Neuroprotective potential of CB1 receptor agonists in an in vitro model of Huntington's disease

Background and purpose:

The therapeutic potential of cannabinoids in Huntington''s disease (HD) has been investigated by several groups with complex and sometimes contrasting results. We sought to examine key points of intersection between cannabinoid receptor 1 (CB₁) signalling, survival and the formation of mutant huntingtin aggregates in HD.

Experimental approach:

Using a simplified pheochromocytoma (PC12) cell model of HD expressing exon 1 of wild-type or mutant huntingtin, we assayed cell death and aggregate formation using high-throughput cytotoxicity and image-based assays respectively.

Key results:

CB₁ activation by HU210 conferred a small but significant level of protection against mutant huntingtin-induced cell death. Pertussis toxin uncoupled HU210 from the inhibition of cAMP, preventing rescue of cell death. Phosphorylation of extracellular signal-regulated kinase (ERK) was also critical to CB₁-mediated rescue. Conversely, treatments that elevated cAMP exacerbated mutant huntingtin-induced cell death. Despite opposing effects on HD cell survival, both HU210 and compounds that elevated cAMP increased the formation of mutant huntingtin aggregates. The increase in aggregation by HU210 was insensitive to Pertussis toxin and UO126, suggesting a G-protein alpha subtype s (G_s)-linked mechanism.

Conclusions and implications:

We suggest that the CB₁ receptor, through G-protein alpha subtype i/o (G_i/o)-linked, ERK-dependent signal transduction, is a therapeutic target in HD. However the protective potential of CB₁ may be limited by promiscuous coupling to G_s, the stimulation of cAMP formation and increased aggregate formation. This may underpin the poor therapeutic efficacy of cannabinoids in more complex model systems and suggest that therapies that are selective for the G_i/o, ERK pathway may be of most benefit in HD.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x     

Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005

Swift PGF, Skinner TC, de Beaufort CE, Cameron FJ, Åman J, Aanstoot H‐J, Castaño L, Chiarelli F, Daneman D, Danne T, Dorchy H, Hoey H, Kaprio EA, Kaufman F, Kocova M, Mortensen HB, Njølstad PR, Phillip M, Robertson KJ, Schoenle EJ, Urakami T, Vanelli M, Ackermann RW, Skovlund SE for the Hvidoere Study Group on Childhood Diabetes. Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005. Objective: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. Methods: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. Results: A total of 2062 adolescents completed questionnaires (age 14.4 ± 2.3 yr; diabetes duration 6.1 ± 3.5 yr). Mean HbA 1c = 8.2 ± 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). Conclusions: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.     

多发性硬化患者脑脊液标本收集和标本库建立的方案

<正> 迄今,多发性硬化(MS)脑脊液生物学标志物中用于临床的仅有寡克隆区带和IgG鞘内合成率,其最重要的制约因素为:生物学标志物研究所需的样本量很大,单一研究中心很难达到,因此多方合作已成为趋势。脑脊液标本的采集和保存很重要。2007年3月,欧洲MS生物学标志物协作网(BioMS-eu)在伦敦召开会议,拟定了MS患者脑脊液采集、分装、储存以及相关数据收集的方案,并于2009年12月1日在Neurology杂志发表。现简要介绍如下。 1 脑脊液标本收集及注意事项 (1) 采集量:至少12mL,采集此量不会引起低颅压。因不同段脑脊液蛋白质浓度不同,建议取最初2mL用于常规检查,其余部分混匀后     

Prolonged migraine aura without headache arrested by sumatriptan. A case report with further considerations

The case of a 42-year-old woman with prolonged migraine visual aura without headache, whose long-lasting episodes of visual aura were successfully controlled by oral sumatriptan, is reported. Effectiveness of sumatriptan was unequivocal, since, after taking sumatriptan, duration of aura would drop from 1.5 h to approximately 20 min. This case suggests that sumatriptan may cross the blood-brain barrier and block spreading depression.     

大环内酯类抗生素麦迪霉素的电化学特性

在K₂HPO₄,NH₄Cl+NH₃和NaOH的10%(v/v)乙醇水溶液中,除0.01mol·L^-1以上NaOH液作为支持电解质外,麦迪霉素的伏安波皆为两个峰。峰A相当于它的甲醛基还原波,峰B为催化吸附氢波。溶液pH对两峰有强烈的影响。实验表明伏安波有吸附特性,且不可逆。两峰的ip与麦迪霉素的浓度成正比,线性范围分别为3×10^-6～3×10^-5mol·L^-1和1×10^-7～4×10^-5mol·L^-1,检测限为:1×10-6mol·L^-1和5×10^-8mol·L^-1。可应用于麦迪霉素的定量测定。研究了两峰的特性和电极机理,测定了有关的物理常数。     

From Hippocrates to modern medicine

Hippocrates was the first to introduce the concept of 'physis' and to transform hieratic or theocratic medicine into rational medicine. The overall construction of the Asclepieion on Kos clearly indicates that he and his school followed a holistic concept, combining scientific thought with drug therapy, diet schedules, and physical and mental exercise, also asking for God's help. Hippocrates also formulated the first standards and ethical rules to be followed in medical profession, which are still valid today. The knowledge of Graeco-Roman medicine has been transferred by Arab scholars into the West, whereas renaissance, urbanization, and industrialisation have changed its face over the centuries. With the entrance of molecular technology and economy, modern medicine now faces the risk of becoming itself industrialized. Correct use of new scientific knowledge, individualized management with a Hippocratic holistic approach and compassionate sympathy for the patient who suffers, should be considered in the years to come for maintaining the level of medical profession. The venue of our European Congress in Rhodes is very close to Kos, another historic Aegean island, the place where Hippocrates has given the first professional standards in European medicine and in medicine in general. They were established 2600 years ago and are still valid today.(1,2) If one draws a red line and marks some cornerstones of the evolution that has taken place in medicine over the past centuries, it is evident that these first rules formulated by Hippocrates and his school also reveal the future responsibilities for our profession and make them better recognizable and more conclusive.