Author: Germann, Allison L ; Pierce, Spencer R ; Germann, Allison L. ; Steinbach, Joe Henry ; Evers, Alex S ; Pierce, Spencer R. ; Covey, Douglas F ; Akk, Gustav ; Evers, Alex S.

The γ-aminobutyric acid type A (GABA_A) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3β-hydroxy steroids inhibit, while 3α-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the α1β3γ2L GABA_A receptor by the endogenous neurosteroid 3α-hydroxy-5β-pregnan-20-one (3α5βP) and the synthetic neuroactive steroid 3α-hydroxy-5α-androstane-17β-carbonitrile (ACN). The receptors were expressed in Xenopus oocytes. All experiments were done using two-electrode voltage-clamp electrophysiology. In the presence of low concentrations of GABA, 3α5βP and ACN potentiate the GABA_A receptor. To reveal inhibition, we conducted the experiments on receptors activated by the combination of a saturating concentration of GABA and propofol to fully activate the receptors and mask potentiation, or on mutant receptors in which potentiation is ablated. Under these conditions, both steroids inhibited the receptor with IC₅₀s of ∼13 μM and maximal inhibitory effects of 70-90%. Receptor inhibition by 3α5βP was sensitive to substitution of the α1 transmembrane domain (TM) 2-2' residue, previously shown to ablate inhibition by pregnenolone sulfate. However, results of coapplication studies and the apparent lack of state dependence suggest that pregnenolone sulfate and 3α5βP inhibit the GABA_A receptor independently and through distinct mechanisms. Mutations to the neurosteroid binding sites in the α1 and β3 subunits statistically significantly, albeit weakly and incompletely, reduced inhibition by 3α5βP and ACN. SIGNIFICANCE STATEMENT: The heteromeric GABA_A receptor is inhibited by sulfated steroids and 3β-hydroxy steroids, while 3α-hydroxy steroids are considered to potentiate the receptor. We show here that 3α-hydroxy steroids have inhibitory effects on the α1β3γ2L receptor, which are observed in specific experimental settings and are expected to manifest under different physiological conditions.

01 Jul 2023·CNS Neuroscience & Therapeutics

Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain

Article

Author: Qiu, Yuxin ; Wang, Linjie ; Gong, Qingjuan ; Wu, Yuning ; Su, Minzhi ; Wei, Xuhong

AbstractAimsBeyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G protein‐coupled receptor 5, TGR5) and the nuclear farnesoid X receptor (FXR). The present study investigated the role of bile acids in alleviating neuropathic pain by activating TGR5 and FXR.MethodNeuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. TGR5 or FXR agonist was injected intrathecally. Pain hypersensitivity was measured with Von Frey test. The amount of bile acids was detected using a bile acid assay kit. Western blotting and immunohistochemistry were used to assess molecular changes.ResultsWe found that bile acids were downregulated, whereas the expression of cytochrome P450 cholesterol 7ahydroxylase (CYP7A1), a rate‐limiting enzyme for bile acid synthesis, was upregulated exclusively in microglia in the spinal dorsal horn after SNI. Furthermore, the expression of the bile acid receptors TGR5 and FXR was increased in glial cells and GABAergic neurons in the spinal dorsal horn on day 7 after SNI. Intrathecal injection of either TGR5 or FXR agonist on day 7 after SNI alleviated the established mechanical allodynia in mice, and the effects were blocked by TGR5 or FXR antagonist. Bile acid receptor agonists inhibited the activation of glial cells and ERK pathway in the spinal dorsal horn. All of the above effects of TGR5 or FXR agonists on mechanical allodynia, on the activation of glial cells, and on ERK pathway were abolished by intrathecal injection of the GABAA receptor antagonist bicuculline.ConclusionThese results suggest that activation of TGR5 or FXR counteracts mechanical allodynia. The effect was mediated by potentiating function of GABAA receptors, which then inhibited the activation of glial cells and neuronal sensitization in the spinal dorsal horn.

01 Jul 2023·Phytotherapy Research

Deoxyschizandrin ameliorates obesity and non‐alcoholic fatty liver disease: Involvement of dual Farnesyl X receptor/G protein‐coupled bile acid receptor 1 activation and leptin sensitization

Article

Author: Feng, Yaru ; Gu, Ming ; Huang, Cheng ; Chen, Yujun ; Fan, Shengjie

AbstractNatural dual farnesyl X receptor (FXR)/G protein‐coupled bile acid receptor 1 (TGR5) activators have received little attention in the management of metabolic diseases. Deoxyschizandrin (DS), a natural lignan, occurs in S. chinensis fruit and has potent hepatoprotective effects, whereas its protective roles and mechanisms against obesity and non‐alcoholic fatty liver disease (NAFLD) are largely elusive. Here, we identified DS as a dual FXR/TGR5 agonist using luciferase reporter and cyclic adenosine monophosphate (cAMP) assays. DS was orally or intracerebroventricularly administrated to high‐fat diet‐induced obesity (DIO) mice, and methionine and choline‐deficient L‐amino acid diet (MCD diet)‐induced non‐alcoholic steatohepatitis to evaluate its protective effects. Exogenous leptin treatment was employed to investigate the sensitization effect of DS on leptin. The molecular mechanism of DS was explored by Western blot, quantitative real‐time PCR analysis, and ELISA. The results showed that DS activated FXR/TGR5 signaling and effectively reduced NAFLD in DIO and MCD diet‐fed mice. DS countered obesity in DIO mice by promoting anorexia and energy expenditure and reversing leptin resistance, involving both peripheral and central TGR5 activation and leptin sensitization. Our findings indicate that DS may be a novel therapeutic approach for alleviating obesity and NAFLD through regulating FXR and TGR5 activities and leptin signaling.

100 Deals associated with FXR and TGR5 ligands 26(Università degli Studi di Napoli Federico II)

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FXR and TGR5 ligands 26(Università degli Studi di Napoli Federico II)

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