Drug Design Development and Therapy
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2018
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IF 2.935
Ankit Parikh,Krishna Kathawala,Jintao Li,Chi Chen,Zhengnan Shan,Xia Cao,Yan-Jiang Wang,Sanjay Garg,Xin-Fu Zhou
Background Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment. Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Aβ), tau phosphorylation, oxidative stress, and neuroinflammation. To enable its oral use, novel edaravone formulation (NEF) was previously developed. The aim of the present investigation was to evaluate safety and efficacy of NEF by using in vitro/in vivo disease model.Materials and methods In vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H2O2 and Aβ42 oligomer, and cellular uptake on SH-SY5Y695 amyloid-β precursor protein (APP) human neuroblastoma cell line. For in vivo safety and efficacy assessment, totally seven groups of APP/PS1 (five treatment groups, one each as a basal and sham control) and one group of C57BL/6 mice as a positive control for behavior tests were used. Three groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 µmol/kg, whereas one group was supplied with each Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF of 414 µmol/kg dose of EDR). Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze). For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period. Moreover, biochemical, hematological, and morphological parameters were determined.Results Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line. Furthermore, it showed nontoxicity of NEF up to 414 µM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner.Conclusion Our results indicate that oral delivery of NEF holds a promise as a safe and effective therapeutic agent for AD.
研究领域:
神经科学
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药物研发
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生物化学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2018
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IF 3.466
Qingguo Li,Wenhai Huang,Juan Yang,Jianfeng Wang,Min Hu,Jianmei Mo,Yuzhu Cheng,Zhanlun Ou,Zhenyu Jason Zhang,Shixia Guan
Absorption mechanism of edaravone (EDR) was studied to inform the preparation of gastric retention pellets with the aim to enhance its oral bioavailability. Three different models, namely, Caco-2 cells model, in situ single-pass intestinal perfusion model, and everted gut sac model in rats, were employed to characterize the gastrointestinal absorption kinetics of EDR. And it was found that passive transfer plays a vital role for the transport of EDR, and acidic condition is preferable for EDR absorption. Further, it is likely that EDR acts as a substrate for P-glycoprotein and multidrug-resistance protein. And hence, an orally available gastric retention pellets were developed accordingly. Pharmacokinetic experiments performed with rats and beagles showed that the absolute bioavailability of EDR solution and enteric-coated pellets following oral administration were 33.85% ± 2.45% and 7.64% ± 1.03%, indicating that stomach absorption is better than intestinal adsorption for EDR. However, the gastric retention pellets resulted in 68.96% absolute bioavailability and about 200% relative bioavailability in comparison to EDR solution, which was 9 times that of enteric-coated pellets. The present work demonstrates that gastric retention pellets has excellent potential as oral administration route for EDR.
研究领域:
药剂学
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药物代谢动力学
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生物医学工程
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DOI
PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 11
·2281
·
IF 6.525
Qian Li,Yizhi Zhang,Jinglu Hu,Bochuan Yuan,Pengcheng Zhang,Yaxin Wang,Xu Jin,Lina Du,Yiguang Jin
Radiation-induced brain injury (RBI) is a common neurological disease caused by ionizing radiation (IR). Edaravone (EDA) is a free radical scavenger, has the potential to treat RBI. EDA loaded temperature-sensitive gels (TSGs) were prepared for subcutaneous injection to improve inconvenient administration of intravenous infusion. RBI mice model was established by irradiation of60Co γ-ray on head. EDA TSGs could improve spontaneous behavior, learning and memory and anxiety of RBI mice by behavior tests, including the open field test, the novel object recognition test, the elevated plus maze test and the fear conditioning test. The therapeutic effects were enhanced with the assistance of ultrasound. Alleviative pathological changes, decreased the expression of Molondialdehyde (MDA) and Interleukin-6 (IL-6) in the hippocampus of brain, indicated reduced oxidative stress and inflammatory response with the treatment of EDA TSGs and ultrasound. Moreover, ultrasound was superior to the use of EDA TSGs. Safe and effective EDA TSGs were prepared for RBI, and the feasibility of brain-targeted drug delivery enhanced by ultrasound was preliminarily demonstrated in this study.Keywords:radiation-induced brain injury;temperature-sensitive gels;edaravone;ultrasound;behavior tests
研究领域:
神经学
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药剂学
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放射生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2016
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IF 3.994
Ankit Parikh,Krishna Kathawala,Chun Chuan Tan,Sanjay Garg,Xin-Fu Zhou
Edaravone (EDR), a strong free radical scavenger, is known for its promising therapeutic potential in oxidative stress (OS) associated diseases, however poor oral bioavailability is the major obstacle in its potential use. Oral liquid dosage form is the most preferred delivery method in paediatric, geriatric and specialised therapies. The present research discusses the development of a Novel Oral Delivery System (NODS) of EDR to enhance oral bioavailability. From preformulation study, solubility, and stability were identified as key challenges and the requirement of an acidic environment and protection against oxidation were found to be critical. The NODS made up of a mixture of Labrasol (LBS) and an acidic aqueous system, was optimized on the basis of solubility and stability study. It can be stored ≤40 °C for at least one month. Drug release from NODS was slow, sustained and significantly better as compared to suspension. The significant reduction in metabolism and improvement in permeability across the small intestine were observed with NODS compared to free EDR. The oral pharmacokinetic study showed 571% relative bioavailability with NODS compared to EDR suspension. From the results obtained, NODS is a promising candidate for use in OS associated diseases.
研究领域:
药剂学
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药物化学
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生物医学
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DOI
PubMed
高影响因子
BRAIN RESEARCH
·
2024
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IF 2.7
Qiang Tian,Jin Li,Rongbin Lv,Guangan Zhou,Xinyun Liu,Yanfen Wang,Baoliang Sun,Zhangyong Xia
Background Ischemic stroke has become one of the leading causes of death and disability worldwide in individuals aged 60 and above. However, currently available drugs show limited efficacy. Therefore, research to find more effective and safer therapeutic strategies is an urgent requirement for the treatment of cerebral ischemia reperfusion injury (CIRI). Methods First, the free radical scavenger Edaravone and a Ginseng active ingredient were coloaded into liposomes (aER@Lip), followed by optimization and characterization. Pluronic F127 and F68 at different concentrations were mixed and stored at 4 °C for more than 24 h to obtain gel solutions. Then, aER@Lip was added to the gel solutions to prepare the drug-loaded in situ gel, termed aER@Lip-TSG. Results In vitro experiments showed that aER@Lip-TSG was taken up by cells and had a good protective effect on oxygen-glucose deprivation/reoxygenation in pheochromocytoma 12 cells. In a rat CIRI model, aER@Lip-TSG delivered by intranasal administration not only decreased the apoptosis in brain tissue induced by CIRI, but also decreased the resultant inflammatory response. Moreover, the results suggested that aER@Lip-TSG had good biosafety. Conclusion This delivery system provides a promising multi-factor combination, synergistic effects, sustained-release capabilities, and is a non-invasive treatment strategy for CIRI. It thus meets the urgent need for effective treatments of central nervous system diseases.
研究领域:
药理学
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神经科学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2023
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IF 5.8
Chuanhui Teng,Wei Lv,Yuqin Chen,Linfeng Liu,Jiaqing Yin,Shengnan Li,Zhiyi Min,Qi Zhang,Weichong He,Kunfang Ma,Xinrui Li,Xiang Cao,Hongliang Xin
Since ischemic stroke occurs by a combination of multiple mechanisms, therapies that modulate multiple mechanisms are required for its treatment. The combination of edaravone (EDA) and borneol can significantly ameliorate the symptoms of neurological deficits in cerebral ischemia–reperfusion model in rats. In this study, the solubility of borneol and edaravone was improved by hydroxypropyl-β-cyclodextrin and PEG 400 . Furthermore, a nasal temperature-sensitive hydrogel containing both edaravone and borneol inclusion complex (EDA-BP TSG S ) was developed to overcome the obstacles of ischemic stroke treatment including the obstruction of the blood–brain barrier (BBB) and the unavailability and untimely of intravenous injection. The effectiveness of the thermosensitive hydrogel was investigated in transient middle cerebral artery occlusion/reperfusion model rats (MCAO/R). The results showed that EDA-BP TSG S could significantly alleviate the symptoms of neurological deficits and decrease the cerebral infarct area and the degree of brain damage. In summary, nasal EDA-BP TSG S is a secure and effective brain-targeting formulation that may provide a viable option for the clinical prophylaxis and treatment of ischemic stroke.
研究领域:
药剂学
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神经科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2022
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IF 5.168
Rongrong Zhao,Huajun Zhao,Quanjuan Guo,Yongliang Mu,Jian Zhang,Yuhang Su,Qiuju Han
Edaravone (EDA), a strong novel free radical scavenger, have been demonstrated to exert neurovascular protective effects clinically. Furthermore, EDA can suppress the lung injury, pulmonary fibrosis and skin fibrosis , while the precise effects and mechanisms of EDA on liver injury and fibrosis remain unclear. The effects of EDA on the Thioacetamide (TAA)-induced liver fibrosis were evaluated by sirius red staining, α-SMA immunohistochemistry. The percentages of immune cell subsets were analyzed by flow cytometry. Immunofluorescence assay was performed to identify the fibrotic properties of hepatic stellate cells (HSCs). Western blot and qPCR were used to detect the levels of liver fibrosis-related molecules and IL-1β. EDA displayed a hepatic protective role in TAA-induced chronic liver fibrosis via inhibiting monocyte/macrophages recruitment and IL-1β production of macrophages. Mechanically, EDA inhibited of NF-κB signal pathway and reactive oxygen species (ROS) production in macrophages. Moreover, EDA treatment indirectly suppressed the activation of HSCs by decreasing the IL-1β secretion of macrophages. Together, EDA protects against TAA-induced liver fibrosis via decreasing the IL-1β production of macrophages, thereby providing a feasible solution for clinical treatment of liver fibrosis.
研究领域:
药理学
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肝病学
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免疫学
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产品关联
DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
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2025
·Vol. 40
·期 5
·1-14
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IF 3.5
Zhao Hexiang,Yang Ping,Zhang Mou,Zheng Wenshu,Qi Renli,Zhu Xiaofeng,Li Jinghui,Li Shipeng
Reperfusion, while essential for restoring blood supply, paradoxically exacerbates neuronal damage through cerebral ischemia-reperfusion injury (CIRI). This study aimed to develop a reactive oxygen species (ROS)-responsive drug delivery system (DDS) loaded with edaravone (EDA) to enhance targeted therapy for CIRI. The stimuli-responsive DDS was synthesized using dextran (DEX) as the biocompatible carrier and benzeneboronic acid pinacol ester (BAPE) as the ROS-sensitive moiety. The physicochemical characteristics of the DEX-BAPE/EDA (DB/EDA) micelles were systematically evaluated. In vitro studies assessed the anti-inflammatory, antioxidant, and anti-apoptotic effects of DB/EDA. Moreover, the neuroprotective efficacy of DB/EDA in vivo was analyzed via behavioral tests, infarct volume measurement, ELISA assays of inflammatory cytokines and OS markers, and Western blot analysis of Nrf2-related pathways. Pharmacokinetics and biosafety were analyzed through plasma profiling and H&E staining. DB/EDA exhibited high stability, efficient drug encapsulation, and ROS-responsive drug release. Cellular uptake studies confirmed enhanced internalization of DB/EDA micelles in BV2 cells. In the oxygen-glucose deprivation/reoxygenation (OGD/R) model, DB/EDA significantly suppressed TNF-α, IL-1β, IL-6, and MDA, restored SOD levels, and attenuated apoptosis. In the middle cerebral artery occlusion/reperfusion (MCAO/R) mice, DB/EDA administration effectively improves cognition and mitigates neuronal damage. Mechanistically, DB/EDA activated the Nrf2/HO-1 pathway, amplifying antioxidant and anti-inflammatory responses. Pharmacokinetic analysis revealed prolonged circulation and increased brain accumulation, and histopathological analysis demonstrated the safety profile of DB/EDA. The ROS-responsive DB/EDA nano-micelles provided targeted EDA delivery to ischemic brain regions, alleviating CIRI via Nrf2 activation, suggesting that DB/EDA is a promising strategy for CIRI treatment. Graphical abstract
研究领域:
药剂学
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神经科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Ping Liu,Jiantao Jia,Yinliang Lu,Hanmin Tang,Chengyi Gao,Suxia Han
Cognitive impairment is a common side effect of docetaxel (DTX)-based chemotherapy. The novel neuroprotective agent edaravone dexborneol (ED) was found to alleviate the adverse phenotype caused by DTX. However, the underlying mechanism remains unexplored. By analyzing mRNA-sequencing data, we noticed that the expression of S100 calcium-binding protein A11 (S100A11), a protector of the nervous system, was decreased in DTX-treated rats with cognitive damage, but ED administration reversed the trend. Therefore, we speculated that S100A11 might be involved in the protective effects of ED on DTX-induced cognitive impairment. Sprague-Dawley rats were intraperitoneally injected with DTX to induce cognitive impairment, followed by intraperitoneal injection of ED after DTX induction. The results showed that ED treatment mitigated cognitive impairment caused by DTX. Next, adenoviruses carrying sequences encoding S100A11 were given to rats receiving DTX treatment. S100A11 overexpression alleviated cognitive dysfunction of DTX-treated rats, as evidenced by the decreased escape latency and swimming distance, and the increased number of platform crossings. Mechanically, S100A11 overexpression inhibited neuronal apoptosis by inactivating the MAPK signaling pathway. Further rescue experiments showed that S100A11 knockdown reversed the defensive role of ED in DTX-induced neuronal damage. In conclusion, ED ameliorates cognitive dysfunction caused by DTX by upregulating the S100A11 expression and subsequently inactivating the MAPK signaling pathway.
研究领域:
神经科学
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药理学
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分子生物学
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肿瘤学
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生物化学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
·
IF 7.5
Bo Xu,Jiaqi Fang,Jianguang Wang,Xuehan Jin,Shengfu Liu,Kaihang Song,Ping Wang,Junjian Liu,Shuhao Liu
The disruption of the blood spinal cord barrier (BSCB) after spinal cord injury (SCI) can trigger secondary tissue damage. Edaravone is likely to protect the BSCB as a free radical scavenger, whereas it has been rarely reported thus far. In this study, the protective effect of edaravone was investigated with the use of compression spinal cord injured rats and human brain microvascular endothelial cells (HBMECs) injury. As indicated by the result of this study, edaravone treatment facilitated functional recovery after rats were subjected to SCI, ameliorated the vascular damage, and up-regulated the expression of BSCB-associated proteins. In vitro results, edaravone improved HBMECs viability, restored intercellular junctions, and promoted cellular angiogenic activities. It is noteworthy that autophagy was activated and RIP1/RIP3/MLKL phosphorylation was notably up-regulated. However, edaravone treatment exhibited the capability of mitigating above-mentioned tendency in vivo and in vitro. Moreover, rapamycin (Rapa) treatment deteriorated the protective effect of edaravone while aggravating the phosphorylation of RIP1/RIP3/MLKL expression. In the model of necrotic activator-induced HBMECs, autophagic expression was increased, whereas edaravone prevented autophagy and phosphorylation of RIP1/RIP3/MLKL. In general, our results suggested that edaravone is capable of reducing the destruction of BSCB and promoting functional recovery after SCI. The possible underlying mechanism is that edaravone is capable of protecting angiogenic activity and improving autophagy and the phosphorylation of RIP1/RIP3/MLKL, as well as their mutual deterioration. Accordingly, edaravone can be a favorable option for the treatment of SCI.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2025
·
IF 3.6
Shui Guan,Chang Sun,Chuzhou Wen,Bing Yao,Jianqiang Xu,Changkai Sun
Cerebrospinal fluid (CSF) leakage caused by accidents or diseases resulting from traumatic brain injury, inflammation, tumor erosion and surgery can lead to many complications. In this study, a multifunctional composite double-layer hydrogel was designed by simulating the structure of native dura mater, which was composed of polyacrylic acid (PAA), polyethyleneimine (PEI), sodium alginate (SA), β-cyclodextrin (β-CD) and edaravone (Ed). The PAA/PEI layer had strong wet adhesion characteristics, while the PEI/SA@β-CD/Ed layer exhibited significant antioxidant, drug release and biocompatibility properties. By controlling the concentration of Ca2+, the gelation time can be adjusted rapidly within 95–215 s. Specifically, the final PAA/PEI/SA@β-CD/Ed composite hydrogel exhibited a porous network structure with high porosity and low swelling rate, improved tensile strength, sufficient biodegradability, favourable adhesion performance, enhanced DPPH and ABTS radicals scavenging abilities, and sustained Ed release capacity. In addition, the resulting hydrogel also showed excellent biocompatibility and protective effect on H2O2-induced oxidative damage in SH-SY5Y cells. These results preliminarily suggested that the PAA/PEI/SA@β-CD/Ed composite hydrogel would appear to be a promising candidate for dural repair.
研究领域:
生物材料学
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神经科学
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药剂学
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产品关联
DOI
PubMed
高影响因子
Anatomical Record-Advances in Integrative Anatomy and Evolutionary Biology
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2023
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IF 2
Guanghong Shen,Chengjian Lou,Qunfeng Li,Bingxin Zhao,Yuhuan Luo,Fei Wu,Dian Jiao,Marong Fang,Yu Geng
Inflammatory injury following ischemia-reperfusion (I/R) severely limits the efficacy of stroke treatment. Edaravone dexborneol (C.EDA) has been shown to reduce inflammation following a cerebral hemorrhage. However, the precise anti-inflammatory mechanism of C.EDA is unknown. In this study, we investigated whether C.EDA provides neuroprotection after I/R in rats, as well as the potential mechanisms involved. A middle cerebral artery occlusion/reperfusion (I/R) model was created using Sprague-Dawley rats. The blood flow of the central cerebral artery was monitored by a laser speckle imaging system. The neurological score was used to assess behavioral improvement. Cerebral infarction volume was measured by TTC staining. And the integrity of the blood–brain barrier was detected by Evan's blue staining. The expression of the nuclear factor kappa-B (NF-κB)/ the NOD-like receptor protein (NLRP3) inflammasome signal pathway and microglia polarization were detected by immunofluorescence and Western blotting. The cerebral blood flow ratio indicates that the cerebral I/R model was successfully established. After reperfusion for 72 h, the improvement of neurological scores, infarct volume reduction, and integrity of the blood–brain barrier was observed in I/R rats with C.EDA treatment. Meanwhile, the immunofluorescence result showed that the expression of iNOS, NLRP3, and NF-κB protein was decreased and the level of Arg1 was increased. Western blot analysis showed that the expression of NF-κB/NLRP3 signal pathway-related protein was decreased. In conclusion, this study indicates that C.EDA alleviates I/R injury by blocking the activation of the NLRP3 inflammasome and regulating the polarization of M1/M2 microglia via the NF-κB signal pathway.
研究领域:
神经科学
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药理学
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炎症
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神经保护
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）