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Dissection of voltage-gated sodium channels in developing cochlear sensory epithelia

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Protein & Cell 2015年第6期6卷 458-462页

作者： You Zhou Fang-Hao Fang Zhi-Rui Liu Yong-Hua Ji Laboratory of neuropharmacology and Neurotoxicology ShanghaiUniversity Shanghai 200436 China

Dear Editor Hair cells （HCs） clustered produce spontaneous spike n cochlear sensory epithelia and evoked action potentials during the developmental stage of auditory, which rely on many ion channels, such as Ca2＋ channels, K＋ channels and Na＋ channels （Housley et al., 2006; Marcotti et al., 2003）. As the dominant molecule acting in action potentials in most of excitable cells, Na＋ channels （VGSCs） were deemed to be indispensable in the spontaneous and evoked action po- tentials of HCs （Marcotti et al., 2003）.

关键词： voltage-gated sodium developing cochlear sensory epithelia

Novel Cryo-EM structures of the D1 dopamine receptor unlock its therapeutic potential

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Signal Transduction and Targeted Therapy 2021年第6期6卷 1634-1635页

作者： David R.Sibley Kathryn D.Luderman RBenjamin Free Lei Shi Molecular neuropharmacology section National Institute of Neurological Disorders and StrokeIntramural Research ProgramNational Institutes of HealthBethesdaMDUSA Computational Chemistry and Molecular Biophysics section Molecular Targets and Medications Discovery BranchNational Institute on Drug AbuseIntramural Research ProgramNational Institutes of HealthBaltimoreMDUSA

Three recent articles published in Cell1,2 and Cell Research3 have reported multiple cryo-electron microscopy(cryo-EM)structures of the D1 dopamine receptor(DRD1)bound to either dopamine,various DRD1 agonists,or a positive allosteric modulator(PAM),while in complex with the active heterotrimeric Gs *** studies describe for the first time active-state structures of the DRD1,an exciting advancement in the field that will allow for a better understanding of selective agonist binding,DRD1 activation,G protein selectivity,and the provision of multiple templates to facilitate future drug design and discovery for this important therapeutic target.

关键词： selectivity activation potential

Role of inflammation in the pathogenesis of Parkinson＇s disease： models, mechanisms, and therapeutic interventions

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中国药理通讯 2006年第4期23卷 15-16页

作者： Hong Jau - Shyong neuropharmacology section Lab. of Pharmacology ＆ Chemistry NIEHS/NIH Research Triangle Park NC USA

Role of inflammation in the pathogenesis of Parkinson's disease:models,mechanisms,and therapeutic interventions

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Role of inflammation in the pathogenesis of Parkinson's dise...

Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotectionJrepair in Parkinson＇s disease

第十二届全国神经精神药理学学术交流会

作者： Hong Jau-Shyong neuropharmacology section Lab.of Pharmacology & Chemistry NIEHS/NIHResearch Triangle ParkNCUSA

The theme of this talk is first to describe newly created rodent Parkinsons disease (PD) models that mimic the progressive disease development in PD patients. With these models, we have elucidated the novel mechanisms of microglial activation that lead to inflammation - mediated neurodegeneration. These insights have then led us to develop innovative anti - inflammatory therapy for PD 1. Creation of inflammation -mediated rodent PD models

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来源： cnki会议评论

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Journal of Molecular Cell Biology 2014年第1期8卷 13-26页

作者： Francesca L'Episcopo Cataldo Tirolo Salvo Caniglia Nuccio Testa Maria Concetta Moral~ Maria Francesca Serapide: Stefano Pluchino Bianca Marchetti OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS) Neuropharmacology Section Via Conte Ruggero 73 94018 Troina Italy Department of Physiolocal Sciences Medical School University of Catania Viale A. Doria 6 95125 Catania Italy Department of Clinical Neurosciences John van Geest Centre for Brain Repair and Wellcome Trust-Medical Research Counci~ Stem Celt Institute University ofCambridge Cambridge CB20PY UK Department of Clinical and Molecular Biomedicine Pharmacology Section Medical School University of Catania Viale A. Doria 6 95125 Catania Italy

During the past three decades, the Wingless-type MMTV integration site （Wnt） signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson＇s disease （PD）, a common neurodegenerative disorder characterized by the pro- gressive loss of midbrain dopaminergic （mDA） neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/β-catenin signaling in mDA neurons and subventricular zone （SVZ） neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/β-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in devetoping therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.

关键词： Wnt/β-catenin signaling Parkinson's disease neuroinflammation dopaminergic neurons neurogenesis neurodegeneration neuroprotection

Clues from a missense mutation of the adenosine A1 receptor gene associated with early-onset Parkinson’s disease

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Neural Regeneration Research 2023年第10期18卷 2204-2205页

作者： Sergi Ferré Leonardo Pardo Francisco Ciruela Integrative Neurobiology section National Institute on Drug AbuseIntramural Research ProgramNational Institutes of HealthBaltimoreMDUSA Laboratory of Computational Medicine Biostatistics UnitFaculty of MedicineUniversitat Autònoma BarcelonaBellaterraBarcelonaSpain Pharmacology Unit Department of Pathology and Experimental TherapeuticsSchool of Medicine and Health SciencesInstitute of NeurosciencesUniversity of Barcelona.Neuropharmacology&Pain GroupNeuroscience ProgramBellvitge Institute for Biomedical ResearchL’Hospitalet de LlobregatSpain

Parkinson’s disease (P D) is a com plex neu rodegenerative disorder for which ra re and common genetic variants contribute to disease risk,onset,and *** genetic contribution to PD can be classified mainly in,first,rare DNA variants that are highly penetrant and therefore causal,which are typically associated with monogenic PD;and second,more common risk polymorphic variants,which individually exert a small increase in the risk of the disease,which are usually identified in the most prevalent and apparently sporadic PD (Blauwendraat et al.,2020).

关键词： typically degenerative

A study of the effects of 3,5-diiodo-L-thyronine in the tail suspension and forced swim models of depression

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Translational Neuroscience and Clinics 2016年第2期2卷 96-107页

作者： Nataliia Markova Anton Chernopiatko Aslan Kubatiev Sergey Bachurin Harry M.W.Steinbusch Tatyana Strekalova Laboratory of Biomolecular screening Institute of Physiologically Active Compounds Russian Academy of Sciences Laboratory of Cognitive dysfunctions Federal State Budgetary Scientific Institution "Institute of General Pathology and Pathophysiology" Department of Neuroscience School for Mental Health and Neuroscience Maastricht University section of neuropharmacology Research

Objectives: Recent findings have further highlighted the role of the thyroid system in the pathophysiology of depression and revealed new physiologically relevant elements of the thyroid system. Our previous study showed an antidepressant-like effect of 3,5-diiodo-L-thyronine(T2), which was previously considered to be a physiologically inactive molecule, in mice. Here, we aimed to investigate the antidepressant-like effects of T2 further. Methods: We studied the effects of bolus injections of T2 to C57Bl6 J mice at doses of 0.25 or 0.75 mg/kg with the tail suspension and forced swim models. The effects of the higher dose were investigated in CD1 mice in the forced swim test. Potential behavioral effects of these treatments were also studied using the novel cage and dark-light box ***: A reduction of depressive-like behavior was found in mice treated with 0.75 mg/kg of T2 in the tail suspension test, but not in the forced swim test. Locomotion and anxiety variables were unaltered following treatment with T2. There were no significant changes after bolus administration of 0.25 mg/kg T2 in either test for depressive-like behavior. Thus, bolus injection of T2 at the dose 0.75 mg/kg can induce antidepressant-like effects without affecting other behaviors. Conclusions: A discrepant result in the forced swim test may be due to its different sensitivity to T2 compared with the tail suspension paradigm. Furthermore, the development of procedural modifications of this model can be useful in its application in pre-clinical studies.

关键词： forced swim test tail suspension test depression animal models thyroid hormones

Identification and optimization of a potent and highly selective D3 dopamine receptor agonist

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中国药理学与毒理学杂志 2017年第10期31卷 950-951页

作者： Amy E MORITZ R Benjamin FREE Warren WEINER Muzna BACHANI Trevor DOYLE Noel SOUTHALL Marc FERRER Jonathan A JAVITCH Joseph STEINER Ara ABRAMYAN Lei SHI Jeffrey AUBé Kevin FRANKOWSKI David R SIBLEY Molecular neuropharmacology section National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 University of North Carolina Chapel Hill NC27599 Neurotherapeutic Development Unit National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 National Center for Advancing Translational Sciences Rockville MD 20892 Columbia University New York NY 10032 Computational Chemistry and Molecular Biophysics Unit Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse National Institutes of Health Baltimore MD 21224

OBJECTIVE Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric *** available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays *** lab employed high throughput screening paradigms to discover highly selective modulators for the *** The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the *** and counter-screens assessed selectivity and mechanisms of *** identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining *** lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BRET)-based β-arrestin recruitment and G-protein activation assays as well as p-ERK *** neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell *** ML417 displays potent,DRD3-selective agonist activity in multiple functional *** and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other ***417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L^(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell *** We have discovered and characterized ML417,a potent and highly selective DRD3 *** compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.

关键词： Dopamine receptor high throughput screening subtype selectivity neuroprotection

Local Peripheral Effects of <i>β</i>-Caryophyllene through CB<sub>2</sub>Receptors in Neuropathic Pain in Mice

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Pharmacology & Pharmacy 2012年第4期3卷 397-403页

作者： Hikari Kuwahata Soh Katsuyama Takaaki Komatsu Hitoshi Nakamura Maria Tiziana Corasaniti Giacinto Bagetta Shinobu Sakurada Tsukasa Sakurada Kazuo Takahama Department of Clinical Pharmaceutics Tohoku Pharmaceutical University Sendai Japan Department of Environmental and Molecular Health and Sciences Graduated School of Pharmaceutical Sciences Kumamoto University Kumamoto Japan Department of Pharmacobiological Sciences University of Magna Gracia of Catanzaro Catanzaro Italy Department of Pharmacobiology and University Consortium for Adaptive Disorders and Headach (UCADH) Section of Neuropharmacology of Normal and Pathological Neuronal Plasticity University of Calabria Arcavacata di Rende Italy Department of Pharmacology Daiichi College of Pharmaceutical Sciences Fukuoka Japan Department of Physiology and Anatomy Tohoku Pharmaceutical University Sendai Japan.

β-Caryophyllene (BCP) is known as a common constitute of the essential oils of numerous food plants and primary component in Cannabis. In this study, we investigated the effect of local intraplantar (***.) injection of BCP on mechanical hypersensitivity induced by partial sciatic nerve ligation (PSNL) in mice. Relative to sham operation controls, mice with the PSNL displayed a maximum level of hyperresponsiveness to von Frey metallic filament on post-operative day 7. PSNL-induced allodynia was seen in the ipsilateral side of nerve ligation, but not in the contralateral side. The ***. injection of BCP into the ipsilateral hindpaw to PSNL attenuated mechanical allodynia in a dose-dependent manner. BCP injection into the contralateral hindpaw did not produce anti-allodynic effects, suggesting a local peripheral anti-allodynic effect of BCP. Anti-allodynic effects induced by ***. injection of BCP were prevented by pretreatment with the cannabinoid (CB2) receptor antagonist AM630, but not by the CB1 receptor antagonist AM251. These data suggest that ***. injection of BCP could produce anti-allodynia by activating peripheral CB2 receptors, but not CB1 receptors in a mouse model of neuropathic pain. Taken together, these results suggest that peripheral CB2 receptors may contribute to the effectiveness of BCP in the treatment of neuropathic pain disorders.

关键词： β-Caryophyllene (BCP) Neuropathic Pain Partial Sciatic Nerve Ligation (PSNL) Peripheral Cannabinoid (CB) Receptor