Sustained increase in α5GABAA receptor function impairs memory after anesthesia

Zurek, Agnieszka A.; Yu, Jin; Wang, Dian-Shi; Haffey, Sean; Bridgwater, Erica M.; Penna, Ana Lúcia Barretto; Lecker, Irene; Liu, Gang; Chang, Tom; Salter, Eric W; Orser, Beverley A.

doi:10.1172/jci76669

Cited by 152 publications

(192 citation statements)

References 25 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…In this case, properties such as high dissociation rates and transient interaction of weak-binding drug can be key elements for drug efficacy with a low side effect profile. Hence, the high fractional occupation may preclude antidepressant or pro-cognitive properties, consistent with the pro-depressant-like [43] and amnesic effect of DZP [48], and the role of the α1 and α5 subunit may follow a biphasic pattern, where low activation facilitates mood and cognitive processes, whereas high activation impairs these same functions [49]. …”

Section: Discussionmentioning

confidence: 99%

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

124

View full text Add to dashboard Cite

Altered gamma-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging, and neurodegenerative disorders and reduced function of GABA interneurons is associated with both mood and cognitive symptoms. Benzodiazepines (BZ) have broad anxiolytic, but also sedative, anticonvulsant and amnesic effects, due to nonspecific GABA-A receptor (GABAA-R) targeting. Varying the profile of activity of BZs at GABAA-Rs is predicted to uncover additional therapeutic potential. We synthesized four novel imidazobenzodiazepine (IBZD) amide ligands and tested them for positive allosteric modulation at multiple α-GABAA-R (α-positive allosteric modulators), pharmacokinetic properties, as well as anxiolytic and antidepressant activities in adult mice. Efficacy at reversing stress-induced or age-related working memory deficits was assessed using a spontaneous alternation task. Diazepam (DZP) was used as a control. Three ligands (GL-II-73, GL-II-74, and GL-II-75) demonstrated adequate brain penetration and showed predictive anxiolytic and antidepressant efficacies. GL-II-73 and GL-II-75 significantly reversed stress-induced and age-related working memory deficits. In contrast, DZP displayed anxiolytic but no antidepressant effects or effects on working memory. We demonstrate distinct profiles of anxiolytic, antidepressant, and/or pro-cognitive activities of newly designed IBZD amide ligands, suggesting novel therapeutic potential for IBZD derivatives in depression and aging.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

124

View full text Add to dashboard Cite

show abstract

“…However, targeting the a4 subunit may offer advantages over a5 for two reasons. First, in recent mouse studies an a5 subunit-selective ligand produced memory impairments (32), and postanesthesia cognitive impairment was associated with up-regulation of the a5 subunit in the brain (33). Second, the expression of GABA A Rs containing a2 and a5 has been demonstrated on human airway epithelium cells, and activation of these receptors was demonstrated to stimulate mucus production (34).…”

Section: Discussionmentioning

confidence: 99%

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Yocum

Gallos

Zhang

et al. 2016

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

We previously demonstrated that airway smooth muscle (ASM) cells express g-aminobutyric acid A receptors (GABA A Rs), and that GABA A R agonists acutely relax ASM. Among the GABA A R a subunits, human ASM cells express only a4 and a5, providing the opportunity for selective pharmacologic targeting. Novel GABA A R-positive allosteric modulators designed for enhanced a4/a6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC 3 ) of GABA [EC 3 ]-induced currents in oocytes expressing a4 or a6 subunits (along with b3 and g2) compared with other a subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABA A R a4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterolmediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABA A R a4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by a1-3 subunit-containing GABA A Rs in the brain.

show abstract

“…One recent animal study also suggested that post-operative memory deficits may be due to anesthetic-induced up-regulation of the alpha 5-subunit containing GABA-A receptors in the hippocampus (91). These alpha 5 containing GABA receptors inhibit long term potentiation (LTP, a cellular correlate of learning and memory).…”

Section: What Causes Pocd?mentioning

confidence: 99%

Postoperative Cognitive Dysfunction

Berger

Nadler

Browndyke

et al. 2015

Anesthesiology Clinics

227

119

View full text Add to dashboard Cite

Ever since Bedford’s seminal Lancet case series in 1955, we have known that perioperative care is sometimes followed by significant cognitive dysfunction (1). Although the safety of perioperative care has improved dramatically since 1955, the descriptions of cognitive dysfunction in that case series are eerily similar to the complaints of current patients suffering from post-operative cognitive dysfunction (POCD). POCD remains a common post-operative complication associated with significant morbidity and even mortality, especially among elderly patients. There has been a great deal of interest in and controversy about POCD, from how it is measured, to how long it lasts, to its precise implications for patients. This interest and controversy is reflected partly in the increasing number of papers published on this subject recently (shown in Figure 1). Recent work has also suggested surgery may be associated with cognitive improvement in some patients (2–4), termed Post-Operative Cognitive Improvement (POCI). As the number of surgeries performed worldwide approaches 250 million per year (5) (with an increasing number elderly patients), optimizing postoperative cognitive function and preventing/treating POCD are major public health issues. In this article we review the literature on POCD and POCI, and discuss current research challenges in this area.

show abstract

Sustained increase in α5GABAA receptor function impairs memory after anesthesia

Cited by 152 publications

References 25 publications

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Postoperative Cognitive Dysfunction

Contact Info

Product

Resources

About