Blood–brain barrier and laser technology for drug brain delivery

Here,we discuss an important problem in medicine as development of efctive strategies for brain drug delivery.This problem is related to the blood-brain barrier(BBB),which is a“customs”controlling the entrance of different molecules from blood into the brain protecting the normal function of central nervous system(CNS).We show three interfaces of anatomical side of BBB and two functional types of BBB一physical and transporter barriers.Although this protective mechanism is essential for health of CNS,it also creates a hindrance to the entry of drugs into the brain.The BBB was discovered over 100 years ago but till now,there is no efective methods for brain drug delivery.There ane more than 70 approaches for overcoming BBB incuding physical,chenical and biological techniques but all of these tools have limitation to be widely used in clinical practice due to invasi venes,challenge in performing,very costly or lim-itation of drug concentration.Photodynamic therapy(PDT)is usual clinical method of surgical navigation for the resection of brain tumor and anti-cancer therapy.Nowadays,the application of PDT is considered as a potential promising tool for brain drug delivery via opening of BBB.Here,we show the first sucoessful experimental results in this field discussing the adventures and disadv antages of PDT-related BBB disruption as well as altematives to overcome these limitations and possi ble mechanisms with new pathways for brain clearance via gly mphatic and lymphatic systems.

Treatment of radiation-induced brain injury with bisdemethoxycurcumin

Radiation therapy is considered the most effective non-surgical treatment for brain tumors.However,there are no available treatments for radiation-induced brain injury.Bisdemethoxycurcumin(BDMC)is a demethoxy derivative of curcumin that has anti-proliferative,anti-inflammatory,and anti-oxidant properties.To determine whether BDMC has the potential to treat radiation-induced brain injury,in this study,we established a rat model of radiation-induced brain injury by administe ring a single 30-Gy vertical dose of irradiation to the whole brain,followed by intraperitoneal injection of 500μL of a 100 mg/kg BDMC solution every day for 5 successive weeks.Our res ults showed that BDMC increased the body weight of rats with radiation-induced brain injury,improved lea rning and memory,attenuated brain edema,inhibited astrocyte activation,and reduced oxidative stress.These findings suggest that BDMC protects against radiationinduced brain injury.

Tall gastrodis tuber combined with antiepileptic drugs repairs abnormal perfusion foci in focal epilepsy

One hundred patients with focal epilepsy were recruited for the present study and their seizures controlled with antiepileptic drugs. The patients then orally received a capsule of tall gastrodis tuber powder, a traditional Chinese drug, and underwent single photon emission computed tomography, long-term electroencephalogram, and CT/MRI. Blood drug levels were monitored throughout the study. Before treatment with tall gastrodis tuber, 35 of the 100 cases had abnormal CT/MRI scans; 79 cases had abnormal single photon emission computed tomography images; 86 cases had abnormal electroencephalogram; and a total of 146 abnormal perfusion foci were observed across the 100 subjects. After treatment, the number of patients with normal single photon emission computed tomography images increased by 12; normal electroencephalogram was observed in an additional 27 cases and the number of patients with epileptiform discharge decreased by 29 （34% of 86）; the total number of abnormal perfusion foci decreased by 52 （36%） and changes in abnormal loci were visible in 65 patients. These changes indicate that the administration of tall gastrodis tuber in combination with antiepileptic drugs repairs abnormal perfusion foci in patients with focal epilepsy Our results demonstrate that traditional Chinese drugs can repair abnormal perfusion foci and, as such, are a promising new pathway in the treatment of focal epilepsy.

Brain natriuretic peptide and optimal management of heart failure

Aside from the important role of brain natriuretic peptide (BNP) in diagnosis, and differential diagnosis of heart failure, this biological peptide has proved to be an independent surrogate marker of rehospitalization and death of the fatal disease. Several randomized clinical trials demonstrated that drugs such as beta blocker, angiotensin converting enzyme inhibitor, spiro- nolactone and amiodarone have beneficial effects in decreasing circulating BNP level during the management of chronic heart failure. The optimization of clinical decision-making appeals for a representative surrogate marker for heart failure prognosis. The serial point-of-care assessments of BNP concentration provide a therapeutic goal of clinical multi-therapy and an objective guid- ance for optimal treatment of heart failure. Nevertheless new questions and problems in this area remain to be clarified. On the basis of current research advances, this article gives an overview of BNP peptide and its property and role in the management of heart failure.

Acute effects of human protein S administration after traumatic brain injury in mice

Despite years of effort,no effective acute phase treatment has been discovered for traumatic brain injury.One impediment to successful drug development is entangled secondary injury pathways.Here we show that protein S,a natural multifunctional protein that regulates coagulation,inflammation,and apoptosis,is able to reduce the extent of multiple secondary injuries in traumatic brain injury,and therefore improve prognosis.Mice subjected to controlled cortical impact were treated acutely(10–15 minutes post-injury)with a single dose of either protein S(1 mg/kg)or vehicle phosphate buffered saline via intravenous injection.At 24 hours post-injury,compared to the non-treated group,the protein S treated group showed substantial improvement of edema and fine motor coordination,as well as mitigation of progressive tissue loss.Immunohistochemistry and western blot targeting caspase-3,B-cell lymphoma 2(Bcl-2)along with terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assay revealed that apoptosis was suppressed in treated animals.Immunohistochemistry targeting CD11 b showed limited leukocyte infiltration in the protein S-treated group.Moreover,protein S treatment increased the ipsilesional expression of aquaporin-4,which may be the underlying mechanism of its function in reducing edema.These results indicate that immediate intravenous protein S treatment after controlled cortical impact is beneficial to traumatic brain injury prognosis.Animal Use Protocols(AUPs)were approved by the University Committee on Animal Resources(UCAR)of University of Rochester Medical Center(approval No.UCAR-2008-102 R)on November 12,2013.

Gene therapy with caspase-3 small interfering RNA-nanoparticles is neuroprotective after optic nerve damage

Apoptosis,a key mechanism of programmed cell death,is triggered by caspase-3 protein and lowering its levels with gene therapy may rescue cell death after central nervous system damage.We developed a novel,non-viral gene therapy to block caspase-3 gene expression using small interfering RNA(siRNA)delivered by polybutylcyanoacrylate nanoparticles(CaspNPs).In vitro CaspNPs significantly blocked caspase-3 protein expression in C6 cells,and when injected intraocularly in vivo,CaspNPs lowered retinal capsase-3 immunofluorescence by 57.9%in rats with optic nerve crush.Longitudinal,repeated retinal ganglion cell counts using confocal neuroimaging showed that post-traumatic cell loss after intraocular CaspNPs injection was only 36.1%versus 63.4%in lesioned controls.Because non-viral gene therapy with siRNA-nanoparticles can selectively silence caspace-3 gene expression and block apoptosis in post-mitotic neurons,siRNA delivery with nanoparticles may be promising for neuroprotection or restoration of central visual system damage and other neurological disorders.The animal study procedures were approved by the German National Act on the use of experimental animals(Ethic Committee Referat Verbraucherschutz,Veterinärangelegenheiten;Landesverwaltungsamt Sachsen-Anhalt,Halle,Germany,#IMP/G/01-1150/12 and#IMP/G/01-1469/17).

Brainstem abscesses caused by Listeria monocytogenes:A case report

BACKGROUNDIntracranial Listeria infections are common in newborns and immunocompromisedindividuals, but brainstem abscesses are rare.CASE SUMMARYWe report a rare case of brainstem abscesses caused by Listeria monocytogenes in apreviously healthy adult patient. The patient’s magnetic resonance imagingexamination showed multiple brain abscesses, and his second cerebrospinal fluidculture test indicated the presence of Listeria monocytogenes. Despite earlyempirical therapy, the patient’s condition progressively deteriorated. Because thepatient's abscesses were located in the brainstem and multiple lobes, surgery wasnot possible. The patient died 40 d after admission.CONCLUSIONThis case highlights the importance of rational clinical use of drugs to avoidpotentially serious infectious complications.

Updates in uveitic macular edema

Macular edema is one of the most common visionthreatening complications of uveitis noted in one third of patients with uveitis. The release of a number of inflammatory mediators induces retinal vascular hyperpermeability leading to uveitic macular edema(UME)which most commonly is of cystoid shape. Fluorescein angiography and non-invasive spectral-domain optical coherence tomography are standard procedures for diagnosis and follow-up of UME with some innovations such as scanning laser ophthalmoscope retro-mode imaging. Effective management of UME requires thorough understanding of the individual case. Proper control of intraocular inflammation is mandatory before targeting macular edema itself. Mainstay of treatment is immunosuppressive therapy with various drug delivery routes including topical, local subconjunctival, peribulbar and sub-Tenon's, intravitreal and systemic. Clinical trials with biologics are under way to study the efficacy of these agents in suppressing intraocular inflammation and resolution of UME. Visual prognosis in UME depends on numerous factors. Younger age and better visual acuity at baseline are associated with more favorable visual outcome in most

High Mobility Group Box 1 and Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. We identify High Mobility Group Box 1 (HMGB1) as a novel causative factor in the development of cerebral oedema, mediating coagulation, preventing secondary brain damage as well as serving as a novel therapeutic target to limit secondary neurological injury after TBI. As a prototypical danger associated molecular patterns (DAMP), HMGB1 is released from necrotic neurons via a NR2B-mediated mechanism during TBI. The secretion of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response. HMGB1 is clinically associated with elevated intracranial pressure (ICP) in patients and functionally promoted cerebral edema after TBI. The detrimental effects of HMGB1 is mediated at least in part between activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel aquaporin-4 (AQP4). Anti-HMGB1mAb remarkably inhibited fluid percussion-induced brain edema by inhibiting HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression and improvement of motor function. Our review demonstrates the pathological role of HMGB1 as well as the possible therapeutic valve of HMGB1 in patients with TBI.

Suppressing Wnt signaling of the blood-tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

基于数据挖掘对中医药治疗CKD合并脑卒中的组方用药分析

基于数据挖掘方法探讨中医药治疗慢性肾脏病(CKD)合并脑卒中(CS)的临床用药规律。收集2017年10月至2022年10月天津中医药大学第一附属医院门诊治疗CKD合并CS的处方,建立中药处方数据库。统计分析用药频次、性味及归经,对处方中的药物进行聚类分析,利用SPSS Modeler 18 Apriori算法对所有药物进行关联分析。最终纳入544个处方,涉及中药258味,总用药频次8 886次。药性以寒性、温性、平性居多;药味以苦味、甘味、辛味为主;归经多为脾经、肝经;得出13个关联组合药对和5个核心药物组合。中医药对CKD合并CS患者的治疗,根据气虚血瘀、脾肾两虚的病机特点,主要采用健脾益气、补肾活血的组方用药。

脑类器官在药物研发中的研究进展

近年来,随着再生医学与组织工程学的飞速发展,脑类器官作为一种创新的体外模型系统,逐渐成为神经科学研究和药物研发领域的热点。脑类器官通过模拟人类大脑的复杂结构和功能,在体外重现了大脑发育的关键过程,为理解神经系统疾病机制、评估药物疗效及毒性提供了前所未有的平台。本文综述了脑类器官技术的最新进展,特别是其在药物研发中的应用,并探讨了该领域面临的挑战与未来发展方向。

获得性脑损伤患者多重耐药菌感染现状及其对脑功能的影响

目的调查获得性脑损伤康复住院患者多重耐药菌(MDRO)感染特征,并分析其对脑功能的影响。方法回顾性调查浙江省中医药大学附属第一医院2021年6月~2023年5月收治的获得性脑损伤康复住院患者334例,记录入院时多重耐药菌感染情况,将患者分为MDRO组96例和非MDRO组238例,并在入院和出院时通过格拉斯哥昏迷量表(GCS)、Barthel指数(BI)进行脑功能评估。结果96例MDRO组共采集到204份微生物标本,分别来源于痰液(152/204,74.5%)、尿液(46/204,22.5%)、伤口分泌物(6/204,2.9%),耐碳青霉烯肠杆菌科细菌(CRZ)为最主要MDRO类型,病原菌前三位是铜绿假单胞菌、肺炎克雷伯菌、鲍曼不动杆菌。两组患者功能量表评分结果显示,MDRO组入院及出院时的功能障碍程度高于非MDRO组(P<0.01),且经过住院康复治疗后,两组出院时的GCS、Barthel指数均有改善(P<0.01)。结论28.7%的康复科获得性脑损伤患者在入院时存在多重耐药菌感染,主要来源于呼吸系统感染,最主要MDRO类型为CRE,其脑功能明显低于未感染患者,故今后在MDRO防控基础上,确保MDRO患者的康复治疗效果,以期改善患者的脑功能预后。

低强度超声促进药物递送的作用机制及研究进展

近年来,低强度超声促进药物递送的相关研究发展迅速,其应用涵盖多个给药场景,包括经皮给药(超声导入术)、声动力治疗以及血脑屏障开放等。从这3个视角入手,阐述了低强度超声促进药物递送的作用机制,包括热效应、空化效应、机械效应及生理调节效应等诸多生物效应,强调了局部空化作用和机械作用的重要性。此外,通过引用相关研究成果,展示了低强度超声在药物递送中的有效性,并指出了需进一步解决的相关问题,如药物释放的可控性与临床治疗的安全性,最后,概述了超声技术与纳米材料相结合,有望拓展药物递送的创新路径,为临床治疗提供更多有效安全的治疗方案。

MECT联合药物治疗精神分裂症患者的效果及对血清BDNF、GFAP、PRL水平的影响

目的:探讨无抽搐电休克疗法(MECT)联合药物治疗精神分裂症患者的效果及对血清脑源性神经营养因子(BDNF)、胶质纤维酸性蛋白(GFAP)、催乳素(PRL)水平的影响。方法:纳入2021年1月—2023年5月江西省精神病院收治的82例精神分裂症患者,遵照随机数字表法将其分为观察组及对照组,各41例。对照组采用利培酮+奥氮平抗精神药物治疗方案,观察组在对照组基础上加用MECT干预。比较两组治疗前后精神状态[阳性与阴性症状量表(PANSS)]、认知状态[蒙特利尔认知评估量表(MoCA)]、记忆功能[韦氏记忆量表(WMS)]、执行功能[威斯康星卡片分类测验(WCST)]、血清指标(BDNF、GFAP、PRL)及不良反应发生情况。结果:治疗后,两组PANSS(阳性症状、阴性症状、一般精神病理评分)、WCST(错误应答数、首次分类应答数)、GFAP、PRL水平均较治疗前降低,且观察组水平均低于对照组,差异均有统计学意义(P<0.05)。治疗后,两组MoCA评分、WMS(再认、图片、联想、背数记忆评分)、WCST(完成分类数、正确应答数、概念水平百分数)及BDNF水平均较治疗前升高(P<0.05),且观察组水平均高于对照组,差异均有统计学意义(P<0.05)。两组不良反应比较,差异无统计学意义(P>0.05)。结论:采用MECT联合抗精神药物治疗效果确切,可明显改善患者精神症状、认知、记忆及执行等功能障碍,改善脑营养状态,且安全性良好。

脑电生物反馈辅助治疗慢性精神分裂症的效果

目的:探讨慢性精神分裂症经脑电生物反馈辅助治疗后的疗效及对认知、社会功能的影响。方法:选取2022年1月至2023年9月我院确诊并接受治疗的慢性精神分裂症患者60例为本次研究的对象,其中30例患者接受抗精神病药物治疗,归为对照组,另30例在抗精神病药物基础上进行脑电生物反馈疗法,归为观察组。比较两组的临床疗效(临床疗效总评量表-疾病严重程度(Clinical Global Impression-SI,CGI-SI))、脑电活动特征(异常不自主运动量表(Abnormal Involuntary Movement Scale,AIMS))、症状改善情况(现状精神病症状检查(Present State Examination,PSE))、生活质量(日常生活评定量表(Activity of Daily Living Scale,ADL))及社会功能(社会功能缺点挑选量表(Social Disability Screening Schedule,SDSS))。结果:治疗后两组CGI-SI评分、AIMS评分、PSE各维度评分、ADL评分及SDSS评分均显著改善(P<0.05),且观察组各项评分均明显优于对照组(P<0.05)。结论:通过对比分析发现,脑电生物反馈疗法联合药物治疗后,患者临床表现、不自主运动症状及认知功能均可得到明显缓解,而且其生活能力及社会功能也得到不同程度的改善,可作为慢性精神分裂症的有效治疗方案。

不同药物治疗创伤性脑水肿的动物实验研究

为研究临床常用的甘露醇和速尿对创伤性脑水肿的治疗作用 ,因改良Feeney自由落体装置致大鼠创伤性脑水肿 ,分别用不同剂量的甘露醇、速尿及 2药合用进行治疗。通过对血 脑脊液屏障通透性的观察、脑组织含水量的测定及光镜、电镜下的病理组织学检查 ,判定各治疗组的疗效。结果 :大剂量甘露醇治疗组的脑水肿蓝染面积和脑组织含水量下降最明显 ,光镜及电镜下观察脑组织损伤最轻 ,但随着治疗次数的增加 ,其治疗效果反而下降 ;小剂量甘露醇和速尿合用组的脱水作用虽不如大剂量甘露醇组强 ,但随着治疗次数的增加 ,其治疗效果并未明显下降。结果提示 :甘露醇对于急性创伤性脑水肿的治疗效果最佳 ,使用甘露醇 5～ 6次后应使用小剂量甘露醇 +速尿治疗 ,单独应用速尿效果欠佳。

替莫唑胺联合全脑放疗治疗恶性肿瘤脑转移的Meta分析

目的系统评价替莫唑胺联合全脑放疗与单纯全脑放疗治疗恶性肿瘤脑转移的疗效和安全性。方法计算机检索Pub Med、The Cochrane Library、Web of Knowledge、中国生物医学文献数据库、中国知网和万方数据库等,收集替莫唑胺联合全脑放疗与单纯全脑放疗治疗恶性肿瘤脑转移的随机对照试验（RCT）,检索时限均从建库至2014年3月1日,并追溯纳入研究的参考文献。由2名研究者按照纳入排除标准独立筛选文献、提取资料和质量评价后,采用Rev Man 5.2软件进行Meta分析。结果纳入10个RCT,共584例患者。Meta分析结果显示,与单纯全脑放疗比较,替莫唑胺联合全脑放疗可以提高恶性肿瘤脑转移的近期疗效（OR=4.27,95%CI：2.67~6.83,P〈0.00001）,但消化道反应较严重（OR=1.78,95%CI：1.11~2.85,P=0.02）,差异有统计学意义,在头痛（OR=1.34,95%CI：0.82~2.18,P=0.24）、白细胞（OR=1.41,95%CI：0.81~2.44,P=0.22）和血小板下降（OR=2.26,95%CI：0.82~6.20,P=0.11）方面的差异无统计学意义。结论与单纯全脑放疗比较,替莫唑胺联合全脑放疗可显著提高恶性肿瘤脑转移患者近期疗效,但同时加重消化道反应,临床应用时需结合患者具体情况进行选择。

不同严重程度急性缺血性卒中患者静脉溶栓预后的影响因素分析

目的：观察不同严重程度急性缺血性卒中（AIS）患者静脉溶栓远期预后和出血转化的影响因素。方法：回顾性分析2009年6月至2013年12月在浙江大学医学院附属第二医院神经内科因AIS接受静脉溶栓治疗患者的资料，根据美国国立卫生研究院卒中量表（NIHSS）将患者分为轻度（≤8分）、中度（9～15分）、重度（≥16分）三组，分别观察影响患者溶栓后的预后（3月时改良Rankin评分≤2分定义为预后良好）及发生出血转化的因素。结果：共365例患者纳入分析：轻度134例、中度121例、重度110例。轻度AIS患者中，年龄[ OR＝0．937，95％可信区间（CI）：0．898～0．978；P＝0．003]、基线NIHSS（OR＝0．732，95％CI：0．564～0．950；P＝0．019）、发病至治疗时间在270 min内（ OR＝4．109，95％CI：1．441～11．719；P＝0．008）是预后良好的独立影响因素；而基线血糖（ OR＝1．326，95％CI：1．009～1．743；P＝0．043）是发生脑实质出血型出血转化的独立影响因素。中度AIS患者中，年龄（ OR＝0．954，95％CI：0．924～0．984；P＝0．003）、基线NIHSS （ OR＝0．760，95％CI：0．619～0．933；P＝0．009）是预后良好的独立影响因素；而心房颤动（ OR＝3．307，95％CI：1．140～9．596；P＝0．028）、收缩压（ OR＝0．967， 95％CI：0．943～0．991；P＝0．008）是发生出血性梗死型出血转化的独立影响因素，心房颤动（ OR＝36．972，95％CI：1．770～772．462；P＝0．02）是发生脑实质出血型出血转化的独立影响因素。重度AIS患者中，基线NIHSS （ OR＝0．808，95％CI：0．677～0．963；P＝0．018）是预后良好的独立影响因素，未发现发生溶栓后出血转化的独立影响因素。结论：对于不同严重程度的AIS患者，影响静脉溶栓后远期预后及发生出血转化的影响因素不尽相同；发病至治疗时间在270 min内是轻度AIS患者静脉溶栓后3个月预后良好的独立影响因素；心房颤动是中度AIS患者静脉溶栓后发生出血转化的独立影响因素。

十二井穴刺络放血联合薏苡仁对颅脑创伤性脑水肿作用的研究进展

十二井穴刺络放血和中药薏苡仁已被广泛应用于临床治疗,两者单独应用也取得不同程度的临床疗效,但对于他们联合应用治疗颅脑损伤的机制及治疗效果的研究报道少之又少。文章查阅了大量文献,总结出十二井穴刺络放血对颅脑创伤性昏迷患者的醒脑开窍作用和通过调节氢离子(H^+)、钾离子(K^+)、钠离子(Na^+)、钙离子(Ca^(2+))等离子而达到减轻脑水肿及神经保护作用的中西医理论依据,并且阐述了薏苡仁治疗创伤性脑水肿的研究进展,以及两者联合应用对颅脑创伤性脑水肿的疗效。