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Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

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Neural Regeneration Research 2025年第8期20卷 2325-2336页

作者： Yafan Bai Hui Ma Yue Zhang Jinfeng Li Xiaojuan Hou Yixin Yang Guyan Wang Yunfeng Li Department of Anesthesiology Beijing Tongren HospitalCapital Medical UniversityBeijingChina Beijing Institute of Basic Medical Sciences BeijingChina Hebei North University ZhangjiakouHebei ProvinceChina Beijing Institute of Pharmacology and Toxicology State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Key Laboratory of NeuropsychopharmacologyBeijingChina

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary *** this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain *** experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain ***,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 ***,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain ***,YL-0919 effectively combated oxidative stress both in vivo and in *** protective effects of YL-0919 were partially inhibited by *** results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist ***-0919 may have potential as a new treatment for traumatic brain injury.

关键词： antidepressant drug blood-brain barrier cognitive function hypidone hydrochloride(YL-0919) neurological function nuclear factor-erythroid 2 related factor 2 oxidative stress sigma-1 receptor superoxide dismutase traumatic brain injury

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sigma-1 receptor:a potential new target for Parkinson's disease?

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Neural Regeneration Research 2014年第21期9卷 1882-1883页

作者： Veronica Francardo Basal Ganglia Pathophysiology Unit Department of Experimental Medical ScienceBMC F11Lund UniversityLundSweden

Parkinson＇s disease （PD） is an age-related neurodegenerative disorder characterized by typical motor signs and symptoms that are due to dopamine （DA） depletion in the basal ganglia. The treatment of PD is symptomatic, and aims at replacing the lost DA input using either L-DOPA or DA agonists. The causes of PD are unknown in approximately 90% of the cases, whereas about 10% of the cases are familial and imputable to mutations in a handful of genes （the gene mutations with the strongest association with PD are shown in Table 1; for a detailed review see （Poulopoulos et al., 2012））. The genetic forms of PD have spurred an intense research on molecular pathways of neurodegeneration that converge on proteostatic deficits, mitochondrial dysfunction and oxidative stress.

关键词： sigma-1 receptor PARK

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sigma-1 receptor: a new player in neuroprotection against chemotherapy-induced peripheral neuropathy

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Neural Regeneration Research 2018年第5期13卷 775-778页

作者： Jordi Bruna Roser Velasco Neuro-Oncology Unit Hospital Universitari de Bellvitge-ICO L'Hospitalet IDIBELL (Institut d'Investigació Biomèdica de Bellvitge) Institute of Neurosciences Department of Cell Biology Physiology and Immunology Universitat Autonoma de Barcelona and Centro de Investigación Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)

Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy（OIN） is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes： acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309（previously developed as E-52862） is a novel selective sigma-1 receptor（S1R） antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase Ⅱ, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer（CRC） treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.

关键词： oxaliplatin chemotherapy-induced peripheral neuropathy sigma-1 receptor neurotoxicity MR309 E-52862

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Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism:WLB-73502,an analgesic with improved efficacy and safety profile compared to strong opioids

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Acta Pharmaceutica Sinica B 2023年第1期13卷 82-99页

作者： Alba Vidal-Torres Begoña Fernández-Pastor Mónica García Eva Ayet Anna Cabot Javier Burgueño Xavier Monroy Bertrand Aubel Xavier Codony Luz Romero Rosalía Pascual Maria Teresa Serafini Gregorio Encina Carmen Almansa Daniel Zamanillo Manuel Merlos JoséMiguel Vela WeLab Barcelona Parc Cientific de BarcelonaBarcelona 08028Spain

Opioids are the most effective painkillers,but their benefit-risk balance often hinder their therapeutic ***-73502 is a dual,bispecific compound that binds sigma-1(S1R)and mu-opioid(MOR)***-73502 is an antagonist at the *** behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificantβ-arrestin-2 recruitment,thus demonstrating low intrinsic efficacy on MOR at both signalling *** its partial MOR agonism,WLB-73502exerted full antinociceptive efficacy,with potency superior to morphine and similar to oxycodone against nociceptive,inflammatory and osteoarthritis pain,and superior to both morphine and oxycodone against neuropathic ***-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive *** to morphine and oxycodone,tolerance to its antinociceptive effect did not develop after repeated 4-week ***,contrary to opioid comparators,WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy,and it was devoid of proemetic effect(retching and vomiting)in ferrets at potentially effective ***-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

关键词： WLB-73502 sigma-1 receptor Mu-opioid receptor Biased agonist Analgesic activity Chronic pain Neuropathic pain Safety

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sigma-1 receptor Stimulation with PRE-084 Ameliorates Myocardial Ischemia-Reperfusion Injury in Rats

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Chinese Medical Journal 2018年第5期131卷 539-543页

作者： Qi-Jun Gao Bo Yang Jing Chen Shao-Bo Shi Hong-Jie Yang Xin Liu Department of Cardiology Renmin Hospital of Wuhan University Wuhan Hubei 430000 China Department of Cardiology First Hospital of Jingmen Jingmen Hubei 448000 China

Background： The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma- 1 receptor agonist PRE-084 exhibits a cardioprotective effect in some studies, the benefits in cases of myocardial ischemia/reperfusion （I/R） are not clear. The aim of this study was to explore the mechanism of action and assess the effect of PRE-084 on myocardial I/R injury in rats. Methods： In this study, rats were assigned randomly to three groups with computer （n = 14 for each group）： a sham group, an I/R group, and a PRE-084 group. In the PRE-084 group, rats were administered PRE-084 I h before operation. In the myocardial I/R model, the left anterior descending branch of rats was ligated and opened half an hour later. Cardiac function was assessed, and the apoptosis index was evaluated. The mechanisms of the cardioprotective effects of PRE-084 were explored. Results： PRE-084 pretreatment preserved cardiac function and reduced myocardial apoptosis （F= 86.0, P 〈 0.01） with Western blotting analysis, showing significantly reduced expression of Bax （F = 75.7, P 〈 0.01） and cleaved-caspase 3 （F = 44.7, P 〈 0.01）, along with increased expression of the Bcl-2 protein （P 〈 0.01 ） and phosphorylated protein kinase B （p-Akt）（P 〈 0.01） and phosphorylated-endothelial nitric oxide synthase （p-eNOS; P 〈 0.01）. Conclusion： PRE-084 preserved cardiac function and reduced myocardial apoptosis through the activation of Akt and eNOS.

关键词： Myocardial Ischemia/Reperfusion PRE-084 sigma-1 receptor

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sigma-1 receptor mediates the effect of cyproheptadine on theⅠK in mouse cortical neurons

Sigma-1 receptor mediates the effect of cyproheptadine on th...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yan-Lin HE,Chun-Lei ZHANG,Xiao-Fei GAO,Jin-Jing YAO,Chang-Long HU,Yan-Ai MEI~* Institutes of Brain Science,School of Life Sciences and State Key Laboratory of Medical Neurobiology,Fudan University,Shanghai 200433,China

Cyproheptadine is a histamine- and serotonin- receptor antagonist,and its effects are observed in the modulation of multiple intracellular signals in previous *** demonstrate here that intracellularly delivered cyproheptadine increased the delayed rectifier outward potassium current(I) by reducing the intracellular levels of phosphorylated PKA in mouse cortical ***-receptor binding assay indicated that cyproheptadine bound to sigma-1 receptor and mediate the cAMP/PKA *** to the sigma-1 receptor mimicked effects of CPH and knock down this receptor abolished the effects of CPH on *** of G eliminated the cyproheptadine-induced effect on I and PKA activity.K2.1α-subunit blocker reduced cyproheptadine-induced effect on I in mouse cortical ***,CPH also enhance the K current when expressed the K2.1α-subunit on HEK293 *** reveal for the first time that CPH enhances I by a sigma-1 receptor-dependent mechanism and selective targeting of the K2.1α-subunit. This result may help to explain some of the uncharacterized effects of CPH on neuron excitability and contribute to the understanding of CPH as more than just a competitive inhibitor of the histamine H and serotonin receptors.

关键词： sigma-1 receptor cyprohetadine IK Kγ2.1α-subunit cAMP/PKA pathway cortical neurons

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The sigma-1 receptor as a Pharmacologic Chaperone: Energetics

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Journal of Biosciences and Medicines 2024年第8期12卷 347-356页

作者： Robert B. Raffa Joseph V. Pergolizzi Jr. School of Pharmacy (Emeritus) Temple University Philadelphia PA USA College of Pharmacy (Adjunct) University of Arizona Tucson AZ USA NEMA Research Naples FL USA

Initially thought to be an opioid receptor subtype, sigma-1 receptors (S1R) are now known to be unique proteins that have chaperone-like properties. As such, they play critical roles in cellular signaling, homeostasis, and cell survival. These roles offer significant insight for understanding homeostasis of normal physiologic processes, and the pathophysiologic consequences of disruption of normal function. Because of the broad nature of chaperone action, S1R agonists and antagonists represent potential drug discovery goals for the pharmacotherapeutic treatment of a variety of disorders that result from dysfunctional proteins. The present study summarizes the S1R as a pharmacologic chaperone crucial for protein folding and cellular homeostasis. Through literature review and thermodynamic analysis, it explores how S1R stabilizes target proteins, influencing neuroprotection and potential drug therapies. The binding of chaperones to target proteins is thermodynamically favorable, offering insights into treating diseases linked to protein misfolding.

关键词： Chaperone sigma-1 receptor Energetics Thermodynamics Isothermal Titration Microcalorimetry

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sigma-1 receptors enhance presynaptic Ca2+level via L-type Ca2+channel in medial prefrontal cortex

Sigma-1 receptors enhance presynaptic Ca2+level via L-type C...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Yan-Yan ZHAO,Ymg-Mei FU,Wen-Jie LUAN,Yi DONG,Bin LAI,Yan-Hua ZHU,Ping ZHENG~* State Key Laboratory of Medical Neurobiology,Shanghai Medical College and Institutes of Brain Science,Fudan University,Shanghai 200032,China

The effect and its mechanism of the activation of the sigma-1 receptors on the intracellular Ca

关键词： sigma-1 receptor synaptosome medial prefrontal cortex Ca2+ concentration protein kinase C L-type Ca2+ channel

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Neuroprotective and anti-inflammatory effects of a therapy combining agonists of nicotinic α7 and σ1 receptors in a rat model of Parkinson’s disease

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Neural Regeneration Research 2021年第6期16卷 1099-1104页

作者： Steven Vetel Laura Foucault-Fruchard Claire Tronel Frédéric Buron Jackie Vergote Sylvie Bodard Sylvain Routier Sophie Sérrière Sylvie Chalon UMR 1253 iBrainUniversitéde ToursInsermToursFrance CHU Tours Service pharmacieToursFrance Institut de Chimie Organique et Analytique ICOAUMR CNRS 7311Universitéd’OrléansOrléansFrance

To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson’s *** was recently observed in a rodent model of Alzheimer’s disease that the interaction between the α7 subtype of nicotinic acetylcholine receptor(α7-nAChR)and sigma-1 receptor(σ1-R)could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson’s *** this context,the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide(PHA)543613 as an α7-nAChR agonist and 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate(PRE)-084 as aσ1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson’s *** animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 *** no effect was noticed in the amphetamine-induced rotation test,our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons(15-20%),assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia ***,this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion,i.e,the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum,and the CD11b and glial fibrillary acidic protein staining in the substantia ***,this study reports for the first time that concomitant activation of α7-nAChR andσ1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial *** study was approved by the Regional Ethics Committee(CEEA Val de Loire n°19)validated this protocol(Authorization N°00434.02)on May 15,2014.

关键词： 6-hydroxydopamine astrocytes microglial activation neurodegeneration neuroinflammation nicotinicα7 receptor Parkinson’s disease PHA 543613 PRE-084 sigma-1 receptor

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Cyproheptadine Regulates Pyramidal Neuron Excitability in Mouse Medial Prefrontal Cortex

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Neuroscience Bulletin 2018年第5期34卷 759-768页

作者： Yan-Lin He Kai Wang Qian-Ru Zhao Yan-Ai Mei Institutes of Brain Science State Key Laboratory of Medical Neurobiology and School of Life Sciences Fudan University

Cyproheptadine （CPH）, a first-generation anti- histamine, enhances the delayed rectifier outward K＋ current （IK） in mouse cortical neurons through a sigma-1 receptor-mediated protein kinase A pathway. In this study, we aimed to determine the effects of CPH on neuronal excitability in current-clamped pyramidal neurons in mouse medial prefrontal cortex slices. CPH （10 μmol/L） significantly reduced the current density required to generate action potentials （APs） and increased the instan- taneous frequency evoked by a depolarizing current. CPH also depolarized the resting membrane potential （RMP）, decreased the delay time to elicit an AP, and reduced the spike threshold potential. This effect of CPH was mim- icked by a sigma-1 receptor agonist and eliminated by an antagonist. Application of tetraethylammonium （TEA） to block IK channels hyperpolarized the RMP and reduced the instantaneous frequency of APs. TEA eliminated the effects of CPH on AP frequency and delay time, but had no effect on spike threshold or RMP. The current-voltage relationship showed that CPH increased the membrane depolarization in response to positive current pulses and hyperpolarization in response to negative current pulses, suggesting that other types of membrane ion channels might also be affected by CPH. These results suggest that CPH increases the excitability of medial prefrontal cortex neurons by regulating TEA-sensitive IK channels as well as other TEA-insensitive K＋ channels, probably ID and inward-rectifier Kir channels. This effect of CPH may explain its apparent clinical efficacy as an antidepressant and antipsychotic.

关键词： Cyproheptadine Neuronal excitability Te-traethylammonium-sensitive Ik cortical neurons sigma-1 receptor

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