRK-dependent signaling and cognitive function. ResultsIn males, loss of pyramidal GIRK-dependent signaling in the PL, but not IL, differentially impacted measures of affect and motivation, and impaired working memory and cognitive flexibility. CUS produced similar deficits in affect and cognition that paralleled a reduction in PL pyramidal GIRK-dependent signaling akin to viral approaches. Viral- and stress-induced behavioral deficits were rescued by systemic injection of a novel, GIRK1-selective agonist, ML-297. Unexpectedly, neither ablation of PL GIRK-dependent signaling or exposure to the CUS regimen impacted affect or cognition in female mice. ConclusionsGIRK-dependent signaling in male mice, but not females, is critical for maintaining optimal PL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.

neuroscience↗