Roles of GABAA receptor α5 subunit on locomotion and working memory in transient forebrain ischemia in mice

Kim, Dong Hyun; Kwon, Huiyoung; Choi, Ji Woong; Shin, Chan Young; Cheong, Jae Hoon; Park, Se Jin; Ryu, Jong Hoon

doi:10.1016/j.pnpbp.2020.109962

Cited by 9 publications

(6 citation statements)

References 54 publications

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“…Its movements were recorded by a camera for 5 minutes and evaluated by Ethovision software version 8. In the OFT, the horizontal (distance moved, number of crossing by 4 feet from each square) and vertical (number of rearings) activities were measured [ 21 ]. The apparatus was cleaned with 70% ethanol after the experiment with each mouse.…”

Section: Methodsmentioning

confidence: 99%

Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress

Lorigooini

Boroujeni

Sayyadi-Shahraki

et al. 2021

Behavioural Neurology

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Background and Aim. Depression is a social problem with high economic burden in the society. Finding an effective agent with high efficacy and few side effects is therefore needed. Involvement of neuroimmune response as well as nitric oxide (NO) has been determined in the pathophysiology of depression. Limonene is a terpene with various pharmacological properties. Thus, we aimed to evaluate antidepressant-like effect of limonene on a mouse model of maternal separation (MS) focusing on neuroinflammation and NO level in the hippocampus. Methods. Mice were randomly divided into experimental groups as follows: the control group received normal saline and MS groups received normal saline, limonene (10 and 20 mg/kg), L-NAME (10 mg/kg), L-arginine (L-arg) (75 mg/kg), limonene (10 mg/kg) plus L-NAME, and limonene (20 mg/kg) plus L-arg. Behavioral tests including the forced swimming test (FST), open field test (OFT), and splash test were performed. Finally, serum and hippocampal nitrite levels as well as the expression of inflammatory genes (IL-1β and TNF-α) in the hippocampus were measured. Results. We showed that MS caused depressive-like behavior. Treatment of MS mice with limonene reduced the duration of immobility time in FST and increases the grooming activity time in the splash test. Limonene also reduces serum and brain nitrite levels and reduces the expression of IL-1β and TNF-α in the hippocampus. We found that L-NAME potentiated the effects of a subeffective dose of limonene. Conclusion. We concluded that the antidepressant-like effects of limonene are probably mediated through inhibition of neuroinflammation and attenuation of nitrite levels in the hippocampus.

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Section: Methodsmentioning

confidence: 99%

Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress

Lorigooini

Boroujeni

Sayyadi-Shahraki

et al. 2021

Behavioural Neurology

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“…Behavioral Tests: NOR, Y maze, and OFT tests were performed with mice as previously described [68,69] and animal behaviors were recorded by using a SMART video tracking system and analyzed with a SMART 3.0 software (Panlab Harvard Apparatus, Barcelona, Spain). In the NOR test, object preference% = the number of novel or old object exploration/the total number of object exploration.…”

Section: Methodsmentioning

confidence: 99%

E4BP4 Coordinates Circadian Control of Cognition in Delirium

et al. 2022

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Improved understanding of the etiologies of delirium, a common and severe neuropsychiatric syndrome, would facilitate the disease prevention and treatment. Here, the authors invesitgate the role of circadian rhythms in the pathogenesis of delirium. They observe perturbance of circadian rhythms in mouse models of delirium and disrupted clock gene expression in patients with delirium. In turn, physiological and genetic circadian disruptions sensitize mice to delirium with aggravated cognitive impairment. Likewise, global deletion of E4bp4 (E4 promoter‐binding protein), a clock gene markedly altered in delirium conditions, results in exacerbated delirium‐associated cognitive decline. Cognitive decline in delirium models is attributed to microglial activation and impaired long‐term potentiation in the hippocampus. Single‐cell RNA‐sequencing reveals microglia as the regulatory target of E4bp4 . E4bp4 restrains microglial activation via inhibiting the ERK1/2 signaling pathway. Supporting this, mice lacking in microglial E4bp4 are delirious prone, whereas mice with E4bp4 specifically deleted in hippocampal CA1 neurons have a normal phenotype. Mechanistically, E4bp4 inhibits ERK1/2 signaling by trans‐repressing Mapk1/3 (genes encoding ERK1/2) via direct binding to a D‐box element in the promoter region. These findings define a causal role of clock dysfunction in delirium development and indicate E4bp4 as a regulator of cognition at the crosstalk between circadian clock and delirium.

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“…Importantly, benzodiazepine tolerance completely blocks the protective effect of diazepam, a drug used to control anxiety and sleep in modern society (Iwata et al., 2012). The effect of diazepam changes slightly after a few days of ischemia, but not because of its anxiolytic property (Kim et al., 2020). The hypothermia promoted by diazepam and clomethiazole contributes to the beneficial effects (Kuhmonen et al., 2002).…”

Section: The Role Of Gaba In Ischemic Brainmentioning

confidence: 99%

GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia

Nascimento,

Pereira‐Figueiredo,

Borges‐Martins

et al. 2024

J of Neuroscience Research

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Gamma aminobutyric acid (GABA) is a critical inhibitory neurotransmitter in the central nervous system that plays a vital role in modulating neuronal excitability. Dysregulation of GABAergic signaling, particularly involving the cotransporters NKCC1 and KCC2, has been implicated in various pathologies, including epilepsy, schizophrenia, autism spectrum disorder, Down syndrome, and ischemia. NKCC1 facilitates chloride influx, whereas KCC2 mediates chloride efflux via potassium gradient. Altered expression and function of these cotransporters have been associated with excitotoxicity, inflammation, and cellular death in ischemic events characterized by reduced cerebral blood flow, leading to compromised tissue metabolism and subsequent cell death. NKCC1 inhibition has emerged as a potential therapeutic approach to attenuate intracellular chloride accumulation and mitigate neuronal damage during ischemic events. Similarly, targeting KCC2, which regulates chloride efflux, holds promise for improving outcomes and reducing neuronal damage under ischemic conditions. This review emphasizes the critical roles of GABA, NKCC1, and KCC2 in ischemic pathologies and their potential as therapeutic targets. Inhibiting or modulating the activity of these cotransporters represents a promising strategy for reducing neuronal damage, preventing excitotoxicity, and improving neurological outcomes following ischemic events. Furthermore, exploring the interactions between natural compounds and NKCC1/KCC2 provides additional avenues for potential therapeutic interventions for ischemic injury.

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Roles of GABAA receptor α5 subunit on locomotion and working memory in transient forebrain ischemia in mice

Cited by 9 publications

References 54 publications

Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress

Limonene through Attenuation of Neuroinflammation and Nitrite Level Exerts Antidepressant-Like Effect on Mouse Model of Maternal Separation Stress

E4BP4 Coordinates Circadian Control of Cognition in Delirium

GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia

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