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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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Copper homeostasis and neurodegenerative diseases

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Neural Regeneration Research 2025年第11期20卷 3124-3143页

作者： Yuanyuan Wang Daidi Li Kaifei Xu Guoqing Wang Feng Zhang International Research laboratory of Ethnomedicine of Ministry of Education Key Laboratory of Basic Pharmacology of Ministry of EducationLaboratory Animal Center and Key Laboratory of Basic Pharmacology of Guizhou ProvinceZunyi Medical UniversityZunyiGuizhou ProvinceChina

Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of *** homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and *** in copper homeostasis can lead to either the deficiency or accumulation of copper in brain *** evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative ***,the exact mechanisms underlying these processes are not *** is a potent oxidant that increases reactive oxygen species production and promotes oxidative *** reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial *** oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory ***,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell *** study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease *** synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of heredit

关键词： Alzheimer's disease amyotrophic lateral sclerosis disease copper homeostasis copper toxicity Huntington's disease Menkes'disease multiple sclerosis neurodegenerative disease Parkinson's disease Wilson's disease

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Direct and rapid detection of serum amino acid and monoamine neurotransmitters to assist the diagnosis of panic disorder

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Science China Chemistry 2025年第1期68卷 377-384页

作者： Shiwen Liu Xuerui Wan Meng Zhao Jiaqi Wang Weilan Wu Linlin You Yonggui Yuan Qian Xu Rong Gao Key laboratory of Environmental Medicine Engineering Ministry of Education School of Public Health Southeast University Key laboratory of Modern toxicology of Ministry of Education Department of Hygienic Analysis and Detection School of Public HealthNanjing Medical University Department of Psychosomatics and Psychiatry Zhongda Hospital School of Medicine Southeast University

The measurement of amino acid and monoamine neurotransmitters（NTs） in serum plays a central role in the identification and monitoring of clinical panic disorder（PD）. However, the strong polarity and chemical heterogeneity of NTs make direct extraction and rapid detection extremely challenging. Herein, we developed a strategy that integrated solid phase extraction based on magnetic Fe3O4coated with polydopamine（Fe3O4@PDA） and direct analysis of mass spectrometry in real time（DART-MS） for quantification of 10 NTs. We systematically investigated the optimal conditions of this strategy to achieve good accuracy and precision. Compared with existing magnetic solid phase extraction methods for NTs detection in biological samples, this strategy could adsorb more targets while having similar adsorption efficiencies, and the total process time was reduced by an average of 69.42%. We rapidly determined the metabolic abnormality of 6 types of NTs in the serum of PD patients and demonstrated their diagnostic accuracy. In addition, an outstanding feature of PD in which tryptophan was more metabolized by the KYN pathway and the 5-hydroxytryptamine pathway was inhibited could be elucidated by this strategy. Our results highlighted the potential ability of Fe3O4@PDA coupled with DART-MS to assist in the clinical diagnosis of PD.

关键词： neurotransmitters panic disorder magnetic solid phase extraction direct analysis of mass spectrometry in real time

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Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor-and Cygb-associated signaling pathways

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Neural Regeneration Research 2025年第9期20卷 2706-2726页

作者： Biao Xiao Chaoyang Chu Zhicheng Lin Tianyuan Fang Yuyu Zhou Chuxia Zhang Jianghui Shan Shiyu Chen Liping Li Department of Physiology and pharmacology Health Science CenterNingbo UniversityNingboZhejiang ProvinceChina Ningbo Key laboratory of Behavioral Neuroscience Health Science CenterNingbo UniversityNingboZhejiang ProvinceChina Key laboratory of Addiction Research of Zhejiang Province NingboZhejiang ProvinceChina

A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's ***,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and ***,nonpharmacological interventions aimed at inducing adult neurogenesis are currently *** individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully *** this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 *** deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease ***,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus *** findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 ***,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice

关键词： acousto-optic stimulation adult neurogenesis Alzheimer's disease amyloid precursor protein/presenilin 1 mice amyloid-beta deposition brain cell apoptosis cognitive impairment depression-like behavior involuntary treadmill exercise olfactory stimulation serum metabolites

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Quantification of flupirtine maleate polymorphs using X-ray powder diffraction

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Chinese Chemical Letters 2016年第11期27卷 1666-1672页

作者： Yu-Mei Zhao Zhi-Bing Zheng Song Li laboratory of Computer-Aided Drug Design & Discovery Beijing Institute of Pharmacology and Toxicology laboratory of Structure Identification Beijing Institute of Pharmacology and Toxicology State Key laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

Flupirtine maleate, a pharmaceutical compound for treating psychotic disease in clinics, has seven polymorphs. Form A, with better crystal stability and bioavailability, has been widely used as the pharmaceutical crystal form. Unfortunately, it is usually found in a polymorphic mixture with form B. In this study, pure crystal forms of A and B were prepared and characterized by X-ray powder diffraction （XRPD）, Fourier transform infrared spectroscopy （FT-IR） and thermal analysis. An XRPD-based method for the quantitative determination of the amount of the flupirtine maleate polymorphs form A and form B was also established through a systematic optimization of instrumental parameters. The results of the analytical methodology validation showed that the XPRD method had a broad quantitative range of 0- 100% （w/w）, good linear relationship, with R2= 0.999, excellent repeatability and precision and low limits of detection （LoD） of 0.15% （w/w） and quantification （LoQ） of 0.5% （w/w）. The results also showed that the single-peak method was not as good as the whole pattern in reducing the influence of the preferred orientation, but this can be compensated for by a systematic optimization of instrumental parameters and validating the analytical methodology to reduce errors and obtain a good, repeatable, sensitive, and accurate method. This XRPD method can be used to analyze mixtures of flupirtine maleate polymorphs （forms A and B） quantitatively and control the quality of the bulk drug.

关键词： Flupirtine maleate X-ray powder diffraction Quantitative analysis of polymorphs Preferred orientation Transmission

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Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

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Neural Regeneration Research 2025年第5期20卷 1258-1276页

作者： Qing Qiu Mengting Yang Danfeng Gong Haiying Liang Tingting Chen Department of pharmacology School of PharmacyNantong UniversityNantongJiangsu ProvinceChina Jiangsu Province Key laboratory of Inflammation and Molecular Drug Target NantongJiangsu ProvinceChina Department of Pharmacy Longyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujian ProvinceChina

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be u

关键词： astrocytes calcium channels central nervous system extracellular ion concentration microglia neurological disorders neurons potassium channels

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Improvements in SOD mimic AEOL-10150, a potent broad-spectrum antioxidant

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Military Medical Research 2019年第1期6卷 78-88页

作者： Xiao-rui Zhang Wen-xia Zhou Yong-xiang Zhang State Key laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

AEOL-10150 is a broad-spectrum metalloporphyrin superoxidase dismutase(SOD) mimic specifically designed to neutralize reactive oxygen and nitrogen species. Research has shown that AEOL-10150 is a potent medical countermeasure against national security threats including sulfur mustard(SM), nerve agent exposure and radiation pneumonitis following a radiological/nuclear incident sufficient to cause acute radiation syndrome(ARS). AEOL-10150 performed well in animal safety studies, and two completed phase 1 safety studies in patients demonstrated that the drug was safe and well tolerated, indicating that AEOL-10150 has potential as a new catalytic antioxidant drug. In this article, we review improvements in AEOL-10150 in preclinical pharmacodynamic studies, especially regarding anti-SM,chlorine gas and radiation exposure studies.

关键词： Catalytic antioxidant Metalloporphyrins Chemical warfare agent Radiation damage Pharmacodynamics Pharmacokinetics

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Vascular endothelial growth factor:a double-edged sword in the development of white matter lesions

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Neural Regeneration Research 2025年第1期20卷 191-192页

作者： Narek Manukjan Daniel Fulton Zubair Ahmed WMatthijs Blankesteijn Sébastien Foulquier Department of pharmacology and toxicology Maastricht UniversityMaastrichtThe Netherlands CARIM-School for Cardiovascular Diseases Maastricht UniversityMaastrichtThe Netherlands Neuroscience and Ophthalmology Institute of Inflammation and AgeingUniversity of BirminghamEdgbastonBirminghamUK Centre for Trauma Sciences Research University of BirminghamEdgbastonBirminghamUK MHeNs-School for Mental Health and Neuroscience Maastricht UniversityMaastrichtThe Netherlands Department of Neurology Maastricht University Medical CenterMaastrichtThe Netherlands

As the population ages,the burden of age-related diseases becomes ***,over 55 million people suffer from dementia worldwide,with Alzheimer’s disease being the most common ***,it is becoming clearer that underlying vascular pathology such as cerebral small vessel disease(cSVD)may be a more detrimental cause for dementia(Cuadrado-Godia et al.,2018).It is estimated that 10%-30%of the elderly population and 35%-90%of all dementia patients exhibit signs of *** term cSVD refers to pathology affecting the small vessels of the brain,which can lead to lacunar cerebral infarcts,enlarged perivascular spaces,and cortical hemorrhages(Cuadrado-Godia et al.,2018).CSVD is often associated with cognitive decline,gait problems,and dementia(Cuadrado-Godia et al.,2018).

关键词： pathology becoming white

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Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats

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Neuroscience Bulletin 2016年第6期32卷 523-530页

作者： Xiao-Fei Wang Tai-Yun Zhao Rui-Bin Su Ning Wu Jin Li State Key laboratory of toxicology and Medical Countermeasures Beijing Key Laboratory of NeuropsychopharmacologyBeijing Institute of Pharmacology and Toxicology

Abstract Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hip- pocampal extracellular glutamate level induced by nalox- one （2 mg/kg, i.p.） precipitation. Agmatine （20 mg/kg, s.c.） administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synapto- somes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agrnatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors （NMDARs） was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine pre- vented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including mod- ulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

关键词： Agmatine Opioid addiction HippocampusExtracellular glutamate NMDA receptors

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Characteristics of the traditional Liu-Wei-Di-Huang prescription reassessed in modern pharmacology

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Chinese Journal of Natural Medicines 2019年第2期17卷 103-121页

作者： CHENG Xiao-Rui QI Chun-Hui WANG Tong-Xing ZHOU Wen-Xia ZHANG Yong-Xiang Academy of Military Medical Science Institute of Pharmacology and Toxicology State Key laboratory of toxicology and Medical Countermeasures

Liu-Wei-Di-Huang(LW) is a Yin nourishing and kidney tonifying prescription in traditional Chinese medicine with promising pharmacological characteristics that can be further exploited and developed in modern medicine. We provide a comprehensive and detailed literature report on the clinical and experimental pharmacology of LW,including its quality control parameters, phytochemistry, pharmacokinetics, and toxicology. Our literature review indicates that the LW prescription possesses a unique combination of pharmacological characteristics that can be safely used for treating very different diseases. Quality control and pharmacokinetic parameters of LW are mostly based on its major bioactive phytochemical constituents. We postulate that modulating or rebalancing the neuroendocrine immunomodulation network in the body is the underlying mechanism of the multiple pharmacological activities displayed by LW.

关键词： Liu-Wei-Di-Huang Traditional Chinese medicine pharmacology Phytochemistry Pharmacokinetics toxicology

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