Oxidative Medicine and Cellular Longevity
·
2015
·
IF 3.516
Xinhua Zhou,Longjun Zhu,Liang Wang,Baojian Guo,Gaoxiao Zhang,Yewei Sun,Zaijun Zhang,Simon Ming-Yuen Lee,Pei Yu,Yuqiang Wang
Edaravone (EDA) is clinically used for treatment of acute ischemic stroke in Japan and China due to its potent free radical-scavenging effect. However, it has yet to be determined whether EDA can attenuate iodoacetic acid- (IAA-) induced neuronal death in vitro. In the present study, we investigated the effect of EDA on damage of IAA-induced primary cerebellar granule neurons (CGNs) and its possible underlying mechanisms. We found that EDA attenuated IAA-induced cell injury in CGNs. Moreover, EDA significantly reduced intracellular reactive oxidative stress production, loss of mitochondrial membrane potential, and caspase 3 activity induced by IAA. Taken together, EDA protected CGNs against IAA-induced neuronal damage, which may be attributed to its antiapoptotic and antioxidative activities.
研究领域:
神经科学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Yi Zhou,Fengjiao Chen,Yutao Lin,Qiyao Wang,Yirui Hong,Sifang Zhao,Kangyang Gao,Hongze Liang,Wei Cui,Lingling Zhao
Ischemic stroke is a leading cause of mortality and disability, with ischemia-reperfusion injury exacerbating neuronal damage and neuroinflammation due to pathologically activated reactive oxygen species (ROS) production in the ischemic penumbra. Edaravone, a free radical scavenger, is approved for the clinical treatment of ischemic stroke. However, edaravone directly decreases ROS even at low concentrations, which may inhibit the physiological effects of ROS and largely limit the clinical application of edaravone. To overcome this challenge, a ROS-response nanoparticle system, edaravone-loaded DEX-CDIPBE (DEX-CDIPBE-ED), is developed for the selectively releasing edaravone in the ischemic penumbra during reperfusion, mitigating oxidative stress while minimizing off-target effects. DEX-CDIPBE-ED produces potent antioxidant and neuroprotective effects in neuronal cells mimicking ischemic and/or reperfusion phases of ischemic stroke. DEX-CDIPBE-ED further prevents behavioral deficits, reduces oxidative stress, and inhibites neuroinflammation with a higher potency than edaravone in the ischemic penumbra in middle cerebral artery occlusion/reperfusion (MCAO/R)-treated rats. These findings highlight the potential of DEX-CDIPBE-ED as a pathological activated antioxidative therapy for ischemic stroke, offering enhanced neuroprotection and reduced systemic toxicity.
研究领域:
纳米医学
·
神经病学
·
药学
·
生物医学工程
·
卒中研究
·
自由基生物学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Wang Zhenhua,Li Yuan,Wang Zhixu,Liao Yuhui,Ye Qingqing,Tang Shilong,Wei Ting,Xiao Pengyu,Huang Juan,Lu Weitian
Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood–brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH.
研究领域:
神经科学
·
药理学
·
病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2020
·Vol. 35
·期 2
·373-383
·
IF 2.726
Zhou Yiying,Wu Xiang,Ye Luying,Bai Yujing,Zhang Hui,Xuan Zhenquan,Feng Yi,Zhang Panpan,Chen Yi,Yan Yushan,Zhu Binbin,Cui Wei
Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3β (pSer9-GSK3β) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD.
研究领域:
药理学
·
神经科学
·
麻醉学
·
老年医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
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
·
神经科学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
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
·
药物代谢动力学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Junpeng Xu,Peng Dai,Chen Zhang,Na Dong,Caiyan Li,Chonghui Tang,Zhihao Jin,Shih-Ho Lin,Luyang Ye,Tianmiao Sun,Yukai Jin,Fenzan Wu,Lihua Luo,Ping Wu,Shengcun Li,Xiaokun Li,Shan-hui Hsu,Dawei Jiang,Zhouguang Wang
Parkinson's disease (PD) is one of the most common long-term neurodegenerative disorders, with multiple comorbid psychiatric and behavioral abnormalities. The combination of clinical drugs targeting different symptoms with smart hydrogels to achieve asynchronous releases is highly translational and challenging. Here, a hierarchical bioactive hydrogel (OACDP) is designed with asynchronous release based on PD pathology. The hydrogel with caffeic acid-grafted polymer main chain is crosslinked using a micellar nanocrosslinker, with sufficient modulus (≈167 Pa), antioxidant activity (> 50%), injectability (30-gauge syringe needle), and shape-adaptability. Each of the three drugs (caffeic acid, fibroblast growth factor 21, and Edaravone) is separately engaged in different micro- or nanostructures of the hydrogel and released with asynchronous kinetics of first-order release, zero-order release, or matching Korsmeyer–Peppas model. The triple-loaded hydrogel is injected into the brains of PD rats, showing behavioral improvement. Histological analysis revealed that the triple-loaded OACDP hydrogels are effective in achieving immediate neuroprotection, i.e., reduction the loss of tyrosine hydroxylase in substantia nigra compacta and striatum (retained ≈10-fold versus control), decreasing oxidative stress, reducing astrocyte and microglia activation, and stimulating the AMPK/PGC-1α axis to regulate the mitochondrial function, providing a multi-dimensional PD therapy. The asynchronous release of OACDP hydrogel provides a new conception for PD treatment and other neurodegenerative diseases.
研究领域:
神经科学
·
药学
·
生物材料
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2025
·Vol. 40
·期 5
·1-14
·
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
·
神经科学
·
生物医学工程
✓ 已验证
产品关联
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
·
药剂学
·
放射生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
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
·
药理学
·
分子生物学
·
肿瘤学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
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
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2018
·
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
·
药物研发
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
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