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Size,shape,charge and“stealthy”surface:Carrier properties affect the drug circulation time in vivo

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Asian Journal of Pharmaceutical Sciences 2021年第4期16卷 444-458页

作者： Jinwei Di Xiang Gao Yimeng Du Hui Zhang Jing Gao Aiping Zheng State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.

关键词： Drug carrier Circulation time Physical and chemical properties Macrophages Phagocytosis

TRPV4 Regulates Soman-Induced Status Epilepticus and Secondary Brain Injury via NMDA Receptor and NLRP3 Inflammasome

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Neuroscience Bulletin 2021年第7期37卷 905-920页

作者： Shuai Wang Huanhuan He Jianhai Long Xin Sui Jun Yang Guodong Lin Qian Wang Yongan Wang Yuan Luo State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and ToxicologyAcademy of Military Medical SciencesBeijing 100850China

Nerve agents are used in civil wars and terrorist attacks,posing a threat to public safety.Acute exposure to nerve agents such as soman(GD)causes serious brain damage,leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation.However,data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited.Here,we evaluated the potential effects of transient receptor vanilloid 4(TRPV4)in the treatment of soman-induced status epilepticus(SE)and secondary brain injury.We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures.Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity.TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure.Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity.The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1βand IL-18 increased in soman-exposed rat hippocampus.However,TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway.In conclusion,our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation.To our knowledge,this is the first study regarding the“dual-switch”function of TRPV4 in the treatment of soman intoxication.

关键词： Nerve agents Soman TRPV4 NMDA receptor NLRP3 inflammasome

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

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： keywords Agmatine Opioid addiction HippocampusExtracellular glutamate NMDA receptors

Efficacy evaluation and neurobiological mechanism of psychedelics based on looming model

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中国药理学与毒理学杂志 2023年第7期37卷 533-534页

作者： XIA Ke YAN Haitao SU Ruibin Beijing key laboratory of Neuropsychopharmacology State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and Toxicology Academy of Military Medical Sciences

OBJECTIVE To investigate the effect of psychedelics on innate fear behavior of mice in Looming model(LM) and its neurobiological mechanism. METHODS(1) Adult male C57BL/6J mice were randomly divided into saline group, DOM group, psilocybin group and mescaline group. The drugs of the corresponding groups were given ip injecction 5 min in advance and LM were used to test the effect of them on freezing time in shelter of mice.(2) The mice were performing ip given DOM or psilocybin following 5-HT2Areceptor antagonist M100907 ip30 min later involved looming experiments.(3) Quantified the expression of EGR1 protein in mouse brains by immunofluorescence staining, then use ibotenic acid(IBO) damaged the mouse brain regions based on the result above and performed looming experiments.(4) Specifically activate or inhibit CaMK Ⅱ, PV, VIP and SOM neurons of mice in saline or psilocybin groups respectively by chemical genetic methods and followed looming experiments. RESULTS(1) In LM, the freezing time in shelter of mice in DOM, psilocybin and mescaline groups was significantly shorter compared to the saline group(P<0.05), and the dose-effect curves of above psychedelics were U-shaped.(2) Compared with the vehicle +psilocybin/DOM groups, the freezing time in shelter of mice in M100907 + psilocybin/DOM groups was significantly prolonged(P<0.05), and there was no significant difference between the vehicle + saline group and the M100907 + psilocybin/DOM groups.(3) Psilocybin significantly increased the expression of EGR1 protein in prelimbic cortex(PrL) compared with saline, and the damage of PrL could effectively antagonized the effect of psilocybin shortening the freezing time in LM.(4) Chemicalgenetic specific inhibition of CaMK Ⅱ, PV or VIP neurons in PrL could effectively antagonize the effect of psilocybin in LM,while chemicalgenetic specific activation of CaMK Ⅱneurons could significantly shorten the freezing time of saline-treated mice. CONCLUSION Psychedelics have capability to waken the innate fear behavior like freezing

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PBPK modeling and simulation in drug research and development

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Acta Pharmaceutica Sinica B 2016年第5期6卷 430-440页

作者： Xiaomei Zhuang Chuang Lu State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Department of DMPK BiogenInc.

Physiologically based pharmacokinetic(PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data.It can also explore the effects of various physiologic parameters such as age,ethnicity,or disease status on human pharmacokinetics,as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment.PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry,and has become an integral tool in drug discovery and development.In this mini-review,the concept and methodology of PBPK modeling are briefly introduced.Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development.These case studies are from our own work and the literature for better understanding of the absorption,distribution,metabolism and excretion(ADME) of a drug candidate,and the applications to increase efficiency,reduce the need for animal studies,and perhaps to replace clinical trials.The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

关键词： PBPK PK prediction Absorption Metabolism Drug–drug interaction Special population

Role of the anterior insular cortex microcircuits in observation fear of mice

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中国药理学与毒理学杂志 2023年第7期37卷 551-552页

作者： LI Fengan FU Yuan XIAO Zhiyong SHI Tianyao ZHOU Wenxia State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Nanjing University of Chinese Medicine

OBJECTIVE Fear can be learned indirectly, but excessive transmission of fear is essential for the development of mental illness. Previous research has indicated that the anterior insular cortex(AIC) may play a crucial role in the process of fear transmission,and abnormal AIC activity is a possible mechanism underlying various affective disorders. Inhibitory neurons are crucial for maintaining local microcircuit homeostasis.With the support of novel specific neuroregulatory techniques, it is now possible to monitor and regulate different types of neurons in real-time. Therefore, investigating distinct subtypes of inhibitory neurons in the AIC that are involved in fear contagion may provide valuable insights into potential mechanisms underlying mental disorders.METHODS We established a modified observational fear(OF) model. A demonstrator(DM) mouse was placed in an acrylic cup at the center of the apparatus,and two observer(OB) mice were allowed to explore the DM mouse simultaneously from separate areas on either side. During the OF training, electric foot shocks were administered to the DM mouse and freezing, the side and corner time, and social interaction behavior were scored. Next, we characterized the activity patterns of distinct neuronal subtypes in the AIC using GCaMPbased calcium recording. Finally, we employed a Credependent optogenetic approach to selectively modulate excitatory or inhibitory neurons in the AIC, and investigated empathic fear behavior across different Cre transgenic mouse lines(CK2-Cre, PV-Cre, SOM-Cre, VIP-Cre).RESULTS During the training phase, the OB mice exhibited significantly higher levels of fear compared to the control group(which did not observe a traumatic event),as evidenced by increased freezing time, decreased interaction time, and increased corner zone time. Calcium fiber recording results suggested that CK2 neurons are involved in risk prediction, while PV and VIP neurons exert inhibitory control on this behavior. Optogenetic silencing of CK2-positive neurons in the AIC th

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The speed-limiting role in the onset of antidepressants: the re-establishment of the excitation/inhibition(E/I) function balance in the mPFC of rats

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中国药理学与毒理学杂志 2023年第7期37卷 527-528页

作者： YAN Jiaozhao YIN Yongyu LI Yunfeng Beijing Institute of Basic medical Sciences Beijing Institute of Pharmacology and toxicology State Key Laboratory of Toxicology and Medical Countermeasures Beijing Key Laboratory of Neuropsychopharmacology

OBJECTIVE There are serious hazards in depression, and the precise mechanism underlying the delayed onset of clinical antidepressants remains unclear.The purpose of this study was to investigate the regular pattern of the speed-limiting role of excitation/inhibition(E/I) function balance in the mechanism of antidepressant action. METHODS Based on the previous study, we focused on glutamatergic pyramidal neurons in the medial prefrontal cortex(mPFC) here and used its excitability to represent the establishment of a new E/I functional balance. We studied the changes in the firing activity of glutamatergic pyramidal neuron in the mPFC at different administration times for five types of antidepressants that act on different pharmacological targets and different onset times, including fluoxetine(SSRI), duloxetine(SNRI), vilazodone [serotonin 1A receptor(5-HT1A) agonist and SSRI], ketamine [N-methyl-D-aspartate(NMDA)receptor antagonist], and hypidone hydrochloride(YL-0919, new antidepressant with sigma-1 receptor agonist and SSRI). We first examined the initial onset time of activation of pyramidal neurons using multichannel electrophysiological recordings and tested the antidepressant behavioral effects using the FST. We then selected three antidepressants(fluoxetine, ketamine, and vilazodone) to explore its effects on the BDNF-mTOR pathway by Western blotting. In addition, we disrupted the E/I function balance using chemogenetics to investigate the antidepressant-like effects of YL-0919 and ketamine in the FST and TST. RESULTS We found that treatment with fluoxetine for 17 days significantly increased the firing activity of pyramidal neurons and decreased the immobility duration in the FST. Similarly, it took duloxetine for 10 d, vilazodone for 4 d, YL-0919 for 3 d and ketamine for 24 h, to exert such effects. Meanwhile, Western blotting results suggested that the expression of BDNF and phosphorylation of mTOR in the mPFC significantly increased. However, haloperidol, a classic antipsychotic(without antidepressant ef

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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

Synthesis and evaluation of peptide-fentanyl analogue conjugates as dualμ/δ-opioid receptor agonists for the treatment of pain

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Chinese Chemical Letters 2022年第8期33卷 4107-4110页

作者： Jing Li Tao Zhang Jialin Sun Fengxia Ren Hongxin Jia Zixing Yu Jingchao Cheng Weiguo Shi State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China School of Chemical Engineering and Technology Tianjin UniversityTianjin 300350China

Novel peptide-fentanyl analogue conjugates were synthesized by the covalent coupling of carfentanyl derivatives to the C-terminus or N-terminus of the conformationally constrained dermorphin tetrapeptide BVD03 via a chemical linker.The carfentanyl-related analogues displayed distinct binding and functional activities atμ/δopioid receptors(MOR/DOR)and antinociceptive effects when conjugated to the peptide.The most potent compound,SW-LJ-11,displayed mixed MOR/DOR agonist properties in the low nanomolar range and significant analgesic efficacy in vivo in four classic mouse models of pain.Interestingly,SW-LJ-11 did not exhibit any physical dependence or respiratory depression,in contrast to an equipotent analgesic dose of morphine or BVD03,indicating that the use of opioid peptide-fentanyl analogue conjugates as dual MOR/DOR agonists may be a promising strategy for obtaining safer opioids.

关键词： Peptide-small molecule conjugates Dual MOR/DOR agonists Lead compound Analgesics Physical dependence