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.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

Brain delivering RNA-based therapeutic strategies by targeting mTOR pathway for axon regeneration after central nervous system injury

Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising intrinsic capability of recovering itself after injury.However,the hostile extrinsic microenvironment significantly hinders axon regeneration.Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration.Particularly,substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin(mTOR)signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries.In this review,we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury.Importantly,we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog(PTEN).Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway,we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose,and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination.To specifically tackle the blood-brain barrier issue,we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology.We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.

Acute liver failure following levetiracetam therapy for seizure prophylaxis in traumatic brain injury

This case report investigates an uncommon occurrence of drug induced acute liver injury directly associated with the administration of levetiracetam in a patient following traumatic brain injury.

The Use of Antiepileptic Drugs in Acute Neuropsychiatric Conditions: Focus on Traumatic Brain Injury, Pain, and Alcohol Withdrawal

Antiepileptic drugs (AEDs), have demonstrated efficacy treating a number of acute conditions, encompassing a broad range of symptoms and syndromes, in addition to being first-line treatment for epilepsy. Clinically, since their inception, AEDs have been used off-label for acute and chronic medical conditions, both as primary and as adjuvant therapies. In this review, we describe the observed clinical effectiveness of AEDs across a set of commonly encountered acute conditions in the general hospital: traumatic brain injury, pain, alcohol withdrawal. In describing the individual benefits and usages of specific agents, the applicability of these agents to other common neuropsychiatric conditions may be further explored.

Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

载药外泌体在中枢神经系统疾病中的热点问题

背景:利用外泌体作为药物载体不仅可以精确靶向治疗部位,还能提高局部浓度,为药物进入中枢神经系统开辟了一条新途径。目的:探讨外泌体的生物发生、生物学功能,综述当前有关细胞外囊泡作为药物载体在中枢神经系统疾病治疗中的最新进展。方法:由第一作者检索Web of Science、Pub Med和中国知网数据库1976年1月至2024年1月发表的相关文献,以“exosomes,extracellular vesicles,central nervous system,drug delivery,ischemic stroke,Alzheimer’s disease,Parkinson’s disease,spinal cord injury,brain tumor”为英文检索词,以“外泌体,细胞外囊泡,中枢神经系统疾病,载药,脑卒中,阿尔兹海默病,帕金森病,脊髓损伤、脑肿瘤”为中文检索词,最终纳入94篇文献进行分析。结果与结论:(1)外泌体可以轻易通过血脑屏障输送蛋白质、代谢物和核酸到受体细胞中,调节细胞代谢。由于外泌体是由细胞分泌的小囊泡,具有更低的循环免疫原性,在体内循环中能够更少被巨噬细胞识别清除。(2)外泌体可以被设计为递送不同的治疗成分,包括RNA、蛋白质、化疗药物和免疫调节剂,能够将治疗成分传送至期望的目标。经过工程修饰的外泌体具有更好的靶向性,并且这种外泌体介导的传递免疫原性极低,有望为将来中枢神经系统疾病的精准治疗提供更加安全有效的方法。

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.

Neuroprotective effects of the immunomodulatory drug Setarud on cerebral ischemia in male rats

immunomodulary drug Setarud, which is composed of herbal extracts including Rosa canina, Urtica dioica and Tanacetum vulgare, supplemented with selenium exhibits anti-inflammatory and anti-oxidant properties. Therefore, we hypothesized that Setarud will have a neuroprotective effect against ischemic cerebral injury. To validate this hypothesis, rats were intraperitoneally administered with 0.66 mL/kg Setarud for 30 minutes after middle cerebral artery occlusion. Triphenyltetrazolium chloride staining showed that Setarud could reduce cerebral infarct volume of rats subjected to cerebral ischemia. Transmission electron microscopy and hematoxylin-eosin staining results showed that Setarud could alleviate the degenerative changes in cortical neurons of rats with cerebral ischemia. The inclined plate test and prehensile test showed that Setarud could significantly improve the motor function of rats with cerebral ischemia. These findings suggest that Setarud shows neuroprotective effects against ischemic brain injury.

创伤性脑损伤及其治疗药物

创伤性脑损伤(traumatic brain injury,TBI)是一种威胁人类生命安全的常见损伤。由于其损伤机制复杂,目前外科手术是临床首选治疗手段,但针对手术后继发性TBI的预防与治疗尚没有有效治疗药物。研究TBI损伤机制、寻找有效治疗药物以减轻患者痛苦、提高生活质量,成为目前的研究热点。本综述概括了近几年有关TBI治疗的最新进展,包括TBI损伤机制、TBI动物模型建立和评价指标、治疗药物及其新型递送系统,其中新型药物递送系统概括了聚合物纳米粒、水凝胶、树枝状聚合物、脂质体、胶束和细胞外囊泡作为新型药物载体在TBI治疗中的应用,希望为安全、有效地治疗TBI提供新思路。

治疗下丘脑性肥胖的药物研究进展

下丘脑性肥胖(HO)是一种复杂而罕见的疾病,影响大脑中能量摄入和支出调节通路以及自主神经系统和外周激素信号的调节。目前药物治疗主要通过刺激交感神经兴奋和脂肪组织产热,从而以增加脂肪分解和能量消耗的方式抑制体质量的快速增长。此外,部分药物还可作用于大脑奖励中心,抑制HO患者过度摄食。本文介绍了外源性催产素(OXT)、芬特明/托吡酯合剂(Ph/T)、特索芬辛、赛美拉肽等新近研发药物的临床获益数据、不良反应和应用前景。

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。

药物抑制率联合K值、年龄与GCS评分对钝性重型颅脑损伤预后的评估价值

目的探讨药物[血小板花生四烯酸(AA)、血小板二磷酸腺苷(ADP)]抑制率联合血凝块形成时间(K值)、年龄与格拉斯哥昏迷量表(GCS)评分对钝性重型颅脑损伤(TBI)患者预后的评估价值。方法选择2021年1月至2022年12月该院收治的未使用抗血小板药物治疗的急诊钝性重型TBI患者184例,根据患者28 d病情好转情况分为预后良好组、预后不良组,比较两组患者一般资料。采集两组患者静脉血,均行TEG检查并比较两组患者凝血反应时间(R值)、血凝块形式时间(K值)、血凝块形成的最大幅度(MA值)、血凝块形成速率(α角)、血凝块力学强度(G值)、AA抑制率、ADP抑制率。采用多因素Logistic回归分析影响钝性重型TBI患者预后的因素。采用受试者工作特征(ROC)曲线分析药物抑制率联合K值、年龄、GCS评分对钝性重型TBI患者预后的评估价值。结果预后良好组138例,预后不良组46例。预后不良组患者年龄≥45岁、头部AIS评分5~6分、入院后插管比例、K值、AA抑制率、ADP抑制率明显高于预后良好组,R值、α角、MA值、G值、GCS评分明显低于预后良好组,差异均有统计学意义(P<0.05)。多因素Logistic回归分析显示,年龄≥45岁,K值、AA抑制率、ADP抑制率升高为钝性重型TBI患者预后不良的危险因素(P<0.05),GCS评分升高为钝性重型TBI患者预后不良的保护因素(P<0.05)。ROC曲线分析发现,AA抑制率、ADP抑制率、年龄、K值及GCS评分联合检测对钝性重型TBI预后的评估价值较高。结论AA抑制率和ADP抑制率升高、GCS评分降低、K值升高可作为预警指标,辅助评估钝性重型TBI患者的预后情况。

高压氧对大鼠脑缺血区线粒体氧自由基影响的实验研究

目的:研究高压氧(HBO)对大鼠脑缺血区线粒体氧自由基及抗自由基酶的影响。方法:参照改良的Koizumi方法,在激光多普勒血流仪监测局部脑血流的条件下,建立线栓法大鼠局灶性脑缺血模型,缺血90min后再灌注,缺血后3h高压氧治疗(3个标准大气压,1h),缺血后24h分别取缺血核心区和半暗区脑组织,差速离心提取线粒体,进行超氧阴离子自由基(O2.)生成速率、H2O2含量、丙二醛(MDA)含量测定,以及线粒体超氧化歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)和还原型谷胱甘肽(GSH)含量测定。结果:脑缺血再灌注24h后缺血半暗区和核心区线粒体的H2O2、O2.、MDA的含量较正常对照组明显增加,而SOD、GSH-PX活性以及GSH的含量较正常对照组明显下降(P<0.05)。经HBO治疗后,缺血半暗区线粒体O2.含量增加(P<0.05),SOD活性提高(P<0.05),而MDA含量减少(P<0.05);缺血核心区线粒体O2.含量增加(P<0.05),SOD活性提高(P<0.05),但MDA含量不变。HBO治疗对脑缺血区的H2O2、GSH-PX和GSH作用无影响。结论:在脑缺血时间窗内,HBO治疗能增加脑缺血区线粒体自由基生成,提高线粒体抗自由基酶活性;能抑制脑缺血半暗区线粒体的脂质过氧化损伤,但对核心区作用不明显。提示线粒体的功能状态在HBO治疗后的自由基反应中起重要作用。

针刺预处理脑组织提取液抗大鼠脑缺血再灌注损伤作用探讨

目的 :证实针刺预处理脑组织提取液的抗脑缺血再灌注损伤作用 ,为针刺效应物质的探讨提供初步的实验依据。方法 :先以“肾俞”“百会”穴针刺预处理大鼠脑组织提取液行大鼠腹腔注射 ,再采用颈动脉引流法脑缺血再灌注造模 ,脑组织石蜡包埋切片 ,HE染色 ,观察脑片缺血性病理变化 ,进行顶皮质Ⅰ区Ⅴ层幸存神经元计数。结果 :在 3个时间段F组幸存神经元密度均显著高于C、D、E 3组 (P <0 0 5 )。结论 :针刺预处理脑组织提取液具有明显的抗脑缺血再灌注损伤作用。

川芎嗪对大鼠脑急性缺血缺氧损伤的保护作用

利用脑片技术、电镜及检测自由基代谢指标，从离体与整体、功能与形态结构结合上，观察了川芎嗪对大鼠不完全性脑缺血的影响。结果表明，川芎嗪可以提高海马脑片的耐缺氧能力，并呈量效关系；能抑制神经突触传递和脑细胞过度兴奋，有效地防止缺氧对脑细胞造成的不可逆性损伤；对脑缺血大鼠大脑皮层的超微结构有显著保护作用；能减少大鼠缺血脑组织中血清脂质过氧化物（ＬＰＯ）的生成，增加血清超氧化物岐化酶（ＳＯＤ）和谷胱甘肽过氧化物酶（ＧＳＨ＿Ｐｘ）的含量。由此可见，川芎嗪对大鼠急性脑缺血缺氧损伤具有保护作用。

针刺治疗急性重型颅脑损伤临床疗效对比观察

目的 :观察针刺治疗急性重型颅脑损伤的临床疗效。方法 :随机分为治疗组与对照组各 30例 ,两组予相同的西医治疗 ,治疗组另加用针刺治疗 2个疗程。结果 :治疗组神志、语言、运动功能及预后评分均优于对照组 ,两组差异有显著性意义 (P <0 0 5 )。结论 :针刺有助于急性重型颅脑损伤患者神志、语言。

甘露醇和高渗盐水缓解家兔颅内高压的效果比较

目的:比较等渗透摩尔浓度的20%甘露醇和7.5%NaCl溶液降低颅内高压的效果,以及比较等体积量的高渗盐水7.5%NaCl溶液和23.4%NaCl溶液降低颅内高压的效果。方法:通过侧脑室插管灌注恒定压力的人工脑脊液建立家兔颅内高压模型,观察一定剂量的上述三种高渗溶液,分别对颅内高压家兔的平均动脉压、呼吸频率、潮气量、人工脑脊液灌流速度和脑含水率的影响。结果:当颅内压力从15 cmH2O升高到75 cmH2O时,家兔的平均动脉压升高,潮气量降低;经上述三种高渗溶液分别治疗后,家兔的平均动脉压,呼吸频率和潮气量在颅内高压前后的变化率与对照模型组比均无显著差异;经20%甘露醇5 ml/kg体重治疗或23.4%NaCl溶液2.2 ml/kg体重治疗后,颅内高压家兔的人工脑脊液灌流速度显著增加,脑含水率显著地降低,但两高渗溶液之间没有效应的差异;与对照组相比,7.5%NaCl溶液不能明显改变脑脊液的灌流速度和脑含水率。结论:在等渗透摩尔浓度下,20%甘露醇降颅内高压的效果要优于7.5%NaCl溶液;使用更高渗透摩尔浓度的高渗盐水23.4%NaCl溶液,能有效地降低颅内高压,可以替代甘露醇。

尼莫地平对脑出血患者脑损害保护作用的研究

目的:探讨脑出血后脑损害机制以及尼莫地平对脑出血后脑损害的保护作用。方法:将60例脑出血患者随机分为尼莫地平组与常规治疗组,患者均分别在治疗前后观察临床神经功能缺损评分、Barthel指数评分、血肿体积、水肿带体积。结果:治疗后临床神经功能缺损评分减少值尼莫地平组明显高于常规治疗组(P<0.01);尼莫地平组总有效率为73%,显著高于常规治疗组(40%,P<0.05)。治疗后BI评分增加值尼莫地平组明显高于常规治疗组(P<0.01);治疗后日常生活活动依赖程度尼莫地平组显著低于常规治疗组(P<0.05)。尼莫地平组和常规治疗组经治疗后血肿体积均明显缩小,尼莫地平组治疗后血肿体积减小值与常规治疗组治疗后血肿体积减少值比较无显著性差异(P>0.05)。尼莫地平组和常规治疗组治疗后水肿带均明显缩小,水肿带体积减少值尼莫地平组明显高于常规治疗组(P<0.01)。结论:临床神经功能缺损及临床残疾程度与脑出血后脑出血量、继发性脑水肿有着密切的关系。尼莫地平治疗脑出血有确切疗效,可减轻脑水肿,保护神经细胞,可减轻患者神经功能缺损程度,提高患者生活质量。

精制清开灵干预MCAO再灌注损伤的药效及机制研究

目的:观察工艺改进后的精制清开灵对大鼠局灶脑缺血再灌注损伤的拮抗作用。方法:选取成年雄性大鼠120只,采用线栓法建立大鼠脑缺血再灌注模型,应用核磁共振弥散加权成像技术、病理学指标判断不同治疗组对大鼠脑缺血再灌注的拮抗作用,原位杂交技术检测脑组织海马脑源性生长因子(BDNF)含量的变化。结果:精制清开灵减轻脑缺血大鼠再灌注损伤,核磁共振表现为病灶周边区RA值,FA值明显高于模型组,脑源性生长因子BDNF表达多于模型组。结论:精制清开灵具有脑神经保护作用,在有效时间窗内给予该药物的干预可能是减少脑缺血再灌注损伤的重要措施,其作用与BDNF有关。