多发性硬化病人体内高水平cICAM-1和TNF-α的研究

目的 研究多发性硬化（ＭＳ）免疫异常过程中肿瘤坏死因子（ＴＮＦ－α）和循环细胞间粘附分子－１（ｃＩＣＡＭ－１）的变化及与血脑屏障（ＢＢＢ）的相关性。方法 用酶联免疫吸附试验（ＥＬＩＳＡ）及单项琼脂扩散（ＳＩＲＤ）检测临床确诊为ＭＳ的３１例病人血清及脑脊液（ＣＳＦ）中ＴＮＦ－α、ｃＩＣＡＭ－１及白蛋白（Ａｌｂ）比值。结果 ①例ＭＳ虱中Ａｌｂ比值轻度异常８例（２５％）,正常者２３例;ＩｇＧ指数增高（〈     

Approaches for CNS delivery of drugs – nose to brain targeting of antiretroviral agents as a potential attempt for complete elimination of major reservoir site of HIV to aid AIDS treatment

Introduction: Human immune-deficiency virus (HIV) infection causing acquired immune-deficiency syndrome (AIDS) is one of the most life-threatening infections. The central nervous system (CNS) is reported to be the most important HIV reservoir site where the antiretroviral drugs are unable to reach.

Areas covered: This article includes the review about HIV infections, its pathogenesis, HIV infections in CNS, its consequences, current therapies, challenges associated with the existing therapies, approaches to overcome them, CNS delivery of drugs – barriers, transport routes, approaches for transporting drugs across the blood–brain barrier, nasal route of drug delivery, and nose to brain targeting of antiretroviral agents as a potential approach for complete cure of AIDS.

Expert opinion: Various approaches are exploited to enhance the drug delivery to the brain for various categories of drugs. However, very few have investigated on the delivery of antiretrovirals to the brain. Targeting antiretrovirals to CNS through oral/nasal routes along with oral/parenteral delivery of drug to the plasma can be a promising approach for an attempt to completely eradicate HIV reservoir and cure AIDS, after clinical trials. Further research is required to identify the exact location of the HIV reservoir in CNS and developing good animal models for evaluation of different newly developed formulations.     

双配体修饰聚合物泡囊的制备及细胞摄取

目的构建一种主动靶向的新型纳米药物载体——聚合物泡囊(polymer vesicles,PVs),并考察其细胞摄取。方法以马来酰亚胺-聚乙二醇-聚乳酸-羟基乙酸共聚物(MAL-PEG-PLGA)为载体材料,通过自组装制备PVs,用转铁蛋白(Tf)与Tet-1对PVs进行修饰,构建纳米药物载体(Tf/Tet-1-PVs)。以香豆素-6作为荧光探针包载于药物载体,考察脑微血管内皮细胞(BCEC)及神经细胞(Neuro-2a)对载体系统的摄取。结果 PVs粒径约80nm,形态圆整,电镜观察具有明显膜层结构。BCEC细胞和Neuro-2a细胞对Tf/Tet-1-PVs的摄取均显著优于空白对照组和单配体修饰对照组。结论 PVs经双配体Tf及Tet-1修饰后可促进脑微血管内皮细胞和神经细胞的摄取。     

CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment

Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one of the major limitations in the use of triptans. However their use had to be discontinued because of risk of liver toxicity after continuous exposure. As an alternative approach to block CGRP transmission, fully humanized monoclonal antibodies towards CGRP and the CGRP receptor have been developed for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo.The effectiveness of these various molecules raises the question of where is the target site(s) for antimigraine action. The gepants are small molecules that can partially pass the blood–brain barrier (BBB) and therefore, might have effects in the CNS. However, antibodies are large molecules and have limited possibility to pass the BBB, thus effectively excluding them from having a major site of action within the CNS. It is suggested that the antimigraine site should reside in areas not limited by the BBB such as intra- and extracranial vessels, dural mast cells and the trigeminal system. In order to clarify this topic and surrounding questions, it is important to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB.     

Repeated Baclofen treatment ameliorates motor dysfunction,suppresses reflex activity and decreases the expression of signaling proteins in reticular nuclei and lumbar motoneurons after spinal trauma in rats

The interruption of supraspinal input to the spinal cord leads to motor dysfunction and the development of spasticity. Clinical studies have shown that Baclofen (a GABA_B agonist), while effective in modulating spasticity is associated with side-effects and the development of tolerance. The aim of the present study was to assess if discontinued Baclofen treatment and its repeated application leads antispasticity effects, and whether such changes affect neuronal nitric oxide synthase (nNOS) in the brainstem, nNOS and parvalbumin (PV) in lumbar α-motoneurons and glial fibrillary acidic protein in the ventral horn of the spinal cord. Adult male Wistar rats were exposed to Th9 spinal cord transection. Baclofen (30 mg/b.w.) diluted in drinking water, was administered for 6 days, starting at week 1 after injury and then repeated till week 4 after injury. The behavior of the animals was tested (tail-flick test, BBB locomotor score) from 1 to 8 weeks. Our results clearly indicate the role of nitric oxide, produced by nNOS in the initiation and the maintenance of spasticity states 1, 6 and 8 weeks after spinal trauma. A considerable decrease of nNOS staining after Baclofen treatment correlates with improvement of motor dysfunction. The findings also show that parvalbumin and astrocytes participate in the regulation of ion concentrations in the sub-acute phase after the injury.     

骨髓间充质干细胞和嗅黏膜神经干细胞共移植治疗大鼠脊髓损伤

【摘要】目的 探讨骨髓间充质干细胞(BMSCs)和嗅黏膜神经干细胞(OM NSCs)共移植对大鼠脊髓损伤后运动功能的影响。方法 分别提取培养并鉴定大鼠BMSCs和OM NSCs。将60只雄性SPF级SD大鼠随机分为假手术组（仅做椎板切除,不损伤脊髓）,对照组（在脊髓损伤区域注射5 μL生理盐水）,BMSCs移植组（在脊髓损伤区域注射5 μL 5×104个细胞BMSCs单细胞悬液）,OM NSCs移植组（在脊髓损伤区域注射5 μL 5×104个细胞 OM NSCs单细胞悬液,BMSCs和OM NSCs共移植组（在脊髓损伤区域注射5μL 1〖DK〗∶1 5×104个细胞BMSCs和OM NSCs细胞混悬液）。细胞移植后第1、3、7、14、21、28天分别对大鼠进行BBB评分,28天后处死大鼠,分离脊髓组织,进行免疫荧光染色观察细胞迁移情况。结果 造模后,大鼠双后肢瘫痪,BBB评分0分。细胞移植后14天起,与对照组相比,干细胞移植组运动功能有显著改善,BBB评分比较差异具有统计学意义（P＜005）。与BMSCs移植组和OM NSCs移植组相比,移植后21、28天,共移植组BBB评分显著增加（P＜005）。免疫荧光观察结果表明,脊髓损伤28天后,损伤区脊髓内可见空泡形成,两种干细胞聚集在空泡周围,BMSCs在损伤区分布较为集中,而OM NSCs相对散在分布,细胞较为伸展。结论 干细胞移植可以一定程度上恢复脊髓损伤大鼠的运动功能,BMSCs和OM NSCs两种干细胞共移植效果优于单细胞移植。     

AS1411 Aptamer/Hyaluronic Acid-Bifunctionalized Microemulsion Co-Loading Shikonin and Docetaxel for Enhanced Antiglioma Therapy

In this study, we developed an AS1411 aptamer/hyaluronic acid-bifunctionalized microemulsion co-loading shikonin and docetaxel (AS1411/SKN&DTX-M). Such microemulsion was capable of penetrating the blood-brain barrier (BBB), targeting CD44/nucleolin-overexpressed glioma, and inhibiting the orthotopic glioma growth. AS1411/SKN&DTX-M showed a spherical morphology with a diameter around 30 nm and rapidly released drugs in the presence of hyaluronidase and mild acid. In the U87 cellular studies, AS1411/SKN&DTX-M elevated the cytotoxicity, enhanced the cellular uptake, and induced the cell apoptosis. In the artificial blood-brain barrier model, the transepithelial electrical resistance was decreased after the treatment with AS1411/SKN&DTX-M and thereby of increasing the apparent permeability coefficient. Furthermore, AS1411/SKN&DTX-M showed a strong inhibition against the formation of cancer stem cell–enriched U87 cell spheroids, in which the expression of CD133 was downregulated significantly. In the biodistribution studies, AS1411/SKN&DTX-M could selectively accumulate in the brains of orthotopic luciferase-transfected U87 glioma tumor–bearing nude mice. Importantly, AS1411/SKN&DTX-M exhibited the overwhelming inhibition of glioma growth of orthotopic luciferase-transfected U87 glioma models and reached the longest survival period among all the treatments. In summary, the codelivery of shikonin and docetaxel using bifunctionalization with hyaluronic acid and AS1411 aptamer offers a promising strategy for dual drug-based combinational antiglioma treatment.     

Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies

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“Tau Protein Targeting Via Radioiodinated Azure A For Brain Theranostics: Radiolabeling,Molecular Docking,in vitro And in vivo Biological Evaluation”

Azure-A is one of the phenothiazines (PTZs) derivatives which for decades have been used as antipsychotic drugs due to good lipophilic characteristics which enable them to pass through the blood brain barrier (BBB), besides the important property of enabeling investigation of the pathological forms of aggregated tau protein found in the neurons of the central nervous system. Radioiodination of Azure-A was carried out via an electrophilic substitution reaction using chloramine-T as oxidizing agent. The influence of various reaction parameters and conditions on radioiodination efficiency was investigated, and a high radiochemical yield of 92.07 ± 0.9 % was obtained. An in vitro cytotoxicity study of iodinated Azure-A on three cell lines (HCT-116, human colon carcinoma cell line; Hep-G2, liver carcinoma cell line and HFB-4, normal human melanocytes) was carried out, and the data revealed that ioiodinated Azure A has no to very low toxic effect. The in vivo biodistribution study of ¹³¹I-Azure A showed a high brain uptake of 6.15 ± 0.09 % injected dose/g tissue organ at 30 minutes post-injection, and its retention in brain remained high up to 2 hours, whereas the clearance from the body appeared to proceed via the renal system. The experimental data were confirmed by the molecular docking studies to predict the effect of radioiodination on the binding affinity of the parent molecule (Azure A) to tau paired helical filaments (PHFs). Both ligands showed better binding to S2 and S3 pockets of (PHFs). Consequently, radioiodinated Azure A seems to be a good candidate as an imaging agent for taupathies such as Alzheimer's disease, chronic traumatic encephalopathy, and corticobasal degeneration. Furthermore, it could be a very potent theranostics agent for brain tumors.