A multi-dosing regimen to enhance the spatial memory of normal rats with α5-containing GABAA receptor negative allosteric modulator L-655,708

Yuan, Congcong; Gao, An; Xu, Qiang; Zhang, Beibei; Xue, Rui; Dou, Yan; Yu, Chunshui

doi:10.1007/s00213-021-05951-3

Cited by 3 publications

(2 citation statements)

References 72 publications

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“…[29][30][31] α5-GABAAR possesses a unique dual-anchor structure, primarily distributed both within and surrounding the inhibitory postsynaptic cleft, serving as the main trigger site for cognitive dysfunction and the key synaptic target for sevoflurane. 18,25,32,33 The molecular mechanism of α5-GABAAR in learning and memory damage under the clinical concentration of sevoflurane remains to be fully clarified. Our research results indicate that 24 h following 1 h anesthesia treatment with 2.7% to 3% sevoflurane, the ability of synaptic remodeling decreases, and the expression and distribution of α5-GABAAR on the membrane fail to recover to the normal dual-anchor level.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have revealed that the cognitive decline induced by sevoflurane is closely related to its neurotoxicity, manifesting a complex and diverse toxicological and pathological mechanism 29–31 . α5‐GABAAR possesses a unique dual‐anchor structure, primarily distributed both within and surrounding the inhibitory postsynaptic cleft, serving as the main trigger site for cognitive dysfunction and the key synaptic target for sevoflurane 18,25,32,33 . The molecular mechanism of α5‐GABAAR in learning and memory damage under the clinical concentration of sevoflurane remains to be fully clarified.…”

Section: Discussionmentioning

confidence: 99%

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The changing of α5‐GABAA receptors expression and distribution participate in sevoflurane‐induced learning and memory impairment in young mice

Wang,

Wang

et al. 2024

CNS Neurosci Ther

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BackgroundSevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5‐GABAAR.MethodsUsing MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%–3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL‐6 24 h post‐anesthesia. Western blot and RT‐PCR were performed to measure the levels of α5‐GABAAR, Radixin, P‐ERM, P‐Radixin, Gephyrin, IL‐6, and ROCK. The spatial distribution and expression of α5‐GABAAR on neuronal somata were analyzed using histological and three‐dimensional imaging techniques.ResultsMWM test indicated that partial long‐term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL‐6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5‐GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5‐GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5‐GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra‐synaptic space, the expression level of α5‐GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel.ConclusionDysregulated α5‐GABAAR expression and distribution contributes to sevoflurane‐induced partial long‐term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The changing of α5‐GABAA receptors expression and distribution participate in sevoflurane‐induced learning and memory impairment in young mice

Wang,

Wang

et al. 2024

CNS Neurosci Ther

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Emphasizing the Crosstalk Between Inflammatory and Neural Signaling in Post-traumatic Stress Disorder (PTSD)

Govindula

Ranadive

Nampoothiri

et al. 2023

J Neuroimmune Pharmacol

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Post-traumatic stress disorder (PTSD) is a chronic incapacitating condition with recurrent experience of trauma-related memories, negative mood, altered cognition, and hypervigilance. Agglomeration of preclinical and clinical evidence in recent years specified that alterations in neural networks favor certain characteristics of PTSD. Besides the disruption of hypothalamus-pituitary-axis (HPA) axis, intensified immune status with elevated pro-inflammatory cytokines and arachidonic metabolites of COX-2 such as PGE2 creates a putative scenario in worsening the neurobehavioral facet of PTSD. This review aims to link the Diagnostic and Statistical Manual of mental disorders (DSM-V) symptomology to major neural mechanisms that are supposed to underpin the transition from acute stress reactions to the development of PTSD. Also, to demonstrate how these intertwined processes can be applied to probable early intervention strategies followed by a description of the evidence supporting the proposed mechanisms. Hence in this review, several neural network mechanisms were postulated concerning the HPA axis, COX-2, PGE2, NLRP3, and sirtuins to unravel possible complex neuroinflammatory mechanisms that are obscured in PTSD condition.

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Hippocampal Inhibitory Synapsis Deficits Induced by α5-Containing GABAA Receptors Mediate Chronic Neuropathic Pain–Related Cognitive Impairment

et al. 2022

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A multi-dosing regimen to enhance the spatial memory of normal rats with α5-containing GABAA receptor negative allosteric modulator L-655,708

Cited by 3 publications

References 72 publications

The changing of α5‐GABAA receptors expression and distribution participate in sevoflurane‐induced learning and memory impairment in young mice

The changing of α5‐GABAA receptors expression and distribution participate in sevoflurane‐induced learning and memory impairment in young mice

Emphasizing the Crosstalk Between Inflammatory and Neural Signaling in Post-traumatic Stress Disorder (PTSD)

Hippocampal Inhibitory Synapsis Deficits Induced by α5-Containing GABAA Receptors Mediate Chronic Neuropathic Pain–Related Cognitive Impairment

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