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

Prevot, Thomas D.; Li, Guanguan; Vidojević, Aleksandra; Misquitta, Keith; Fee, Corey; Santrač, Anja; Knutson, Daniel E; Stephen, Michael S.; Kodali, Revathi; Zahn, Nicolas M; Arnold, Leggy A.; Scholze, Petra; Fisher, Janet L.; Marković, Bojan; Banasr, Mounira; Cook, James M.; Savić, Miroslav M.; Sibille, Etienne

doi:10.1159/000496086

Cited by 66 publications

(152 citation statements)

References 51 publications

(68 reference statements)

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…This study was based on the observation that normal aging induces neuronal loss contributing to cognitive decline. Here, we first confirmed that normal aging in mice induces cognitive deficits, with old mice exhibiting impaired working memory in the alternation task, consistent with previous finding (59,63,64). Many compounds (65), drugs (66), natural extracts (64) or physical exercises (67) demonstrated potential at reversing cognitive decline in animal models, but with little-to-no success in human populations (68,69).…”

Section: Discussionsupporting

confidence: 88%

“…The drug was left incubating in the culture for 24 hrs. For the behavioral studies, GL-II-73 was administered through the drinking water at a dose of 30mg/kg/day, for 30 days, based on previous studies from our group (59).…”

Section: Drug Preparationmentioning

confidence: 99%

“…The wide range of activity at different subunits is responsible for considerable side effects that can be potentiated by the GABAergic dysregulation occurring during normal or pathological aging (48). Novel developments have tried to reduce the side effects of novel benzodiazepines, or derivatives, by increasing selectivity to the α5-subunit and reducing selectivity to the α1-subunit (59). Previous data from our group showed that the α5positive allosteric modulator (α5-PAM) GL-II-73 improves working memory in mouse model of chronic stress and aging (59).…”

Section: Introductionmentioning

confidence: 99%

“…Novel developments have tried to reduce the side effects of novel benzodiazepines, or derivatives, by increasing selectivity to the α5-subunit and reducing selectivity to the α1-subunit (59). Previous data from our group showed that the α5positive allosteric modulator (α5-PAM) GL-II-73 improves working memory in mouse model of chronic stress and aging (59). Other group demonstrated improved cognitive functions in old rats using different α5-PAMs, namely Compound 44 and Compound 6 (60).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Prevot

Sumitomo

Tomoda

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Over the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years.With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death.Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer's disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Drug Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Prevot

Sumitomo

Tomoda

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…CRS. For example, we frequently observe YM deficits in CRS mice 57 , but did not here. To overcome these challenges, we implemented multiple end-point tests assessing top-down behavioral dimensions 131 and used repeatable tests to (a) track the induction of deficits over time, and (b) provide baseline and endpoint readouts to measure the transition into maladaptive behavior (via PCA).…”

Section: Discussionmentioning

confidence: 67%

Chronic stress exacerbates acute stress-induced neuronal activation in the anterior cingulate cortex and ventral hippocampus that correlates with behavioral deficits in mice

Fee

Prevot

Misquitta

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Altered activity of corticolimbic brain regions is a hallmark of stress-related illnesses, including mood disorders, neurodegenerative diseases, and substance abuse disorders. Acute stress adaptively recruits brain region-specific functions for coping, while sustained activation under chronic stress may overwhelm feedback mechanisms and lead to pathological cellular and behavioral responses. The neural mechanisms underlying dysregulated stress response and how they contribute to behavioral deficits are poorly characterized. Here, we tested whether prior exposure to chronic restraint stress (CRS) or unpredictable chronic mild stress (UCMS) in mice could alter neuronal response to acute stress and whether these changes are associated with chronic stress-induced behavioral deficits. More specifically, we assessed neuronal activation indexed by c-Fos+ cell counts in 24 stress-and mood-related brain regions, and determined if changes in acute stress-induced neuronal activation were linked to chronic stress-induced behavioral impairments. Results indicated that CRS and UCMS led to convergent physiological and anxiety-like deficits, whereas cognition was impaired only in UCMS mice. CRS and UCMS exposure exacerbated neuronal activation in response to an acute stressor in anterior cingulate cortex (ACC) area 24b and ventral hippocampal (vHPC) CA1, CA3, and subiculum. In dysregulated brain regions, levels of neuronal activation were positively correlated with principal components capturing variance across widespread behavioral alterations relevant to stress-related disorders. Our data supports an association between a dysregulated stress response, altered corticolimbic excitation/inhibition balance, and the expression of maladaptive behaviors.

show abstract

An alpha 5‐GABA_A receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero

Souza,

Freitas,

Sharmin

et al. 2024

Autism Research

View full text Add to dashboard Cite

Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5‐containing GABAA receptors (α5‐GABAARs) SH‐053‐2′F‐R‐CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH‐053‐2′F‐R‐CH3 could attenuate these changes. SH‐053‐2′F‐R‐CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self‐grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH‐053‐2′F‐R‐CH3 attenuated the impairments in sociability and cognitive function in male VPA‐exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA‐exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH‐053‐2′F‐R‐CH3. Despite sex differences, our findings indicate that α5‐GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.

show abstract

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

Cited by 66 publications

References 51 publications

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Chronic stress exacerbates acute stress-induced neuronal activation in the anterior cingulate cortex and ventral hippocampus that correlates with behavioral deficits in mice

An alpha 5‐GABA_A receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero

Contact Info

Product

Resources

About

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

Cited by 66 publications

References 51 publications

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

Chronic stress exacerbates acute stress-induced neuronal activation in the anterior cingulate cortex and ventral hippocampus that correlates with behavioral deficits in mice

An alpha 5‐GABAA receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero

Contact Info

Product

Resources

About

An alpha 5‐GABA_A receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero