Stimulation of astrocytic sigma-1 receptor is sufficient to ameliorate inflammation- induced depression

Guo, Lin; Gao, Tianyu; Gao, Ce; Jia, Xiaoxia; Ni, Jing; Han, Chaojun; Wang, Yun

doi:10.1016/j.bbr.2021.113344

Cited by 11 publications

(7 citation statements)

References 31 publications

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“…The animals' memory function was determined using the novel object recognition test 19 . The recognition index used was defined as: time consumed in the new object/(time consumed in the new object + time consumed in the familiar object) 20 . Depressive‐ and anxiety‐like behaviors were evaluated using the tail suspension test (TST) and the open field test (OFT), respectively.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus

Jia

Wang

et al. 2023

Anim Models and Exp Med

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Background Hippocampal damage caused by status epilepticus (SE) can bring about cognitive decline and emotional disorders, which are common clinical comorbidities in patients with epilepsy. It is therefore imperative to develop a novel therapeutic strategy for protecting hippocampal damage after SE. Mitochondrial dysfunction is one of contributing factors in epilepsy. Given the therapeutic benefits of mitochondrial replenishment by exogenous mitochondria, we hypothesized that transplantation of mitochondria would be capable of ameliorating hippocampal damage following SE. Methods Pilocarpine was used to induced SE in mice. SE‐generated cognitive decline and emotional disorders were determined using novel object recognition, the tail suspension test, and the open field test. SE‐induced hippocampal pathology was assessed by quantifying loss of neurons and activation of microglia and astrocytes. The metabolites underlying mitochondrial transplantation were determined using metabonomics. Results The results showed that peripheral administration of isolated mitochondria could improve cognitive deficits and depressive and anxiety‐like behaviors. Exogenous mitochondria blunted the production of reactive oxygen species, proliferation of microglia and astrocytes, and loss of neurons in the hippocampus. The metabonomic profiles showed that mitochondrial transplantation altered multiple metabolic pathways such as sphingolipid signaling pathway and carbon metabolism. Among potential affected metabolites, mitochondrial transplantation decreased levels of sphingolipid (d18:1/18:0) and methylmalonic acid, and elevated levels of D‐fructose‐1,6‐bisphosphate. Conclusion To the best of our knowledge, these findings provide the first direct experimental evidence that artificial mitochondrial transplantation is capable of ameliorating hippocampal damage following SE. These new findings support mitochondrial transplantation as a promising therapeutic strategy for epilepsy‐associated psychiatric and cognitive disorders.

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Section: Methodsmentioning

confidence: 99%

Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus

Jia

Wang

et al. 2023

Anim Models and Exp Med

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“…The experimental details were given in our published work. 30 In TST, the mice were suspended on a retort stand (50 cm far from the floor) individually using an adhesive tape. This tape was adhered approximately 1 cm away from the tip of the tail.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The animal memory function was elevated using the novel object recognition test (NORT) and the Barnes maze, referring to the published studies. − Briefly, the day before the testing, mice were allowed to habituate the experimental chamber for 5 min. On the testing day, the mice freely explored two identical objects for 5 min.…”

Section: Materials and Methodsmentioning

confidence: 99%

“…The depressant-like behavior and the anxiety-like behavior were evaluated using tail suspension test (TST), open field test (OFT), and elevated plus maze (EPM), respectively. The experimental details were given in our published work . In TST, the mice were suspended on a retort stand (50 cm far from the floor) individually using an adhesive tape.…”

Section: Materials and Methodsmentioning

confidence: 99%

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SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor

Guo

Gao

Jia

et al. 2022

ACS Chem. Neurosci.

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Memory impairment and emotional disorder are two common clinical comorbidities in patients with epilepsy. It is imperative to develop a novel therapeutic agent or a strategy. 6-Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a dopamine-1 receptor agonist and sigma-1 receptor allosteric modulator, which displays the neuron-protective and anti-neuroinflammation activity. We examined the effect of SKF83959 on the memory impairment and emotional disorder in the latent period of epilepsy using the mice post-status epilepticus model. We found that SKF83959 ameliorated memory impairment and depressive-like mood, alleviated the neuron damage and the formation of gliosis in hippocampus, suppressed the rise of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3β. All of these protective actions were reversed by BD1047 (a sigma-1 receptor antagonist). In addition, the intra-hippocampus injection of ketoconazole (a dehydroepiandrosterone synthesis inhibitor) also reversed the protective activity of SKF83959. Thus, we concluded that SKF83959 ameliorated the memory impairment and depressive-like mood in epilepsy via allosterically activating the sigma-1 receptor and subsequently inhibiting the calcineurin/glycogen synthase kinase-3β pathway.

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“…This promising result prompted additional investigations aiming at increasing the specificity of gene transfer to the astrocytes by either modifying the genome vector and/or by developing engineered capsids to increase the tropism towards astrocytes. In particular, cell-specific gene expression was achieved using astrocyte-specific promoters [209][210][211][212][213][214][215][216][217][218][219]. In parallel, screening strategies led to the identification of cell-type-specific capsids able to enhance the transduction efficiency of the astrocytes by recombinant vectors, namely AAV Anc80L65 [220] and AAV-PHP.B [221][222][223], when compared to AAV9.…”

Section: Viral Deliverymentioning

confidence: 99%

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

Valori

Possenti

Brambilla

et al. 2021

Cells

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Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions. Among glial cells, astrocytes emerge as promising therapeutic targets in various neurodegenerative disorders. In this review, we present the latest evidence showing the astonishing level of specialization that astrocytes display to fulfill the demands of their neuronal partners as well as their plasticity upon injury. Then, we discuss the controversies that fuel the current debate on these cells. We tackle evidence of a potential beneficial effect of cell therapy, achieved by transplanting astrocytes or their precursors. Afterwards, we introduce the different strategies proposed to modulate astrocyte functions in neurodegeneration, ranging from lifestyle changes to environmental cues. Finally, we discuss the challenges and the recent advancements to develop astrocyte-specific delivery systems.

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Stimulation of astrocytic sigma-1 receptor is sufficient to ameliorate inflammation- induced depression

Cited by 11 publications

References 31 publications

Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus

Mitochondrial transplantation ameliorates hippocampal damage following status epilepticus

SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

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