经鼻给药——有效避开血脑屏障的中枢用药途径

经鼻给药(intranasal administration)是一条可以避开血脑屏障阻碍,使药物直接进入中枢的给药途径.本文对其转运机制、影响因素及其研究进展进行介绍.     

经鼻给药脑靶向性研究进展

血脑屏障（Blood—brain barrier,BBB）的存在使很多药物经传统给药方式难以到达中枢,为神经精神疾病的治疗造成极大挑战。     

胰岛素样生长因子-Ⅰ经鼻给药可进入中枢神经系统并有效治疗实验性脑梗死

目的　寻找无创、简便有效的中枢给药方法 ,将胰岛素样生长因子 (IGF Ⅰ )直接运送到脑损伤区并避开血脑屏障 (BBB)的阻断。方法　制作大鼠大脑中动脉闭塞 (MCAO)脑缺血再灌流模型 ,应用12 5I标记IGF Ⅰ (5 0 μg ,2 5 μCi)和放射自显影等技术 ,比较经鼻嗅觉通路 (IN)和经静脉 (IV)注射IGF Ⅰ后 4 5min时 ,放射性标记的IGF Ⅰ在各脑区、颈髓、脑脊液、血和周围组织中的定量和定性分布 ,并观察IN和IVIGF Ⅰ对局灶性脑梗死的治疗效果。结果　IN组脑部各区域、颈髓和CSF中的12 5I IGF Ⅰ浓度较IV组显著高出 8～ 16 6倍 (P <0 0 1) ,以嗅球的IGF Ⅰ浓度最高 ,其次为CSF和丘脑 ,且IN 5 0 μgIGF Ⅰ与媒介液对照组比较显著降低脑梗死体积达 6 2 %以上 (P =0 0 0 4 ) ,而IV给予同样剂量的IGF Ⅰ却不能明显减轻脑梗死体积。结论　经鼻嗅觉通路的给药方法可以避开BBB的阻碍 ,迅速地将IGF Ⅰ递送到中枢神经系统 (CNS) ,使CNS获得显著提高的IGF Ⅰ浓度 ,并对脑梗死的修复起到良好的效果。     

经动脉脑部给药的研究进展

经动脉(IA)脑部给药,主要指经颈内动脉给药以治疗脑部疾病或研究脑部神经功能,具有局部浓度高、用药量少、全身副作用小等特点。近年来,该途径被广泛应用于脑功能定位、放化疗、治疗脑血管痉挛、溶栓、治疗颅脑感染等领域,并有望进一步应用于临床手术麻醉、亚冬眠治疗、基因及干细胞治疗、脑保护治疗等新兴领域。此综述归纳了IA脑部给药的概况、利弊及近几年的研究进展,并探讨其未来发展趋势。     

经鼻给予VEGF的脑靶向作用

目的观察碘标记血管内皮生长因子(125I-VEGF)经鼻给药在中枢神经系统的分布及其转运机制。方法选取SD大鼠、雄性16只,随机分为经鼻给药(IN)组(n=8),经鼻给予125I-VEGF 100μL,采用两侧鼻孔交替给药,单次给药剂量为10μL,间隔时间2min,给药时间18.5min。静脉给药(IV)组(n=8),单次静脉注射125I-VEGF 100μL。给药30min后,每组取两只大鼠收集脑脊液,其余大鼠留取动脉血后,仔细分离嗅球、纹状体、皮质、海马、下丘脑、中脑、脑桥、小脑和延髓等组织称重并进行放射计数。结果放射计数显示经鼻给予VEGF能进入神经系统,浓度分布依次为三叉神经、视神经、嗅球、嗅结节、纹状体、延髓、前皮质、中脑、脑桥、下丘脑、海马、小脑。脑脊液没有检测到125I-VEGF活性。静脉给予VEGF在外周浓度较高,而中枢系统分布较IN组明显减低(P<0.01)。结论经鼻给予VEGF可以绕过血脑屏障经嗅觉通路和三叉神经通路进入中枢神经系统,经鼻给予VEGF是治疗中枢神经系统疾病的有效方法之一。     

载药纳米系统脑肿瘤靶向给药研究进展

胶质瘤是最常见的原发性脑肿瘤,约占40％。大部分胶质瘤由于具有浸润生长及恶性变的特点,即使通过手术、放疗甚至化疗也难以治愈。有资料显示,胶质母细胞瘤经确诊后1年生存率仅为30％左右,平均生存期仅53周。化疗是恶性脑肿瘤综合治疗重要组成部分,但由于血脑屏障（blood-brain barrier,BBB）的存在,98％的小分子化合物和几乎所有大分子物质不能进入脑病变部位,限制了对化疗药物的选择。有研究表明纳米载体能携带药物穿透BBB,     

经鼻给予VEGF治疗脑缺血/再灌注大鼠的量效关系

目的探讨经鼻给予血管内皮生长因子(VEGF)治疗脑缺血/再灌注损伤大鼠的量效关系。方法48只SD大鼠随机分为四组:低剂量组(100μg/mL)、中剂量组(200μg/mL)、高剂量组(500μg/mL)及盐水对照组(n=12)。通过阻塞大脑中动脉制作大鼠局灶性脑缺血90 m in再灌注损伤模型。缺血后1d、7d和14 d行神经功能评价,14 d动物被麻醉,行组织学检查,应用图像分析系统计算梗死体积、评价血管形成。结果与对照组相比,经鼻给予中剂量VEGF,可明显降低梗死体积,改善神经功能(P<0.01);而低和高剂量组对比于对照组,不能降低脑缺血后大鼠脑梗死体积和改善神经功能(P>0.05)。与对照组相比,经鼻给予中和高剂量VEGF,可增加缺血后脑表面血管形成(P<0.01);而低剂量组对比于对照组,不能促进脑缺血后血管生成(P>0.05)。结论经鼻给予中剂量VEGF可有效降低脑缺血/再灌注损伤大鼠梗死体积,改善神经功能,增加血管密度。因此经鼻给予中等剂量(200μg/mL)VEGF是治疗脑缺血/再灌注损伤的最佳剂量,其可用于进一步评价VEGF作用的有效实验剂量。     

嗅觉系统结构功能及经嗅觉给药通路的研究进展

嗅觉信号的感觉与传导包含:初级嗅觉系统、附属嗅觉系统、三叉神经系统和终神经系统。多种神经递质参与了嗅觉的形成及传导。嗅觉系统与大脑皮层许多部位有广泛联系。当气味受体被一种有气味的物质激活时,就会在嗅觉受体细胞触发一个电信号,经过神经轴突传递到大脑。嗅觉的脑通路可能成为中枢神经系统药物直接进入脑的一条新途径。     

促红细胞生成素及其衍生物经鼻给药发挥神经保护作用研究进展

近年来,促红细胞生成素(EPO)除了在治疗贫血过程中的促红细胞生成作用,其神经保护作用在大量实验中被发现及证实。但是EPO属于生物大分子,难以通过血脑屏障(BBB),经腹腔、静脉及皮下注射EPO时产生的促红细胞生成作用增加了血栓形成的风险,这些因素制约了EPO神经保护作用的进一步研究及临床应用。EPO衍生物的开发和利用为EPO应用提供了新思路,而经鼻腔给药方式因其生物利用度高、损伤性小、不良反应少的特点,成为EPO发挥神经保护作用最具前途的方式之一。     

经鼻给予血管内皮生长因子对脑梗死大鼠梗死灶周区血管新生的影响

目的 观察经鼻给予血管内皮生长因子(VEGF)对大鼠局灶性脑缺血后梗死灶周区血管新生的影响.方法 采用大鼠大脑中动脉阻塞(MCAO)模型,随机分成VEGF组(12只)和生理盐水对照组(12只),分别于右侧MCAO后第3天起经鼻给予VEGF或等量生理盐水直至处死前1天;另设假手术组(6只).所有大鼠均于术后第1天起按体质量50 mg/kg经腹腔注射5-溴脱氧尿嘧啶核苷(BrdU),每日1次,连续13 d用以标记增殖细胞,分别在MCAO后第1、7、14天行改良神经功能评分,于术后第14天经尾静脉注入异硫氰酸荧光素右旋糖酐(FITC-dextran),采用免疫荧光双标及激光共聚焦方法检测梗死侧灶周区BrdU+/vWF+表达和微血管数.结果 与对照组及假手术组相比,术后第7天及第14天经鼻给予VEGF可明显改善大鼠神经功能,术后第14天假手术组仅见少量BrdU+/vWF+细胞,VEGF组梗死灶周区BrdU+/vWF+细胞数与对照组相比显著增高(P<0.01),FITC-dextran标记显示VEGF组梗死灶周区微血管数较对照组显著增加(P<0.01).结论 经鼻给予VEGF可促进局灶性脑缺血后梗死灶周区血管再生,促进梗死后神经功能恢复.     

不典型性中枢神经系统Whipple病:一例报告并文献复习

目的结合文献探讨中枢神经系统Whipple病的诊断与治疗特点,以提高对该病的认识。方法回顾分析1例以头痛、左侧肢休无力,伴记忆力减退为首发症状的不典型性中枢神经系统Whipple病的临床诊断与治疗经过,并进行文献复习。结果女性患者,35岁。首发症状表现为头痛、肢体无力及记忆力减退,但不伴发热、癫癎发作。病程进展过程中相继出现阵发性四肢抽动、右侧下肢无力、小便失禁、多食、体质量增加、停经、体温波动,大剂量糖皮质激素及青露素、复方磺胺甲噁唑等抗炎药物治疗无效,随着颅内压逐渐升高,脑疝形成。腰椎穿刺脑脊液检测仅蛋广白定量显著升高。脑电图提示右侧前额颞区慢波。MRI呈以右侧大脑半球、额顶颢叶、半卵圆中心及基底节为主的大片长T₁、长T₂信号,并不均匀疏松团状强化,病灶周围水肿,占位效应明显,并累及左侧大脑半球。病理学检查呈现大片状坏死,脑组织及血管周围大量淋巴细胞和浆细胞浸润,伴大量格子细胞渗出,胞质丰富,内含大量六胺银和PAS染色阳性的细小颗粒状物质。排除中枢神经系统肿瘤、脱髓鞘病变及炎性假瘤等疾病。结论中枢神经系统Whipple病极为罕见,临床及影像学表现复杂多样,病理学检查仅能提示特殊感染,治疗困难,误诊率及病死率高。早期进行组织活检,结合临床表现及病理学特征可以明确诊断,经规范的抗生素治疗,患者可获得良好预后。     

Autoimmune maintenance and neuroprotection of the central nervous system

The genesis of immune privilege high in the evolutionary tree suggests that immune privilege is necessary, if not advantageous for the progressive development of the CNS. Upon reaching a certain degree of complexity, it seems as if the CNS was obliged to restrain the immune system from penetrating the blood-brain barrier. CNS autoimmunity against myelin proteins is known to be a contributory factor in the pathophysiology of multiple sclerosis and in the animal model of experimental autoimmune encephalomyelitis (EAE) (Wekerle, 1993). Such autoimmunity has therefore been regarded as detrimental and hence obviously undesirable. However, recent findings in our laboratory suggest that T-cell autoimmunity to CNS self-antigens (Moalem et al., 1999), if expressed at the right time and the right place, can do much good in the CNS. We shall review the experiments briefly, and then discuss their implications for our understanding of immune privilege and CNS maintenance after injury.     

肠道微生物与常见中枢神经系统疾病相关性的研究进展

肠道微生物不仅局限作用于胃肠道,可以通过脑肠轴对大脑功能产生重要影响.肠道微生物结构与功能的改变与阿茨海默病、帕金森病、多发性硬化、脑卒中等一系列常见中枢神经系统疾病密切相关,通过改善肠道微生物的微生态疗法有望成为预防和治疗中枢神经系统疾病的有效途径.现对近年来肠道微生物与常见中枢神经系统疾病的相关研究进展进行综述.     

叶酸受体在中枢神经系统肿瘤中的研究进展

叶酸受体是一种锚着于膜上的糖蛋白,对叶酸具有高度亲和力,在正常组织分布较少,而在多种恶性肿瘤有过度表达,以叶酸受体为作用靶点,使药物与特异性配体结合即可将药物主动靶向肿瘤细胞.本文就叶酸和叶酸受体的组成、生物学特性、在中枢神经系统肿瘤中的分布特点,以及叶酸受体介导主动靶向肿瘤细胞治疗的研究进展进行综述.     

Regional distribution of pituitary adenylate cyclase activating polypeptide (PACAP) in the rat central nervous system as determined by sandwich-enzyme immunoassay

We investigated endogenous levels of a novel peptide, pituitary adenylate cyclase activating polypeptide (PACAP), in the rat central nervous system. The amount of PACAP was measured by means of highly specific and sensitive sandwich-enzyme immunoassay. This assay system following HPLC analysis revealed that PACAP38 was a major portion of the total PACAP immunoreactivity and PACAP27 levels were negligibly low in the brain. Therefore, we measured the amount of PACAP38 in 62 regions punched out from frozen tissue sections. High amounts of PACAP38 were found in the lateral septal nucleus (intermediate part), diagonal band, central amygdaloid nucleus, several parts of the hypothalamus (suprachiasmatic, supraoptic, periventricular and arcuate nuclei), central gray, interpeduncular nucleus and dorsal raphe. The suprachiasmatic, paraventricular and periventricular hypothalamic nuclei showed the highest levels. A moderate amount of the peptide was observed in the lateral septal nucleus (dorsal part), medial septal nucleus, medial amygdaloid nucleus, thalamus (paraventricular, paratenial, central medial, ventromedial, reuniens and rhomboid nuclei), hypothalamus (lateral hypothalamic area and mammillary body), ventral tegmental area, interfascicular nucleus and in the locus coeruleus. Such a distribution of endogenous PACAP38 did not parallel the localization of PACAP binding sites which we had demonstrated recently. Moreover, the topographical distribution of PACAP38 observed in the present study differed from that of VIP which had been previously reported. The present results suggest that PACAP38 may have a neurotransmitter/neuromodulator role which is different from that of VIP in the central nervous system.     

Whipple''s disease and the central nervous system a case report and a review of the literature

A 65-year-old man was suffering from recurrent manic psychosis accompanied by weight loss. He also had a history of pleural effusion, aspecific migratory non-deforming seronegative polyarthritis, sensorineural hearing loss and semicircular canal paresis. Whipple's disease (WD) had been diagnosed at the age of 63 years. On admission to hospital)he had weight loss, diarrhoea in combination with an organic, brain syndrome, hemiparesis and ophthalmoplegia, including internuclear ophthalmoplegia (INO). A clinical diagnosis of central nervous system (CNS) WD was made. MRI revealed a thalamus lesion that halved in size during sulfamethoxazole-trimethop:rim treatment. The organic brain syndrome and ophthalmoplegia diminished also, as did the cerebrospinal fluid (CSF) IgG level. A review of CNS WD is presented and implications for treatment are discussed.     

我国人类免疫缺陷病毒和梅毒螺旋体感染中枢神经系统研究进展

获得性免疫缺陷综合征(亦称艾滋病)和梅毒在全球范围内广泛流行,严重危害国家公共卫生安全。我国对人类免疫缺陷病毒(HIV)相关中枢神经系统损害及神经梅毒的研究日益增多。本文检索目前国内学者发表的HIV和梅毒螺旋体感染中枢神经系统的相关文献,总结其流行病学特征、发病机制、临床特点、诊断与治疗策略,以为临床诊断与治疗提供新的思路。     

Morphology of demyelination in the human central nervous system

The principles of the neuropathological classification of disorders of central nervous system myelin are recalled. They are illustrated by a few selected examples. Dysmyelination is characterized by the production of an abnormal and unstable myelin sheath; it is often associated with hypomyelination (paucity of myelin formation) and is due to metabolic disorders. It is the main process in leukodystrophies. Storage of different lipids (e.g. sulfatides, long-chain fatty acids) or associated pathology of various cell types (in Alexander's disease, for example) are used for classifying these disorders. Biochemical and genetic characterizations are presently ongoing. Demyelination is the destruction of apparently normal myelin. It is often followed by remyelination. Our present knowledge on the neuropathology of multiple sclerosis, the most common demyelinating disease, is summarized. Cell-mediated demyelination affects the myelin sheaths for an obscure reason. The causes of the multifocal and sharply demarcated plaques, and of the fading of the remyelination process at the edge of some plaques, are not clear. A few examples of demyelinating diseases of known etiology and of various mechanisms are given. The similarities between acute disseminated leukoencephalitis and experimental autoimmune encephalitis are stressed. In progressive multifocal leukoencephalopathy, chronic infection of oligodendrocytes by JC virus induces poorly defined areas of demyelination. In AIDS, the pathogenesis of the myelin change is unclear. Macrophages may be responsible. Toxic and vascular disorders provide also good models for the understanding of mechanisms of demyelination.     

Viral infections of the central nervous system

Viral infections of the central nervous system in the tropical countries of Asia and the Indian subcontinent are different from those of the Western and developed world. Many of the endemic and epidemic encephalitides that are prevalent in these regions, such as Japanese encephalitis, have characteristic findings on imaging, especially on magnetic resonance imaging, allowing a rapid diagnosis and differentiation from clinically similar syndromes. Other emerging viral infections in the region in recent years have posed new challenges. The contribution of neuroimaging to the management of these emerging infections is also discussed.     

Hexachlorophene and the central nervous system

Summary A study on hexachlorophene encephalopathy in mice and baboons is reported. By light microscopy, a severe spongiform lesion of the central nervous system (CNS) was localized in the white matter, without myelin breakdown or cellular reaction. By electron microscopy, the myelin alteration was characterized by wide intralamellar spaces or splitting developed in the intraperiod line of compact sheaths. The acute changes described were induced by administration of the drug by the digestive or cutancous routes at various dosage levels in an aqueous solution or in talcum powder. The toxic effects depended on the age of the animals, the survival times and the concentrations of hexachlorophene, i.e., 6%, 3%, and 0.5%. The findings are compared with previous reports on the neurotoxicity of hexachlorophene and other chemicals in humans and experimental animals. Hexachlorophene cannot be recommended for use in young infants because of its neurotoxicity in very low doses as demonstrated in the present report.