Targeting metabolic and cognitive pathways of the CNS by intranasal insulin administration

Intranasal administration effectively delivers neuropeptides to the CNS, bypassing the blood-brain barrier and avoiding systemic side effects. Using this route of administration, direct manipulations of central nervous signalling pathways involved in body weight regulation and cognition are possible. Specifically, the subchronic intranasal administration of insulin has been shown to reduce body fat and improve memory function in the absence of adverse peripheral side effects. These results may fuel the future development of therapeutic strategies in disorders such as obesity and Alzheimer's disease that are promoted by dysfunctions of central nervous neuropeptidergic pathways.     

胰岛素鼻黏膜给药系统的研究进展

目的综述胰岛素近年来鼻黏膜给药的相关信息。方法查阅国内外相关文献36篇,进行相关分析、归纳和总结。结果综述出鼻黏膜给药的特点以及提高鼻黏膜生物利用度的诸多方法。在胰岛素制剂中加入安全高效的吸收促进剂或水不溶性粉末将会很大程度上提高其生物利用度。结论胰岛素鼻黏膜给药在药学领域将会有广阔的发展前景。     

鼻腔给药促进盐酸美普他酚在大鼠体内的吸收及脑转运

目的考察大鼠鼻腔给药后血和脑脊液中盐酸美普他酚 (MEP)的浓度，并与口服比较。方法采用连续采集法收集脑脊液样品，用HPLC-荧光检测器测定各生物样品中MEP的浓度。结果鼻腔给药后药物迅速吸收入血，并在血和脑脊液中达到高浓度，而MEP口服后体内药浓很低。鼻腔给药后血和CSF的AUC值分别为口服的7.375和15.6倍。结论MEP鼻腔给药具有起效快、生物利用度高的特点，有望成为口服的替代途径。     

Short interfering RNA and the central nervous system: development of nonviral delivery systems

The development of gene silencing therapies for neurological diseases has placed great importance on the delivery of short interfering RNA (siRNA) to the central nervous system (CNS). However, delivery of siRNA to neurons, glia and brain capillary endothelial cells (BCECs) has not been well established. This editorial describes different approaches that are being used to efficiently deliver siRNA to the CNS via intravenous, intracerebroventricular, or intranasal administration.     

Comparison of pharmacokinetics of Alprazolam after intranasal and intragastric administration in rats

Objective To compare the pharmacokinetics of Alprazolam after intranasal and intragastic administration in rats and evaluate the practicability of Alprazolam as a nasal drug delivery system.Methods 12 rats were randomly divided into two groups.The fate of drug in the serum of rats was monitered after intranasal and intragastic administration of Alprazolam 2 mg·kg-1.Serum levels of Alprazolam were determined by reversed-phase HPLC with Diode array detectors(DAD).Chromatographic conditions were adopted with ODS column as solid phase,methanaol-0.02 M ammonium acetate(pH=5.0)(60∶40)as mobile phase at a flow rate of 1.0 mL·min-1.The detection wavelength was 223 nm.The concentration-time data were analyzed using 3P87 program,and the pharmacokinetic parameters were compared by t-test.Results The pharmacokinetic characteristics were fit to two and one compartment opened model after intranasal and intragastic administration of Alprazolam,respectively.The drug absorption was quicker and the serum concentrations of Alprazolam was significantly higher in rats after intranasal administration group than that intragastic administration group(P<0.05).The eliminate parameters between the two groups were no significant difference(P>0.05).Means of pharmacokinetic parameters in intranasal and intragastic groups were:Ka 37.35±22.98 vs 11.57±12.47 h-1(P<0.05),t1/2ka0.025±0.013 vs 0.156±0.122 h(P<0.05),β(Ke)0.3131±0.1194 vs 0.3091±0.1216 h-1(P>0.05),t1/2β(t1/2Ke)2.51±0.99 vs 2.54±0.97 h(P>0.05),tmax 0.156±0.069 vs 0.618±0.414 h(P<0.01),Cmax 353.11±96.30 vs 62.09±35.08 μg·L-1(P<0.01),AUC 1111.6±473.2 vs 274.1±185.3 μg·L-1·h(P<0.01).Conclusions Alprazolam was absorbed quickly in rats after intranasal administration.And the serum concentration and bioavailability can be significantly increased after intranasal administration,which may be an effective preparation as nasal drug delivery system.     

毒扁豆碱鼻腔给药对小鼠学习记忆功能的影响

目的：研究毒扁豆碱鼻腔给药对小鼠学习记忆功能的影响。方法：采用水迷宫和被动回避性条件反应（跳台法,避暗法）试验观察毒扁豆碱鼻腔给药对小鼠学习记忆功能的影响,并测定鼻腔给药后血浆和脑组织内乙酰胆碱酯酶（AchE）的活力。结果：毒扁豆碱鼻腔给药对东莨菪碱所 致的记忆障碍有改善作用,并能明显降低血浆和大脑组织中AchE的活力。结论：毒扁豆碱鼻腔给药对小鼠学习记忆功能有明显的促进作用。     

The CNS as a target for peptides and peptide-based drugs

Peptides hold great potential as CNS drugs, but their delivery to the CNS is problematic. However, actual roadblocks to peptide delivery are different from those often perceived. Many peptides cross the blood–brain barrier by saturable and non-saturable mechanisms, and accumulate in brain in amounts sufficient to produce physiological effects. Peripheral factors (e.g., short half-life in blood) can be dominant factors limiting therapeutic use. Production of therapeutics that are enzymatically resistant and have long circulation times, even when the blood–brain barrier penetration is low, can result in substances with significant CNS accumulation. Surprisingly low amounts of peptide in brain can result in CNS effects, and so the dose needed for brain delivery is generally much smaller than for peripheral tissues. Brain-to-blood transporters can greatly limit CNS accumulation of a potential therapeutic. Finally, intranasal and intrathecal routes may be especially useful for substances that are rapidly degraded in blood or are large and hydrophobic, respectively.     

Excretion of mephedrone and its phase I metabolites in urine after a controlled intranasal administration to healthy human volunteers

Mephedrone is a stimulant drug structurally related to cathinone. At present, there are no data available on the excretion profile of mephedrone and its metabolites in urine after controlled intranasal administration to human volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Urine was collected at different timepoints on Day 1 and then on Days 2, 3 and 30. Samples were analysed for the presence of mephedrone and its metabolites, namely, dihydro-mephedrone, nor-mephedrone (NOR), hydroxytolyl-mephedrone, 4-carboxy-mephedrone (4-carboxy) and dihydro-nor-mephedrone (DHNM), by a validated liquid chromatography-tandem mass spectrometry method. All analytes were detected in urine, where 4-carboxy (C_max = 29.8 μg/ml) was the most abundant metabolite followed by NOR (C_max = 377 ng/ml). DHNM was found at the lowest concentrations (C_max = 93.1 ng/ml). Analytes exhibited a wide range of detection windows, but only 4-carboxy and DHNM were detectable in all samples on Day 3, extending the detection time of mephedrone use. Moreover, mephedrone had a mean renal clearance of 108 ± 140 ml/min, and 1.3 ± 1.7% of unchanged parent drug was recovered in urine in the first 6 h post administration. It is hoped that this novel information will be useful in future studies involving mephedrone and other stimulant drugs.     

鼻腔给予丙酸睾丸酮对雌性大鼠旷场行为的影响

目的观察雌性大鼠长期鼻腔给予丙酸睾丸酮后的旷场行为变化,推测鼻腔给予丙酸睾丸酮对中枢神经系统的影响。方法通过旷场实验观察雌性大鼠鼻腔给予丙酸睾丸酮后静止闻嗅行为、探索行为、趋触性行为、运动行为和理毛行为的变化。结果Intact-T组的静止状态闻噢次数比正常组增加了47％（P〈0．05）。Intact-T组大鼠鼻腔给予丙酸睾丸酮后climbing、rearing和sniffing行为次数比正常组分别减少了43％（P〈0．05）、56％（P〈0．05）和40％（P〈0．05）。Intact—T组大鼠鼻腔给予丙酸睾丸酮后垂直运动、水平运动和总径长比正常组分别减少了46％、45％和42％（P均〈0．05）。Intact—T组大鼠鼻腔给予丙酸睾丸酮后理毛潜伏期比正常组减少了84％（P〈O．05）,理毛数量和理毛持续时间比正常组分别增加了48％和41％。结论长期鼻腔给予丙酸睾丸酮增加了雌性大鼠的静止行为,减少了其活动行为。     

Pharmacokinetic behavior of huperzine A in plasma and cerebrospinal fluid after intranasal administration in rats

The aim of this study was to investigate the pharmacokinetic behavior of huperzine A (Hup A) in plasma and cerebrospinal fluid (CSF) after intranasal administration (0.5 mg/kg) in male Sprague‐Dawley rats. A pharmacokinetic study of intravenous Hup A (0.5 mg/kg) was also performed. The concentrations of Hup A in the biological samples were measured by high performance liquid chromatography–mass spectrometry. Blood samples were taken from the tail vein and CSF was sampled by cisternal puncture using a stereotaxic frame. The contribution of the olfactory pathway to the uptake of Hup A into CSF was determined by comparing the AUC_CSF/AUC_plasma ratios after intranasal and intravenous administration. The AUC ratios of intranasal to intravenous administration in CSF and plasma were 104% and 118%, respectively. No significant difference was observed between the AUC_CSF/AUC_plasma ratios of Hup A after intranasal administration (20%) and after intravenous infusion (23%). This indicated that approximately 20% of the Hup A level in plasma reached the CSF after both nasal and intravenous administration, and that no direct transport of Hup A from nose to CSF was found in rats. Copyright © 2009 John Wiley & Sons, Ltd.     

Brain microdialysate,CSF and plasma pharmacokinetics of ligustrazine hydrochloride in rats after intranasal and intravenous administration

The aim of this work was to investigate the pharmacokinetics of ligustrazine hydrochloride (LZH) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal (10 mg/kg) or intravenous administration (10 mg/kg) in male Sprague–Dawley rats. Plasma, CSF and cerebral cortex microdialysates were collected at timed intervals for the measurement of LZH by a quick and sensitive HPLC‐UV method. LZH entered the brain quickly following both routes of administration. No significant difference was observed between the AUC_{CSF or cortex}/AUC_plasma ratio of LZH after intranasal administration (38.4%, 17.4%) and that after intravenous injection (45.9%, 19.9%). The drug targeting index (DTI) was 0.85 and 0.91 in the CSF and cortex, respectively. In conclusion, LZH is rapidly absorbed into the systemic circulation following intranasal administration. There is no direct pathway for LZH transport from the nasal cavity to the brain. The rapidity and magnitude of LZH penetration into the brain indicate that intranasal administration of this agent is a promising alternative to intravenous administration. Copyright © 2013 John Wiley & Sons, Ltd.     

石杉碱甲鼻用原位凝胶的制备及其经鼻脑靶向性评价

目的探索利用鼻腔嗅觉区的鼻-脑通道开发经鼻脑靶向给药系统的可行性。方法用阳离子敏感性成胶辅料结冷胶，采用pH梯度沉淀法制备了石杉碱甲鼻用原位凝胶。以市售片剂和注射液为对照，用小脑延髓池插管法采集脑脊液，股动脉插管取血，测定其在大鼠脑脊液和血中药物动力学参数；用组织匀浆法，测定其在大鼠脑组织中的分布；用Morris水迷宫法、跳台法和避暗法试验其对大鼠和小鼠模型的药效。结果大鼠鼻腔给药血浆AUC_{0→6 h}为静注的0.94倍，但脑脊液AUC_{0→6 h}为静注和灌胃的1.3和2.3倍；大鼠鼻腔给药后大脑、海马、小脑、左右嗅球的AUC_{0→6 h}分别为静注的1.5，1.3，1.0，1.2和1.0倍，为灌胃的2.7，2.2，1.9，3.1和2.6倍。药效学研究表明以1/4～1/2口服剂量鼻腔给药与口服等效，与药动学结果相符。结论石杉碱甲原位凝胶鼻腔给药较静注和灌胃显著增加了药物在脑内，特别在其改善记忆障碍作用的靶部位——大脑和海马的分布，提高了药物的脑靶向性。     

降钙素基因相关肽经鼻给药进入中枢神经系统及促脑梗死修复的实验性研究

目的：寻找快速、便捷有效的靶向中枢给药方法,为脑梗死治疗提供新的思路。方法线栓法制作大鼠大脑中动脉闭塞（ Middle cerebral artery occlusion,MCAO）脑缺血再灌注模型,采用ELISA法测定经鼻（ IN）和静脉（ IV）注射CGRP后30 min时,各脑区的CGRP浓度,并观察IN和IV给予CGRP对局灶性脑梗死的治疗效果。结果 IN给药组脑部各区域、颈髓和脑脊液（Cerebro-sPinal fluid,CSF）中CGRP浓度较IV组显著增高（P＜0.01）,与IV组相比较,IN给药组梗死体积减小,脑血流量增加（ P＜0.01）。结论 CGRP经鼻靶向中枢给药可以避开血脑屏障阻碍,并对大鼠局灶性脑梗死有预防和保护作用。     

灯盏花素不同给药途径脑内药物分布的比较

本文比较了灯盏花素鼻腔给药、口服给药与静脉给药在大鼠脑内的药物分布。采用SD大鼠尾静脉注 射、经鼻给药和灌胃0.4 mg·kg^-1灯盏花素后, 于一定时间点用小脑延髓池穿刺术采集大鼠脑脊液, ¹²⁵I标记法测定其在大鼠脑脊液，以及大脑、小脑、延脑、嗅区和嗅球等脑组织及血浆中药物含量, 梯形法分别计算其AUC。结果显示鼻腔给药组大鼠脑脊液、大脑、小脑、延脑、嗅区、嗅球及血浆中AUC_{0-240 min} (μg·min·g^-1) 分别为11.686 ± 1.919, 5.676 ± 1.025, 7.989 ± 0.925, 7.956 ± 1.159, 17.465 ± 2.136, 24.2 ± 2.906和78.51 ± 12.05; 静脉给药组AUC_{0-240 min}分别为6.79 ± 0.661, 6.251 ± 0.40, 10.805 ± 1.161, 9.146 ± 1.04, 9.892 ± 1.532, 7.871 ± 0.842和173.91 ± 10.02; 口服给药组AUC_{0-240 min}分别为0.868 ± 0.167, 1.708 ± 0.266, 2.867 ± 0.725, 2.067 ± 0.313, 1.361 ± 0.308, 1.206 ± 0.255和 45.2 ± 7.52。口服、静脉注射、鼻腔给药后脑组织的AUC_{0-240 min}分别为血浆AUC_{0-240 min}的22.29%, 29.18%, 95.49%, 说明鼻腔给药的吸收率高于口服给药和静脉给药, 并且鼻腔给药后药物在脑组织中分布较高, 其与药效的关系值得进一步探讨。
     

Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

Introduction: Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also the ability to minimize the potentially hazardous off-target effects.

Areas covered: This review covers the role of intranasal insulin therapy for cognitive impairment and neurodegeneration, particularly AD. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The review provides evidence that brain insulin resistance is an important and early abnormality in AD, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy.

Expert opinion: Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy and specificity of intranasal insulin therapy.     

中药干预血脑屏障改善糖尿病认知功能障碍的研究进展

近年来糖尿病认知功能障碍作为一种糖尿病中枢神经系统并发症越来越受到人们的重视。糖尿病导致的中枢神经系统并发症常伴随着血脑屏障结构和功能的破坏。血脑屏障是中枢神经系统所特有的结构,对维持大脑内环境稳定以及分子转运起着重要作用。在糖尿病的病理发生发展过程中,高血糖、晚期糖基化终产物、炎性因子等诸多因素均可导致血脑屏障损伤,进而引起脑内神经元受损,从而导致认知功能障碍的发生。稳定血脑屏障可能成为治疗糖尿病认知功能障碍的主要策略之一,对血脑屏障改善糖尿病认知功能障碍以及相关中药的干预作用进行综述。     

脑中抗坏血酸的功能及神经递质对其的调节

目的综述抗环血酸在中枢神经系统中的功能以及神经递质对其的调节作用。方法查阅近年来国内外公开发表的有关研究论文 ,按功能和调节作用分类汇总。结果研究成果表明 ,抗环血酸在中枢不仅表现为抗氧化作用 ,还对神经递质、酶类及神经肽等物质起到调节作用 ,并且共浓度、释放以及功能受到中枢神经递质的调节。结论抗环血酸在中枢神经系统中的功能复发杂而重要 ,并受到多种节作用     

Challenges and opportunities in CNS delivery of therapeutics for neurodegenerative diseases

With an increase in lifespan and changing population demographics, the incidence of central nervous system (CNS) diseases is expected to increase significantly in the 21st century. The most challenging of the CNS diseases are neurodegenerative diseases, characterized by age-related gradual decline in neurological function, often accompanied by neuronal death. Alzheimer's disease, Parkinson's disease and Huntington's disease are some examples of neurodegenerative diseases and have been well described in terms of disease mechanisms and pathology. However, successful treatment strategies for neurodegenerative diseases have so far been limited. Delivery of drugs into the CNS is one of the most challenging problems faced in the treatment of neurodegeneration. In this review, we describe the difficulties with CNS therapy, especially with the use of biological macromolecules, such as proteins and nucleic acid constructs. CNS therapeutics also represents a huge opportunity and examples of strategies that can enhance therapeutic delivery for the treatment of neurodegenerative diseases are emphasized. It is anticipated that with an increase in biological understanding of neurodegenerative diseases, there will be even more therapeutic opportunities. As such, these delivery strategies have a very important role to play in the future in the translation of CNS therapeutics from bench to bedside.     

Methylation of neuronal and glial macromolecules by methylnitrosourea and dimethylnitrosamine in vivo

Rats were injected i.p. with radioactive methylnitrosourea and dimethyl-nitrosamine and neuronal and glial cell fractions separated from brain tissue after 4 h, 72 h and 10 days. DNA, RNA and protein were purified and specific radioactivity was determined. At all labelling times with methylnitrosourea neuronal nucleic acids were methylated to higher (1.5–2.0:1) specific radio-activity than glial nucleic acids. 7-Methylguanine appeared to be the major purine adduct and O⁶-methylguanine a minor adduct in the two cell fractions. The proportion of O⁶-methylguanine was equal in the two cell fractions. With dimethylnitrosamine, glial macromolecules were methylated to a greater extent than neuronal macromolecules. Neuronal cells appear to be inactive in the metabolism of dimethylnitrosamine. The level of methylation in brain tissue by dimethylnitrosamine was of a lower order than in liver tissue.     

Analysis of the cardiovascular responses to central injection of tryptamine in rats

Tryptamine (2-20 micrograms), administered into the lateral cerebral ventricle of the rat, evoked a pressor response which was sometimes followed by a prolonged depressor response. The intracisternal administration of tryptamine (7-20 micrograms) caused a slow progressive and long-lasting depressor effect without or with an initial pressor effect. The pressor response was accompanied by variable changes in heart rate, whilst the pure depressor response was accompanied by a decrease in heart rate. After transection of the spinal cord between C1 and C2 the pressor response was substantially reduced or abolished. Methysergide, injected centrally, antagonized in a dose-dependent manner the pressor effect, whilst p-chlorophenylalanine, atropine and hexamethonium, administered by the same route, did not diminish this effect. It is concluded that tryptamine, injected centrally, causes both increases and decreases in arterial blood pressure and heart rate. The pressor response to tryptamine results from the activation of central noncholinergic, methysergide-sensitive, receptor sites and the depressor response to tryptamine may be due to a centrally-induced reduction in sympathetic nervous activity. It is tentatively suggested that tryptamine, like 5-hydroxytryptamine, participates in the physiological regulation of the cardiovascular system of the rat, as both a central excitatory and inhibitory regulator.