The effects of ultrasound on blood-brain barrier

The brain is protected from the entry of foreign substances by blood-brain barrier (BBB), but becomes a barrier while chemotherapy is needed for the brain diseases. Ultrasound with microbubbles (MBs) has been shown to noninvasively increase the permeability of the BBB in the normal tissue and brain tumor. The real mechanism for disruption is still unknown. Hemorrhage was usually found in the sonicated region of the brain. Thus, treatment safety is the primary concern when considering clinical application of BBB disruption induced by ultrasound in the presence of MBs. Here we investigate the effects of ultrasound on the permeability of BBB whether the MBs were administered. The data reveals that Evans blue (EB) accumulation was highest in the brain after sonication with MBs. However, the permeability of BBB also can be significantly increased by ultrasound alone. These results demonstrated that noninvasive disruption of BBB by ultrasound alone with no damage is possible.

Anti-Parkinsonian Therapy:Strategies for Crossing the Blood–Brain Barrier and Nano-Biological Effects of Nanomaterials

Parkinson’s disease(PD),a neurodegenerative disease that shows a high incidence in older individuals,is becoming increasingly prevalent.Unfortunately,there is no clinical cure for PD,and novel anti-PD drugs are therefore urgently required.However,the selective permeability of the blood–brain barrier(BBB)poses a huge challenge in the development of such drugs.Fortunately,through strategies based on the physiological characteristics of the BBB and other modifications,including enhancement of BBB permeability,nanotechnology can offer a solution to this problem and facilitate drug delivery across the BBB.Although nanomaterials are often used as carriers for PD treatment,their biological activity is ignored.Several studies in recent years have shown that nanomaterials can improve PD symptoms via their own nano-bio effects.In this review,we first summarize the physiological features of the BBB and then discuss the design of appropriate brain-targeted delivery nanoplatforms for PD treatment.Subsequently,we highlight the emerging strategies for crossing the BBB and the development of novel nanomaterials with anti-PD nano-biological effects.Finally,we discuss the current challenges in nanomaterial-based PD treatment and the future trends in this field.Our review emphasizes the clinical value of nanotechnology in PD treatment based on recent patents and could guide researchers working in this area in the future.

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.

Biomaterials-based anti-inflammatory treatment strategies for Alzheimer's disease

The current therapeutic drugs for Alzheimer's disease only improve symptoms,they do not delay disease progression.Therefo re,there is an urgent need for new effective drugs.The underlying pathogenic factors of Alzheimer's disease are not clear,but neuroinflammation can link various hypotheses of Alzheimer's disease;hence,targeting neuroinflammation may be a new hope for Alzheimer's disease treatment.Inhibiting inflammation can restore neuronal function,promote neuro regeneration,reduce the pathological burden of Alzheimer's disease,and improve or even reverse symptoms of Alzheimer's disease.This review focuses on the relationship between inflammation and various pathological hypotheses of Alzheimer's disease;reports the mechanisms and characteristics of small-molecule drugs(e.g.,nonsteroidal anti-inflammatory drugs,neurosteroids,and plant extracts);macromolecule drugs(e.g.,peptides,proteins,and gene therapeutics);and nanocarriers(e.g.,lipid-based nanoparticles,polymeric nanoparticles,nanoemulsions,and inorganic nanoparticles)in the treatment of Alzheimer's disease.The review also makes recommendations for the prospective development of anti-inflammatory strategies based on nanocarriers for the treatment of Alzheimer's disease.

Nanoparticle drug delivery system for the treatment of brain tumors:Breaching the blood–brain barrier

To the Editor:Malignant brain tumors represent a substantial morbidity and mortality burden globally,with 308,102 new cases and 251,329 cancer-related deaths in 20201.Brain tumors encompass primary tumors originating in the brain and brain metastases(BM)that have been spread from cancer lesions of other organs.Besides,BM are the most prevalent intracranial malignant tumor affecting approximately 20%-40%of cancer patients2.

“Three-in-one” strategy of trifluoromethyl regulated blood-brain barrier permeable fluorescent probe for peroxynitrite and antiepileptic evaluation of edaravone

Epilepsy,as a chronic neurological disease of the brain,is closely related to oxidative stress,and the peroxynitrite(ONOO-)significantly rise up in this event.Therefore,ONOO-is considered as a potential biomarker for early prediction of epilepsy.However,some potential diagnostic reagents for epilepsy are hindered by the blood-brain barrier(BBB).Meanwhile,“drug repurposing”is attracting a growing interest.Edaravone(EDA),as a first-line drug in the clinical treatment of cerebral ischemia,plays antioxidant roles in scavenging free radicals,promising potential antiepileptic activity.Thus,it is imperative to develop fluorescent probes for monitoring ONOO-fluctuations in the epileptic brain.Hence,we proposed a novel fluorescent probe with the thiocarbonate as the promising recognition unit for ONOO-and dicyanoisophorone derivative as the fluorophore.Moreover,by the“three-in-one”strategy,the introduction of trifluoromethyl into DCI-ONOO-3 can extend the emission wavelength of the fluorophore,shorten the response and increase lipophilicity.Consequently,DCI-ONOO-3 was used for monitoring ONOO-fluxes in brain of epileptic mice and evaluating the antiepileptic efficacy of EDA.It opens up a new way for the design of BBB permeable fluorescent probes,and provides a convincing new method for the diagnosis and treatment of epilepsy.

Neuroprotective potential for mitigating ischemia-reperfusion-induced damage

Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition;this phenomenon is known as cerebral ischemia-reperfusion injury.Current studies have elucidated the neuroprotective role of the sirtuin protein family(Sirtuins)in modulating cerebral ischemia-reperfusion injury.However,the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration.In this review,the origin and research progress of Sirtuins are summarized,suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury,including inflammation,oxidative stress,blood-brain barrier damage,apoptosis,pyroptosis,and autophagy.The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways,such as nuclear factor-kappa B signaling,oxidative stress mediated by adenosine monophosphate-activated protein kinase,and the forkhead box O.This review also summarizes the potential of endogenous substances,such as RNA and hormones,drugs,dietary supplements,and emerging therapies that regulate Sirtuins expression.This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors.While Sirtuins show promise as a potential target for the treatment of cerebral ischemiareperfusion injury,most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans,potentially influencing the efficacy of Sirtuinstargeting drug therapies.Overall,this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.

Progress of research in the application of ultrasound technology for the treatment of Alzheimer’s disease

Alzheimer’s disease is a common neurodegenerative disorder defined by decreased reasoning abilities,memory loss,and cognitive deterioration.The presence of the blood-brain barrier presents a major obstacle to the development of effective drug therapies for Alzheimer’s disease.The use of ultrasound as a novel physical modulation approach has garnered widespread attention in recent years.As a safe and feasible therapeutic and drug-delivery method,ultrasound has shown promise in improving cognitive deficits.This article provides a summary of the application of ultrasound technology for treating Alzheimer’s disease over the past 5 years,including standalone ultrasound treatment,ultrasound combined with microbubbles or drug therapy,and magnetic resonance imaging-guided focused ultrasound therapy.Emphasis is placed on the benefits of introducing these treatment methods and their potential mechanisms.We found that several ultrasound methods can open the blood-brain barrier and effectively alleviate amyloid-βplaque deposition.We believe that ultrasound is an effective therapy for Alzheimer’s disease,and this review provides a theoretical basis for future ultrasound treatment methods.

A matrix metalloproteinase-responsive hydrogel system controls angiogenic peptide release for repair of cerebral ischemia/reperfusion injury

Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.

Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.

Intranasal administration of carbamazepine-loaded carboxymethyl chitosan nanoparticles for drug delivery to the brain

Epilepsy is considered as a common and diverse set of chronic neurological disorders and its symptoms can be controlled by antiepileptic drugs(AEDs). The presence of p-glycoprotein and multi-drug resistance transporters in the blood-brain barrier could prevent the entry of AEDs into the brain, causing drug resistant epilepsy. To overcome this problem, we propose using carboxymethyl chitosan nanoparticles as a carrier to deliver carbamazepine(CBZ) intranasally with the purpose to bypass the blood-brain barrier thus to enhance the brain drug concentration and the treatment efficacy. Results so far indicate that the developed CBZNPs have small particle size(218.76 ± 2.41 nm) with high drug loading(around 35%) and high entrapment efficiency(around 80%). The in vitro release profiles of CBZ from the NPs are in accordance with the Korsmeyer-peppas model. The in vivo results show that both encapsulation of CBZ in nanoparticles and the nasal route determined the enhancement of the drug bioavailability and brain targeting characteristics.

Liposome based drug delivery as a potential treatment option for Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions.Alzheimer’s disease is associated with dementia and a progressive decline in memory,thinking,and social skills,eventually leading to a point that the individual can no longer perform daily activities independently.Currently available drugs on the market temporarily alleviate the symptoms,however,they are not successful in slowing down the progression of Alzheimer’s disease.Treatment and cures have been constricted due to the difficulty of drug delivery to the blood-brain barrier.Several studies have led to identification of vesicles to transport the necessary drugs through the blood-brain barrier that would typically not achieve the targeted area through systemic delivered medications.Recently,liposomes have emerged as a viable drug delivery agent to transport drugs that are not able to cross the blood-brain barrier.Liposomes are being used as a component of nanoparticle drug delivery;due to their biocompatible nature;and possessing the capability to carry both lipophilic and hydrophilic therapeutic agents across the blood brain barrier into the brain cells.Studies indicate the importance of liposomal based drug delivery in treatment of neurodegenerative disorders.The idea is to encapsulate the drugs inside the properly engineered liposome to generate a response of treatment.Liposomes are engineered to target specific diseased moieties and also several surface modifications of liposomes are under research to create a clinical path to the management of Alzheimer’s disease.This review deals with Alzheimer’s disease and emphasize on challenges associated with drug delivery to the brain,and how liposomal drug delivery can play an important role as a drug delivery method for the treatment of Alzheimer’s disease.This review also sheds some light on variation of liposomes.Additionally,it emphasizes on the liposomal formulations which are currently researched or used for treatment of Alzheimer’s disease and also discusses the future prospect of liposomal based drug delivery in Alzheimer’s disease.

Brain-targeted drug delivery assisted by physical techniques and its potential applications in traditional Chinese medicine

The blood-brain barrier(BBB)constitutes a major obstacle to effective delivery of drugs to the brain.Recent technological advances have led to improvements in brain-targeted drug delivery.In this review,we summarize existing technologies for efficient drug delivery across the BBB.We discuss the mechanisms of current BBB-based drug delivery strategies and introduce prospects for application in braint-argeted delivery of traditional Chinese medicine.We highlight the use of physical techniques for brain-targeted drug delivery,including electroporation,ultrasound,magnetophoresis,microneedles,microwaves,and laser.The characteristics of these techniques and relevant studies employing these approaches are discussed.In general,microneedles,lasers,ultrasound,electroporation,magnetophoresis,and microwaves are effective for drug delivery across the BBB.Notably,the synergistic effects of multiple approaches are superior to the additive effects of each technique in isolation.Our review provides guidance for the practical application of brain-targeted drug delivery techniques in an efficient and safe manner.

The exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

Delivering therapeutics to the central nervous system（CNS） and brain-tumor has been a major challenge. The current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in providing significant benefits to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier（BBB）. The BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nanotherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer significant ad vantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are briefly discussed. The drug transport mechanisms at the BBB are outlined. The approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic approaches for their enhanced clinical application in brain-tumor therapy are discussed.

肠道屏障功能对消化道肿瘤化学治疗后不良反应及营养状况的影响

目的评价肠道屏障功能指标二胺氧化酶(DAO)、D-乳酸、内毒素对消化道肿瘤化学治疗(以下简称化疗)后常见不良反应发生率和营养状况变化的影响,确定肠道屏障功能指标对于化疗后不良反应和营养状态恶化的最佳预测值。方法收集2019年9月至2022年5月安徽医科大学附属安庆第一人民医院收治的77例消化道肿瘤患者的化疗前血清DAO、D-乳酸和内毒素,以及化疗前、后患者主观整体营养评估量表(PG-SGA)评分等临床资料。通过比较不同临床特征患者的DAO、D-乳酸和内毒素水平探究肠道屏障功能对化疗后不良反应和营养状态的影响。采用二元logistic回归分析筛选化疗后不良反应和营养状态恶化的影响因素,使用ROC曲线和约登指数确定DAO、D-乳酸和内毒素对化疗后不良反应和营养状态恶化的最佳预测值。结果骨髓抑制的发生不受DAO、D-乳酸和内毒素水平影响。化疗后呕吐、腹泻和营养状态恶化患者的化疗前DAO和D-乳酸水平较无呕吐、无腹泻和营养状态未恶化的患者更高(P均<0.05)。化疗后腹泻和转氨酶升高患者的化疗前内毒素水平较无腹泻和转氨酶未升高的患者更高(P均<0.001)。回归分析显示化疗前DAO、D-乳酸和3个月内行胃肠手术与化疗后呕吐相关(P均<0.05),D-乳酸是化疗后腹泻的独立影响因素(P=0.001),后程化疗和D-乳酸增高是化疗后营养状态恶化的影响因素(P均<0.05)。内毒素对于化疗后转氨酶升高的最佳预测值为17.36 U/L(AUC=0.850,P<0.001),DAO和D-乳酸对化疗后呕吐的最佳预测值分别为10.47 U/L(AUC=0.727,P=0.001)和18.55 mg/L(AUC=0.708,P=0.003),D-乳酸对化疗后腹泻的最佳预测值为17.63 mg/L(AUC=0.920,P<0.001),D-乳酸对于化疗后营养状态恶化的最佳预测值为12.77 mg/L(AUC=0.684,P=0.006)。结论肠道屏障功能指标DAO、D-乳酸和内毒素对于化疗后呕吐、腹泻、转氨酶升高和营养状态恶化均有预测作用。

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Bloode-brain barrier(BBB)strictly controls matter exchange between blood and brain,and severely limits brain penetration of systemically administered drugs,resulting in ineffective drug therapy of brain diseases.However,during the onset and progression of brain diseases,BBB alterations evolve inevitably.In this review,we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer’s disease,Parkinson’s disease,epilepsy,stroke,traumatic brain injury and brain tumor.The advances on optimization of small molecules for BBB crossing and non-systemic administration routes(e.g.,intranasal treatment)for BBB bypassing are not included in this review.

Advanced nano drug delivery systems for neuroprotection against ischemic stroke

Ischemic stroke(IS)represents a significant threat to brain health due to its elevated mortality and disability rates.The efficacy of small-molecule neuroprotective agents has been impeded by challenges associated with traversing the blood-brain barrier(BBB)and limited bioavailability.Conversely,advanced nano drug delivery systems hold promise for overcoming these obstacles by facilitating efficient transportation across the BBB and maintaining optimal drug concentrations.This review aims to explore advanced neuroprotective nano drug delivery systems as a means of effectively administering neuroprotective agents to the brain using pharmaceutical approaches in the treatment of IS.By examining these systems,researchers and clinicians can gain valuable insights and innovative concepts,illuminating the potential of advanced neuroprotective nano drug delivery systems.Leveraging these advancements can drive the progress of pioneering and efficacious therapeutic interventions for IS.

Novel drug-delivery approaches to the blood-brain barrier

The blood-brain barrier （BBB） maintains homeostasis by blocking toxic molecules from the circulation, but drugs are blocked at the same time. When the dose is increased to enhance the drug concentration in the central nervous system, there are side-effects on peripheral organs. In recent years, genetic therapeutic agents and small molecules have been used in various strategies to penetrate the BBB while minimizing the damage to systemic organs. In this review, we describe several representative methods to circumvent or cross the BBB, including chemical and physical strategies.

冰片对大鼠脑微血管内皮细胞ICAM-1表达量的影响

目的 :研究冰片对大鼠脑微血管内皮细胞ICAM -1表达量的影响。方法 :采用自由落体撞击硬脑膜致伤方法制成大鼠脑挫裂伤模型 ,将大鼠伤侧脑皮质制成石蜡切片 ,运用免疫组化学染色技术观察空白对照组 (C组 :只灌服石蜡油 )、冰片组 (B组 :灌服等量冰片石蜡油 )、脑外伤组 (M组 :脑挫裂伤组 )和脑外伤加冰片组 (M +B组 :脑挫裂伤大鼠灌服冰片石蜡油 )大鼠脑皮质微血管内皮细胞 (EC)膜表面细胞间粘附分子 -1 (ICAM -1 )量的表达 ,并进行半定量分析。结果 :C组EC无表达或有少量表达 ,服用冰片不能使I CAM -1表达增强 ,脑外伤后ICAM -1表达有明显增强 (P <0 .0 0 1 ) ,及脑外伤大鼠服用冰片可使ICAM -1表达明显减弱。结论 :证明冰片促血脑屏障 (BBB)开放与ICAM -1无关 。

神经退行性疾病状态下血-脑屏障变化机制及中药对血脑屏障的影响研究进展

血-脑屏障(BBB)结构和功能的完整性是维持中枢神经系统动态平衡的关键因素。BBB异常伴随神经退行性疾病的发展过程,不同的神经退行性疾病,其BBB异常的病理机制不同,而药物对BBB异常的改善作用也严重影响药物对神经退行性疾病的疗效。该文主要针对神经退行性疾病状态下BBB异常的分子机制及中药的调控作用及其机制两方面进行综述,为神经退行性疾病靶向血脑屏障药物的研发提供基础理论参考。