EXPERIMENTAL NEUROLOGY
·
2020
·
IF 4.691
Xing Li,Jiajia Zhu,Kewei Liu,Yafang Hu,Kaibin Huang,Suyue Pan
Blood brain barrier (BBB) hyperpermeability and brain edema contribute to increased seizure susceptibility and brain injury in status epilepticus (SE). The endothelial glycocalyx is the coating on luminal side of the endothelium and can be considered as the first barrier of BBB. Currently, little is known about the effects of endothelial glycocalyx in SE. We hypothesized glycocalyx degradation could be considered as a first step in the pathophysiology of SE. The study aimed to investigate the impacts of glycocalyx integrity loss on brain damage in a C57BL/6 mouse model of SE induced by lithium-pilocarpine and whether heparin, a competitive antagonist against heparinase , improves survival and neurological outcome. Compared to controls, glycocalyx was significantly degraded after SE, which was mitigated by heparin. The glycocalyx disruption was associated with higher BBB permeability and aggravated brain edema at 72 h after SE, as well as lower survival rate and poorer neurologic outcome. Conversely, preservation of glycocalyx by heparin could reduce SE-induced activation of glia cells , BBB leakage, brain edema, decrease the expressions of inflammatory factors and improve neurologic outcome. The study highlights the importance of glycocalyx degradation in cerebral edema and SE outcome, and indicates heparin treatment may be a new strategy for brain protection in SE.
研究领域:
神经科学
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药理学
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神经病学
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病理生理学
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DOI
PubMed
高影响因子
Nanoscale
·
2023
·Vol. 15
·期 27
·11625-11646
·
IF 6.7
Kai Wang,Wentao Zhou,Xiangyu Jin,Xuwei Shang,Xiaomei Wu,Lijuan Wen,Sufen Li,Yiling Hong,Jia Ke,Yichong Xu,Hong Yuan,Fuqiang Hu
Ischemic stroke is characterized by high morbidity, disability, and mortality. Unfortunately, the only FDA-approved pharmacological thrombolytic, alteplase, has a narrow therapeutic window of only 4.5 h. Other drugs like neuroprotective agents have not been clinically used because of their low efficacy. To improve the efficacy of neuroprotective agents and the effectiveness of rescue therapies for hyperacute ischemic stroke, we investigated and verified the variation trends of the blood–brain barrier (BBB) permeability and regional cerebral blood flow over 24 h in rats that had ischemic strokes. Hypoperfusion and the biphasic increase of BBB permeability are still the main limiting factors for lesion-specific drug distribution and drug brain penetration. Herein, the nitric oxide donor hydroxyurea (HYD) was reported to downregulate the expression of tight junction proteins and upregulate intracellular nitric oxide content in the brain microvascular endothelial cells subjected to oxygen–glucose deprivation, which was shown to facilitate the transport of liposomes across brain endothelial monolayer in an in vitro model. HYD also increased the BBB permeability and promoted microcirculation in the hyperacute phase of stroke. The neutrophil-like cell-membrane-fusogenic hypoxia-sensitive liposomes exhibited excellent performance in targeting the inflamed brain microvascular endothelial cells, enhancing cell association, and promoting rapid hypoxic-responsive release in the hypoxic microenvironment. Overall, the combined HYD and hypoxia-sensitive liposome dosing regimen effectively decreased the cerebral infarction volume and relieved neurological dysfunction in rats that had ischemic strokes; these therapies were involved in the anti-oxidative stress effect and the neurotrophic effect mediated by macrophage migration inhibitory factor.
研究领域:
神经科学
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药理学
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治疗学
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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
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Jinlian Gu,Chang Yan,Shun Yin,Hao Wu,Chi Liu,Ao Xue,Xia Lei,Ning Zhang,Fang Geng
Alzheimer's disease (AD) is an aging-related neurodegenerative disease , and the main pathological feature was β-amyloid protein (Aβ) deposition. Recently, bioactive materials-based drug delivery system has been widely investigated for the treatment of AD. In this study, we developed a red blood cells (RBC) membrane-coated polycaprolactone (PCL) nanoparticles (NPs) loading with a therapeutic agent for AD, curcumin (Cur). A functional peptide TGNYKALHPHN (TGN) was conjugated to the surface of membrane for blood-brain barrier (BBB) transport (TGN-RBC-NPs-Cur). TGN peptide can be recognized by receptors on the BBB and has great potential for brain transport. To confirm the targeted delivery of Cur to the brain, a cell co-culturing immortalized human cerebral microvascular endothelial cells and human brain astrocytes glioblastoma (hCMEC/D3 and U-118MG) in vitro model was established. As a result, the BBB transporting ratio of TGN-RBC-NPs-FITC was 29.64% at 12 h which was approximately eight-fold than RBC-NPs-FITC. The improvement of drug accumulation in the AD lesion was confirmed by the NPs modified with the BBB-penetrating peptide in the fluorescence imaging and quantitative analysis with UPLC-MS/MS in vivo . The neuroprotective effects were evaluated with new object recognition behavioral test, in vitro AD cell model, dendritic spine stain, GFAP and IBA1 immunofluorescence stain. The spatial learning and memory abilities of the AD model mice treated with TGN-RBC-NPs-Cur were obviously enhanced compared with the AD control mice and were also better than Cur at the same dosage. These results were consistent with the values of protection index of rat adrenal pheochromocytoma cells (PC12 cells) treated by Aβ 25 – 35 . TGN-RBC-NPs-Cur increased the dendritic segments densities and restrained activation of microglia and astrocytes of AD mice, as well as reversed cognitive function of AD mice. All of the results demonstrated TGN-RBC-NPs-Cur a promising therapeutic strategy for delaying the progression of AD by designing biomimetic nanosystems to deliver drugs into the brain.
研究领域:
神经科学
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药学
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纳米技术
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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
Advanced Science
·
2024
·
IF 14.3
Rong-Rong Lin,Lu-Lu Jin,Yan-Yan Xue,Zhe-Sheng Zhang,Hui-Feng Huang,Dian-Fu Chen,Qian Liu,Zheng-Wei Mao,Zhi-Ying Wu,Qing-Qing Tao
The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C–C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.
研究领域:
纳米技术
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神经科学
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药学
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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
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Siqing Zhu,Yu Zhang,Chang Li,Zhiqing Deng,Ying Yin,Zhufeng Dong,Lei Kuang,Chuanming Li,Xiaoye Hu,Tieying Yin,Yazhou Wang
Aging is a critical factor in the onset and progression of neurodegenerative diseases and cognitive decline, with aging-related neuroinflammation and cellular senescence being major contributors. In the aging brain, the cerebral vascular endothelium overexpresses vascular cell adhesion molecule 1 (VCAM1), activating microglia and leading to neuroinflammation and cognitive impairment. Quercetin, a natural neuroprotective agent widely used for treating neurodegenerative diseases, their therapeutic efficacy, however, is limited by its poor water solubility and inability to penetrate the blood-brain barrier (BBB). To address these challenges, we developed a multifunctional micellar platform (Anti-VCAM1-GM1@Q) to improve age-related neurodegenerative diseases. The micelles incorporate anti-VCAM1 antibodies to target cerebral vascular endothelial cells and block VCAM1. Additionally, monosialoganglioside (GM1) was utilized to deliver quercetin due to its biparental properties, high BBB permeability, and neuroprotective effects. Anti-VCAM1-GM1@Q micelles demonstrated strong anti-aging properties. They improved quercetin's bioavailability, effectively penetrated the BBB, targeted cerebral vascular endothelial cells, and reduced neuroinflammation. In animal models, these micelles provided effective neuroprotection, improved memory function and age-related cognitive impairment, and mitigated age-related neurodegeneration. Notably, this system exhibited remarkable treatment efficacy and high safety, indicating substantial potential for clinical translational applications.
研究领域:
神经科学
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药理学
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衰老研究
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纳米技术
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医学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Yanan Wang,Xutao Ma,Xinyuan Wang,Liru Liu,Xue Zhang,Qiuyue Wang,Yingfei Zhu,Huanhua Xu,Liangmin Yu,Zhiyu He
The scarcity of effective neuroprotective agents and the presence of blood-brain barrier (BBB)-mediated extremely inefficient intracerebral drug delivery are predominant obstacles to the treatment of cerebral ischemic stroke (CIS). Herein, ROS-responsive borneol-based amphiphilic polymeric NPs are constructed by using traditional Chinese medicine borneol as functional blocks that served as surface brain-targeting ligand, inner hydrophobic core for efficient drug loading of membrane-permeable calcium chelator BAPTA-AM, and neuroprotective structural component. In MCAO mice, the nanoformulation (polymer: 3.2 mg·kg −1 , BAPTA-AM: 400 µg·kg −1 ) reversibly opened the BBB and achieved high brain biodistribution up to 12.7%ID/g of the total administered dose after 3 h post single injection, effectively restoring intracellular Ca 2+ and redox homeostasis, improving cerebral histopathology, and inhibiting mitochondrial PI3K/Akt/Bcl-2/Bax/Cyto-C/Caspase-3,9 apoptosis pathway for rescuing dying neurons (reduced apoptosis cell from 59.5% to 7.9%). It also remodeled the inflammatory microenvironment in cerebral ischemic penumbra by inhibiting astrocyte over-activation, reprogramming microglia polarization toward an anti-inflammatory phenotype, and blocking NF-κB/TNF- α /IL-6 signaling pathways. These interventions eventually reduced the cerebral infarction area by 96.3%, significantly improved neurological function, and restored blood flow reperfusion from 66.2% to ≈100%, all while facilitating BBB repair and avoiding brain edema. This provides a potentially effective multiple-stage sequential treatment strategy for clinical CIS.
研究领域:
药学
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神经科学
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药物递送系统
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传统中药
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中风治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
·
2025
·
IF 5
Yue-Xin Ning,Ji-Ru Cai,Ting-Ting Wang,Yi-Han Wang,Yu Cui,Hui-Sheng Chen
Background Endovascular treatment (EVT) alone was not demonstrated to be non-inferior to intravenous alteplase bridging EVT in acute large vessel occlusion (LVO) stroke. Using cerebral ischemia/reperfusion (I/R) injury model, intravenous tenecteplase (TNK) was administrated after ischemia followed by reperfusion at various time points. Objectives To investigate whether intravenous TNK bridging EVT vs EVT alone could improve I/R injury, and this effect may be associated with the time from TNK to reperfusion. Methods Rats received intravenous TNK (1.4 mg/kg) or vehicle (sterile water) 1.0 hour after middle cerebral artery occlusion (MCAO), followed by reperfusion after 0.5 or 1.0 hour following TNK. Neurological deficit scores, infarct volume, and brain edema were measured at 24 hours after MCAO. Microthrombi were determined by immunofluorescence staining for CD31 + /fibrinogen + and CD31 + /thrombocyte + . Inflammatory cell infiltration in the ischemic brain region was determined by flow cytometry. Results Compared with vehicle, TNK significantly reduced neurological deficit scores, brain infarction, neuro-inflammation, and blood-brain barrier (BBB) disruption, and significantly reduced intravascular fibrin and platelet deposition, and brain inflammatory cell infiltration in penumbra of I/R rats. Furthermore, a better beneficial trend was found in TNK bridging reperfusion at 0.5 hour after TNK compared with TNK bridging reperfusion at 1.0 hour after TNK. Conclusions Our results demonstrate that intravenous TNK bridging reperfusion produced neuroprotective action through dissolving microvascular thrombus and alleviating inflammatory cell infiltration to improve microcirculation, with the result of maintaining BBB integrity and inhibiting neuroinflammation, and the neuroprotective benefit may be associated with the time from TNK to reperfusion.
研究领域:
神经科学
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药理学
·
实验性卒中研究
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Chang Liu,Qi Yan,Xuying Ding,Meijun Zhao,Chen Chen,Qian Zheng,Huiying Yang,Yining Xie
Brain-derived neurotrophic factor (BDNF) is a neurotrophic protein that promotes neuronal survival, increases neurotransmitter synthesis, and has potential therapeutic effects in neurodegenerative and psychiatric diseases, but its drug development has been limited by the fact that recombinant proteins of BDNF are unstable and do not penetrate the blood-brain barrier (BBB). In this study, we fused a TAT membrane-penetrating peptide with BDNF to express a recombinant protein (TBDNF), which was then PEG-modified to P-TBDNF. Protein characterization showed that P-TBDNF significantly improved the stability of the recombinant protein and possessed the ability to penetrate the BBB, and in cellular experiments, P-TBDNF prevented MPTP-induced nerve cell oxidative stress damage, apoptosis and inflammatory response, and its mechanism of action was closely related to the activation of tyrosine kinase B (TrkB) receptor and inhibition of microglia activation. In animal experiments, P-TBDNF improved motor and cognitive deficits in MPTP mice and inhibited pathological changes in Parkinson's disease (PD). In conclusion, this paper is expected to reveal the mechanism of action of P-TBDNF in inhibiting neurotoxicity, provide a new way for treating PD, and lay the foundation for the future development of recombinant P-TBDNF.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2021
·
IF 12.479
Lu Lu,Kui Wang,Chuanchuan Lin,Weihu Yang,Qiaojian Duan,Ke Li,Kaiyong Cai
The blood−brain barrier (BBB) is one of the major limitations of glioblastoma therapy in the clinic. Nanodrugs have shown great potential for glioblastoma therapy. Herein, we purposefully developed a multicomponent self-assembly nanocomplex with very high drug loading content for curing orthotopic glioblastoma with synergistic chemo-photothermal therapy. The nanocomplex consisted of self-assembled pH-responsive nanodrugs derived from amino acid-conjugated camptothecin (CPT) and canine dyes (IR783) coated with peptide Angiopep-2-conjugated copolymer of Ang-PEG-g-PLL. Specifically, the carrier-free nanocomplex exhibited a high drug loading content (up to 62%), good biocompatibility , and effective glioma accumulation ability. Moreover, the nanocomplex displayed good stability and pH-responsive behavior ex vivo . Both in vitro and in vivo results revealed that the nanocomplex could effectively cross the BBB and target glioma cells. Furthermore, the combination of chemotherapy and photothermal therapy of the nanocomplex achieved a better therapeutic effect, longer survival time, and minimized toxic side effects in orthotopic glioblastoma tumor-bearing nude mice . Overall, we modified the chemotherapeutic drug CPT so that it could self-assemble with other molecules into nanoparticles , which providing an alternative for the preparation of the carrier-free nanodrugs. The results highlighted the potential of self-assembly nanodrugs as a novel platform for effective glioblastoma therapy.
研究领域:
纳米技术
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药学
·
癌症治疗
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生物医学工程
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Hao Cui,Yanchi Liu,Ying Yu,Dong Lv,Sha Ma,Mingju Gao,Ye Yang,Cheng Yuan,Yuan Liu,Chengxiao Wang
In this study, we aimed to develop brain-targeted co-delivery liposomes for the concurrent delivery of Panax notoginseng saponins (PNS) and acetylsalicylic acid (ASA) for the treatment of ischemic stroke. Within this system, PNS served as a cholesterol substitute, integrating into the phospholipid bilayer of the liposomes, while ASA was encapsulated internally. A poly-2-methacryloyloxyethyl phosphorylcholine (PMPC) polymer was synthesized and incorporated into the liposome surface. This formulation demonstrated an enhanced PNS-loading capacity and facilitated the synchronized delivery of key saponin components. Following PMPC modification, the liposomes exhibited prolonged circulation and improved transport across the blood–brain barrier (BBB) through acetylcholine receptor-mediated pathways. Furthermore, the co-delivery system exhibited enhanced therapeutic efficacy in a rat model of cerebral ischemia–reperfusion injury via the phosphoinositide 3-kinase/protein kinase C pathway. Additional analyses revealed significant effects on the metabolism of neurotransmitters, amino acids, folate, and various other pathways, indicating a multi-faceted therapeutic effect. Overall, this study presents an innovative research strategy for the comprehensive delivery of diverse components in traditional Chinese medicine formulations, highlighting the potential for synergistic treatments that combine traditional Chinese medicine with chemical agents.
研究领域:
药学
·
神经科学
·
中医药
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药物递送系统
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中风治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2020
·
IF 5.162
Shuaishuai Xing,Ying Chen,Baichen Xiong,Weixuan Lu,Qi Li,Yuanyuan Wang,Mengxia Jiao,Feng Feng,Yao Chen,Wenyuan Liu,Haopeng Sun
In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schrödinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513–4169 displayed the highest inhibitory activity and selectivity against BChE ( ee AChE IC 50 > 10 μM, eq BChE IC 50 = 3.73 ± 1.90 μM). Molecular dynamic (MD) simulation validated the binding pattern of 2513–4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513–4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513–4169 against toxic Aβ 1 – 42 . In vivo behavioral study further confirmed the great efficacy of 2513–4169 on reversing Aβ 1 – 42 -induced cognitive impairment of mice and clearing the toxic Aβ 1 – 42 in brains. Moreover, 2513–4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513–4169 is a promising lead compound for future optimization to discover anti-AD treating agents.
研究领域:
神经科学
·
药理学
·
药物发现
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分子生物学
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DOI
PubMed
高影响因子
Biomedical Optics Express
·
2018
·Vol. 9
·期 10
·4850-4862
·
IF 3.482
Chao Zhang,Wei Feng,Elena Vodovozova,Daria Tretiakova,Ivan Boldyrevd,Yusha Li,Jurgen Kürths,Tingting Yu,Oxana Semyachkina-Glushkovskaya,Dan Zhu
The photodynamic (PD) effect has been reported to be efficient for the opening of the blood-brain barrier (BBB), which provides a new informative platform for developing perspective strategies towards brain disease therapy and drug delivery. However, this method is usually performed via craniotomy due to high scattering of the turbid skull. In this work, we employed a newly-developed optical clearing skull window for investigating non-invasive PD-induced BBB opening to high weight molecules and 100-nm fluid-phase liposomes containing ganglioside GM1. The results demonstrated that the BBB permeability to the Evans blue albumin complex is related to laser doses. By in vivo two-photon imaging and ex vivo confocal imaging with specific markers of the BBB, we noticed PD-related extravasation of rhodamine-dextran and liposomes from the vessels into the brain parenchyma. The PD induced an increase in oxidative stress associated with mild hypoxia and changes in the expression of tight junction (CLND-5 and ZO-1) and adherens junction (VE-cadherin) proteins, which might be one of the mechanisms underlying the PD-related BBB opening for liposomes. Our experiments indicate that optical clearing skull window will be a promising tool for non-invasive PD-related BBB opening for high weight molecules and liposomes that provides a novel useful tool for brain drug delivery and treatment of brain diseases.
研究领域:
神经科学
·
药理学
·
生物医学工程
·
光学
✓ 已验证
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）