Allopregnanolone-mediated GABAA-Rα4 function in amygdala and hippocampus of PMDD liver qi-invasion syndrome model rats

Sun, Ya; Gao, Mingzhou; Gao, Dongmei; Chen, Dan; Wang, Jieqiong

doi:10.18632/aging.204541

Cited by 2 publications

(4 citation statements)

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“…PMD rats were injected (intraperitoneally) with either ALLO (10 mg/kg in sesame oil, once each morning (between 9:00 AM and 10:00 AM) over a 48-h period for a total of three injections during this period. Control group rats were given the same number of injections of vehicle (sesame oil), rats were behavioral tested 0.5 h after the nal hormone injection [11].…”

Section: Drug Treatment Regimenmentioning

confidence: 99%

“…The Open-Fierutin Test (OFT) protocol was performed as previously described [11]. An opaque laboratory box was divided into 9 squares of equal size.…”

Section: Open Erutin Testoftmentioning

confidence: 99%

“…ALLO-mediated expression of GABAAR subunits is one of the pathological mechanisms underlying various emotional disorder in women, including premenstrual dysphoric disorder and postpartum depression. Sun [11] discovered that ALLO mediated sensitivity of GABAAR α4 subunit plays a signi cant role in premenstrual dysphoric disorder. The biological mechanisms underlying postpartum depression are elucidated by numerous studies indicating that signi cant uctuations in ALLO levels can induce alterations in the expression of GABAAR subunits [12].…”

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confidence: 99%

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Rutin Treats Perimenopausal Depression Rats through Allopregnanolone Mediated mRNA Expression of Gabra4, Gabrb2 in the Prefrontal Cortex

Gao,

et al. 2024

Preprint

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Objective We determined whether the pathogenesis of perimenopausal depression (PMD) is associated with allopregnanolone (3α,5α-THP, ALLO) mediated GABAA receptors subunits expression changes in different brain regions. Simultaneously, we aimed to investigate the therapeutic efficacy and intervention mechanisms of the flavonoid rutin in treating PMD. Methods The PMD rat model was established by ovariectomy surgery followed by chronic unpredictable mirutin stress processes. ALLO was administered via intraperitoneal injection to increase ALLO levels in PMD rats, while rutin was administered via oral gavage for PMD treatment. Behavioral assessments, including open-fierutin test, sucrose preference test, and forced swimming test, were conducted to evaluate depressive-like behaviors in rats. ELISA was employed to measure the levels of E2, 5-HT, NE, ALLO, and GABA in the serum. Quantitative PCR was used to assess the mRNA expression of Gabra4, Gabrb2, and Gabrd in the prefrontal cortex, hippocampus, hypothalamus, and amygdala. Results The PMD rats exhibited depressive-like behavior, with decreased levels of E2, 5-HT, NE, ALLO, and GABA in the serum. The mRNA expression of Gabra4 and Gabrb2 increased in the prefrontal cortex, hippocampus, and hypothalamus of PMD rats, while Gabrd showed a increase in the hypothalamus and amygdala. ALLO improved depressive-like behavior and increased serum levels of E2, 5-HT, NE, and ALLO in PMD rats. ALLO acted on PMD rats, reduced mRNA expression of Gabra4 and Gabrb2 in the prefrontal cortex, increased mRNA expression of Gabrd in the prefrontal cortex, elevated mRNA expression of Gabra4 and Gabrd in the hippocampus, and decreased Gabrb2 mRNA expression in the hypothalamus.Rutin improved depressive-like behavior in PMD rats, increased serum levels of 5-HT and ALLO, and decreased mRNA expression of Gabra4 and Gabrb2 in the prefrontal cortex. Conclusion ALLO-mediated mRNA expression of Gabra4, Gabrb2 in the prefrontal cortex, and Gabrb2 in the hypothalamus is one of the pathological mechanisms in PMD. ALLO can improve depressive symptoms in PMD rats. Rutin (8.65 mg/kg) exerts a therapeutic effect on PMD by upregulating serum ALLO levels, subsequently downregulating mRNA expression of prefrontal cortex Gabra4 and Gabrb2.

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Section: Drug Treatment Regimenmentioning

confidence: 99%

“…The Open-Fierutin Test (OFT) protocol was performed as previously described [11]. An opaque laboratory box was divided into 9 squares of equal size.…”

Section: Open Erutin Testoftmentioning

confidence: 99%

mentioning

confidence: 99%

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Rutin Treats Perimenopausal Depression Rats through Allopregnanolone Mediated mRNA Expression of Gabra4, Gabrb2 in the Prefrontal Cortex

Gao,

et al. 2024

Preprint

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“…1). These receptors are implicated in diverse diseases and disorders of the human central nervous system, such as Alzheimer's disease, schizophrenia, autism spectrum disorder, anxiety, attention-deficit/hyperactivity disorder, and premenstrual dysphoric disorder (PMDD) (5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Identification of a binding site for bupropion inGloeobacter violaceusligand-gated ion channel

Pirayesh,

Do,

Ferreira

et al. 2023

Preprint

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Bupropion is an atypical antidepressant and smoking cessation drug which causes adverse effects such as insomnia, irritability, and anxiety. Bupropion inhibits dopamine and norepinephrine reuptake transporters and eukaryotic cation-conducting pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT3A) receptors, at clinically relevant concentrations. However, the binding sites and binding mechanisms of bupropion are still elusive. To further understand the inhibition of pLGICs by bupropion, in this work, using a prokaryotic homologue of pLGICs as a model, we examined the inhibitory potency of bupropion inGloeobacter violaceusligand-gated ion channel (GLIC), a proton-gated ion channel. Bupropion inhibited proton-induced currents in GLIC with an inhibitory potency of 14.9 ± 2.0 μM, comparable to clinically attainable concentrations previously shown to also modulate eukaryotic pLGICs. Using single amino acid substitutions in GLIC and two-electrode voltage-clamp recordings, we further determined a binding site for bupropion in the lower third of the first transmembrane segment M1 at residue T214. The sidechain of M1 T214 together with additional residues of M1 and also of M3 of the adjacent subunit have previously been shown to contribute to binding of other lipophilic molecules like allopregnanolone and pregnanolone.SIGNIFICANCEGLIC,Gloeobacterligand-gated ion channel, has been extensively used as a model to identify and understand binding sites and mechanisms for cholesterol, neurosteroids, and anesthetics interacting with neurotransmitter-gated ion channels, such as, GABAAreceptors and nicotinic acetylcholine receptors. Recently, increasing evidence has revealed that another neurotransmitter-gated ion channel, the serotonin type 3A receptor, binds to an atypical antidepressant, bupropion, at clinically relevant concentrations. Our work here proposes a binding site for bupropion in GLIC and suggests a new approach to characterize binding mechanisms of bupropion in other neurotransmitter-gated ion channels.

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Allopregnanolone-mediated GABAA-Rα4 function in amygdala and hippocampus of PMDD liver qi-invasion syndrome model rats

Cited by 2 publications

References 38 publications

Rutin Treats Perimenopausal Depression Rats through Allopregnanolone Mediated mRNA Expression of Gabra4, Gabrb2 in the Prefrontal Cortex

Rutin Treats Perimenopausal Depression Rats through Allopregnanolone Mediated mRNA Expression of Gabra4, Gabrb2 in the Prefrontal Cortex

Identification of a binding site for bupropion inGloeobacter violaceusligand-gated ion channel

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