胰岛素样生长因子1、载脂蛋白酶E基因多态性与阿尔茨海默病关系的研究

目的探讨河南省汉族人群胰岛素样生长因子1(insulin like growth factor 1,IGF-1)基因rs972936位点多态性、载脂蛋白酶E(Apo E)基因多态性与阿尔茨海默病(Alzheimer’s disease,AD)之间的相关性。方法选取58例AD患者和126例年龄、性别相匹配的健康对照(ND)者为研究对象,柱层析法提取外周血基因组DNA,采用PCR和基因测序技术检测IGF-1基因rs972936位点及Apo E基因型多态分布,并进行对比分析。结果与ND组比较,AD组IGF-1基因rs972936位点3种基因型分布总体差异有统计学意义(χ~2=6.108,P=0.047),其中AD组中GG基因型的频率高于对照组(70.7%51.6%,χ~2=5.935,P=0.015),G等位基因频率明显高于健康对照组(χ~2=6.502,P=0.011);AD组Apo Eε4等位基因频率可能增加AD的患病风险(OR=2.872,95%CI 1.542~5.351)(P=0.001);Apo Eε4等位基因不影响IGF-1基因rs972936位点的基因型或等位基因的分布频率(P0.05)。结论 IGF-1基因rs972936位点多态性与河南汉族人群AD的发病可能有相关性,其中GG基因型、G等位基因可能是AD发病的独立于Apo Eε4等位基因的危险因素。Apo Eε4等位基因是散发性AD的主要危险因素。     

肾素-血管紧张素系统与阿尔茨海默病

肾素-血管紧张素系统(RAS)是一循环内分泌系统,脑内存在RAS活性,目前关于RAS在脑内定位、以及与阿尔茨海默病(AD)相关的遗传学和分子生物学研究已取得了一定进展。文章综述了RAS与AD的关系,并从血管紧张素转化酶抑制剂(ACEI)、血管紧张素II受体1阻滞剂(ARB)类降压药物在AD中的临床应用等方面总结了RAS在AD中的研究进展。     

ATP结合盒转运子7与阿尔茨海默病关系的研究进展

最近随着全基因组关联研究(genome-wide association study,GWAS)在AD遗传研究方面的进展,发现了新的易患基因—三磷酸腺苷结合盒转运体7(ABCA7)。ABCA7基因多态性与AD的关系成了研究的热点。本文将ABCA7基因及其在AD发病中潜在的作用予以综述,为AD的临床研究提供方向。     

胰岛素样生长因子-1与抑郁症

本文综述了胰岛素样生长因子-1(IGF-1)与抑郁症在神经内分泌方面的关系的研究进展。     

迟发性运动障碍与IGF-1关系的研究

迟发性运动障碍(Tardive dyskinesia,TD)是精神科常见的一种由长期服用抗精神病药物所诱发的运动系统运动不良,有明显的不可逆性和致残性,发生率高。目前有关迟发性运动障碍的病因学研究包括多巴胺超敏、氧化应激、神经元毒性学说以及基因关联研究等,大都只局限于神经损伤,而相应的神经保护研究很少。胰岛素样生长因子-1(Insulin-like growth factor-1,IGF-1)是一种与机体组织分化、增殖和成熟有关的重要细胞因子。IGF-I具有较强的抗凋亡作用,是一个重要的细胞存活因子;作用包括对神经损害的保护、神经发生、髓鞘形成、突触发生和树突形成。IGF-1在神经损伤后的保护方面发挥着非常重要的作用,以往的研究表明首发精神分裂症患者在抗精神病药物治疗之前就存在糖代谢相关因子IGF-1的异常,精神分裂症伴发TD患者中IGF-1的异常是否并不是由抗精神病药物引起,而是在抗精神治疗之前就存在。通过对IGF-1在TD发生中的保护机制研究,以确定IGF-1异常是TD的内在素质因素,试图提出TD发生的可能预测指标,为TD的早期预防和选择药物治疗靶点提供理论依据。     

线粒体 DNA 与阿尔茨海默病的关系

阿尔茨海默病(AD)是最常见的与痴呆有关的神经退行性疾病。已证实家族聚集性 AD与淀粉样前体蛋白基因及早老素1、早老素2基因的突变有关,而迄今为止,仍未发现与散发性 AD 相关的致病基因。研究表明,线粒体 DNA(Mitochondrial DNA,mtDNA)突变可导致能量代谢障碍、氧化应激增多以及β淀粉样蛋白的积累,进而导致 AD 的发生、发展。然而,关于 mtDNA 突变或单倍群与 AD关系的研究结果是有争议的。现对 mtDNA 与 AD 的关系进行综述,以期指导后续研究。     

IGF-Ⅰ与血管性痴呆关系的研究进展

血管性痴呆是老年性痴呆的常见病因,是脑血管疾病造成的脑部损伤所致的智力损害。IGF-1属于胰岛素家族,CNS中的IGF-1通过与其受体结合发挥促进神经元分化的作用。血循环和脑中的IGF-1浓度随年龄增长而降低,并与年龄老化产生的智能减退有关。在脑缺血性损伤后,脑组织中IGF-1及其受体表达增加,能减少梗死面积,修复损伤的神经元。血管性痴呆患者组织病理学上有胆碱能活性降低,脑内炎性斑块形成等AD脑特征,IGF-1是脑内胆碱能系统潜在调节因子,并可减弱β淀粉样片断的毒性作用。     

IGF-1与血管性痴呆关系的研究进展

血管性痴呆是老年性痴呆的常见病因,是脑血管疾病造成的脑部损伤所致的智力损害.IGF-1属于胰岛素家族,CNS中的IGF-1通过与其受体结合发挥促进神经元分化的作用.血循环和脑中的IGF-1浓度随年龄增长而降低,并与年龄老化产生的智能减退有关.在脑缺血性损伤后,脑组织中IGF-1及其受体表达增加,能减少梗死面积,修复损伤的神经元.血管性痴呆患者组织病理学上有胆碱能活性降低,脑内炎性斑块形成等AD脑特征,IGF-1是脑内胆碱能系统潜在调节因子,并可减弱β淀粉样片断的毒性作用.     

早期生长反应因子1参与阿尔茨海默病发病的研究进展

阿尔茨海默病(AD)是一种进行性发展的神经系统退行疾病,由于病因不明和发病隐匿,对于该疾病的诊疗和预后仍是我们当前迫切需要面对的挑战。因此,探究AD的发病机制显得日益重要。早期生长反应因子1(EGR1)是一种与细胞增殖、分化有关的核转录因子,参与人体内多个靶基因的表达调控。有研究发现,AD患者脑内的EGR1表达水平增高,且EGR1蛋白在神经元纤维缠结密度高的神经元中富集,提示EGR1与AD的发病或进展存在密切联系。该文主要从β淀粉样蛋白肽、异常磷酸化tau蛋白、胆碱能神经系统障碍、调控衰老程序以及细胞炎症等方面探讨EGR1与AD的病理关系,并对其参与AD发病机制的研究进展做一综述,旨在为未来AD的临床治疗及研究方向提供新思路。 [国际神经病学神经外科学杂志, 2022, 49(3): 97-101.]     

精神分裂症患者血清胰岛素样生长因子水平分析

目的探讨精神分裂症患者血清胰岛素样生长因子(insulin-like growth factors,IGFs)水平与精神病理症状的关系。方法研究共纳入精神分裂症患者41例(患者组)和健康受试者40例(对照组),采用阳性与阴性症状量表(PANSS)评估患者精神病性症状,使用酶联免疫吸附法(ELISA)测定血清IGF-1和IGF-2水平。结果患者组血清IGF-1和IGF-2含量均显著低于正常对照组(P<0.05)。相关性分析发现,患者血清IGF-1水平与PANSS阳性症状评分负性相关(r=-0.462,P=0.026),而血清IGF-2水平则与阴性症状评分负性关联(r=-0.395,P=0.034)。结论精神分裂症患者血清IGFs水平存在异常,并与精神病理症状有关,提示IGFs参与精神分裂症的病理过程,可能是疾病症状评估的生物学指标。     

Effects of insulin-like growth factor 1 on synaptic excitability in cultured rat hippocampal neurons

Insulin-like growth factor 1 (IGF-1) has important functions in the brain, including metabolic, neurotrophic, neuromodulatory and neuroendocrine actions, and it also prevents beta amyloid-induced death of hippocampal neurons. However, its functions in the synaptic excitability remain uncertain. Here we investigated the effects of IGF-1 on synaptic excitability in cultured rat hippocampal neurons using whole-cell patch clamp recordings. Incubation the hippocampal neurons with different concentrations of IGF-1 for 24 h or 30 min significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), but had no effect on the frequency of miniature EPSCs (mEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs). The mean amplitudes, rise, and decay kinetics of sEPSCs, mEPSCs, and sIPSCs were not significantly affected by IGF-1, indicating that IGF-1 increased the probability of neurotransmitter release but did not modulate postsynaptic receptors. The effects of IGF-1 were mediated by mitogen-activated protein kinase (MAPK). IGF-1 activated the ERK1/2 signaling pathway in cultured hippocampal neurons, and the inhibitor PD98059 blocked the enhancement of sEPSCs induced by IGF-1. These results demonstrated the regulatory function of IGF-1 on synaptic excitability in hippocampal neurons and its underlying signaling mechanism.     

IGF-1 produced by cone photoreceptors regulates rod progenitor proliferation in the teleost retina

Teleost eyes grow throughout life by adding neurons and stretching extant tissue. New retinal neurons of all types are added at the ciliary margin and new rod photoreceptors are inserted throughout retina in the outer nuclear layer (ONL). New rod photoreceptors result from the division of progenitor cells located in the ONL amidst functioning rod photoreceptor cell nuclei, but it is not known how new rod addition is regulated. Previous experiments using an organotypic retinal slice preparation revealed that insulin-like growth factor 1 (IGF-1) up-regulates the division of the rod progenitor cells [Dev. Brain Res. 76 (1993) 183], but the site of IGF-1 action was unknown. Here, we show where in the retina IGF-1 is made, where IGF receptors are located, and we identify the role of IGF-1 in adult retinal rod neurogenesis with both gain-and loss-of-function experiments. We found that IGF-1 is expressed by cone photoreceptor cells and its abundance varies with a daily rhythm, being significantly higher at night. In vivo application of exogenous IGF-1 increases rod progenitor cell division, an effect that is greater at night than during the day. We also show that inhibiting the function of IGF receptors decreases proliferation of rod progenitor cells. Finally, we show that IGF receptors are located on rod progenitor cells as well as on cone and rod photoreceptors. Taken together, these data suggest that the rhythmic production and release of IGF-1 plays a role in regulating the insertion of new rod photoreceptors into the retina. The diurnal change in IGF-1 abundance and effects of exogenous IGF-1 are consistent with the previous demonstration that rod progenitor cell division is threefold greater at night than in the day [Brain Res. 673 (1995) 119; Brain Res. 712 (1996) 40]. We also show that the insertion of new rod photoreceptors at the central edge of the ciliary neurogenic zone very likely also depends on IGF-1 production by cone photoreceptors. We propose that addition of new rod photoreceptors into the functioning retina is regulated through a feedback mechanism mediated at least in part via the IGF-1 produced in the cone photoreceptors.     

Clinical correlates of serum insulin-like growth factor-1 in patients with Parkinson's disease,multiple system atrophy and progressive supranuclear palsy

BackgroundRecently, increased serum insulin-like growth factor-1 (IGF-1) levels have been reported in patients with Parkinson's disease (PD) and multiple system atrophy (MSA).ObjectiveTo assess a correlation between the serum IGF-1 levels and clinical background factors in patients with PD and related disorders such as MSA and progressive supranuclear palsy (PSP).MethodsA total of 79 PD patients, 25 MSA patients, 16 PSP patients and 52 healthy controls were included in this study. The serum IGF-1 and growth hormone (GH) levels were measured in a fasting state. Unified PD Rating Scale (UPDRS) part III was used to evaluate motor function. Unified MSA Rating Scale (UMSARS) part II was also employed for the MSA patients.ResultsThe serum IGF-1 levels were significantly increased in the MSA patients compared with the PD patients and controls. No significant differences were observed in the serum GH levels among the patients and controls. The serum IGF-1 levels of PD patients with Hoehn and Yahr stage 2 were significantly higher than those of patients with Hoehn and Yahr stages 3–5. In patients with PD and PSP, the serum IGF-1 levels were negatively correlated with UPDRS part III. In contrast, patients with MSA showed a positive correlation of the serum IGF-1 levels with disease duration, UPDRS part III and UMSARS part II.ConclusionThe difference in the serum IGF-1 level and its correlation with clinical variables among these disorders may reflect different ongoing disease processes in each disorder.     

Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for ischemic brain injury

Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application. The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis, and the analogue may have a vascular effect. Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (cG-2allylP) are neuroprotective after ischemic injury. cG-2allylP crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of cG-2allyP improves somatosensory-motor function and long-term histological outcome.     

IGF-1 protects against diabetic features in an in vivo model of Huntington's disease

Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HTT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9 week-old and age-matched wild-type mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14 days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels.     

Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia

OBJECTIVE: The purpose of this study was to examine the evidence for the insulin-like growth factor-1 (IGF-1) deficiency hypothesis in the pathogenesis of schizophrenia. METHOD: The authors examined the fasting plasma levels of glucose, insulin, IGF-1, and cortisol in antipsychotic-naive schizophrenia patients (N=44) relative to age- and sex-matched healthy comparison subjects (N=44). Patients and comparison subjects were also matched for anthropometric measures and physical activity. RESULTS: Schizophrenia patients had a significantly higher mean plasma insulin level as well as a significantly higher mean insulin resistance score relative to healthy comparison subjects. The mean plasma IGF-1 level was significantly lower in patients. IGF-1 levels had a significant negative correlation with plasma insulin levels. The total positive symptoms score as well as the hallucinations subscore had a significant inverse relationship with IGF-1 levels. CONCLUSIONS: Deficient IGF-1 might underlie insulin resistance in schizophrenia. The IGF-1 deficit in antipsychotic-naive schizophrenia patients and its significant correlation with psychopathology scores suggest that IGF-1 might be potentially involved in the pathogenesis of schizophrenia.     

Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice

The mammalian lifespan is dramatically extended by both caloric restriction (CR) and insulin-like growth factor-1 (IGF-1) suppression. Both interventions involve neuroendocrine alterations directed by the hypothalamus. Yet, it remains unclear whether CR exerts its affects by altering central IGF-1 sensitivity. With this question in mind, we investigated the influence of CR and normal aging on hypothalamic IGF-1 sensitivity, by measuring the changes in IGF-1 receptor (IGF-1R) populations. Taking IGF-1 receptor (IGF-1R) immunoreactivity as an index of sensitivity to IGF-1, we counted IGF-1R immunoreactive and non-immunoreactive cells in the paraventricular nucleus (PVN) of Young-ad libitum fed (Young-Al, 6 weeks old), Old-ad libitum fed (Old-Al, 22 months old), and old calorically restricted (Old-CR, 22 months old) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each cross-section of PVN hypothalamus. Ad libitum fed mice show a 37% reduction in IGF-1R immunoreactive cells and a 12% reduction in the total cell population of the PVN with aging. In comparison, caloric-restricted mice show a 33% reduction in IGF-1R immunoreactive cells and a notable 24% decrease in the total cell population with aging. This selective maintenance of IGF-1R expressing cells coupled with the simultaneous loss of non-immunoreactive cells, results in a higher percentage of IGF-1R immunoreactive cells in the PVNs of CR mice. Thus, the decline in the percentage of IGF-1 sensitive cells in the PVN with age is attenuated by CR.     

Changes in the expression of insulin-like growth factor 1 variants in the postnatal brain development and in neonatal hypoxia–ischaemia

Insulin-like growth factor-1 (IGF-1) is a multifunctional peptide of which numerous isoforms exist. The predominant form, IGF-1Ea is involved in physiological processes while IGF-1Ec (mechano-growth factor, MGF) is expressed in response to a different set of stimuli. We have identified specific changes in the expression patterns of these IGF-1 variants in brain development in normal rats and following neonatal hypoxia–ischaemia (HI). Both IGF-1Ea and IGF-1Ec are expressed during normal postnatal brain development, albeit with highly specific temporal distributions. In contrast, HI produced increased and prolonged expression of the IGF-1Ec isoform only. Importantly, hypoxia alone stimulated the expression of IGF-1Ec as well. Thus, IGF-1Ec may play a role in HI pathology. Neonatal hypoxia–ischaemia occurs in approximately 1:4000–1:10,000 newborns and causes neurological deficits in ∼75% of those affected. Unfortunately, no specific treatment is available. IGF-1 is known to have neuroprotective activity and its IGF-1Ec variant appears to be an endogenous protective factor in hypoxia–ischaemia. Therefore, IGF-1Ec could potentially be developed into a therapeutic modality for the attenuation or prevention of neuronal damage in this and related disorders.     

Craniopharyngioma cell growth is promoted by growth hormone (GH) and is inhibited by tamoxifen: Involvement of growth hormone receptor (GHR) and IGF-1 receptor (IGF-1R)

Hormone receptors are related to the biological behavior and recurrence of craniopharyngioma (CP). The effect of therapeutic growth hormone (GH) replacement on CP growth remains largely unclear. We intended to study expression patterns of GH-related receptors in CP, and to study the effect of GH and its mediator, insulin-like growth factor-1 (IGF-1), as well as tamoxifen, on primary CP cell cultures. Primary cell cultures were established from fresh tumor specimens. The expression of GH receptor (GHR) and IGF-1 receptor (IGF-1R) in tumor specimens was studied using immunohistochemistry. Cell cultures were treated with various concentrations of recombinant GH, IGF-1 and tamoxifen. Cell growth promotion or inhibition was assayed using the Trypan blue dye exclusion test of cell viability. Expression of GHR, IGF-1R, phosphorylated-Akt and Akt after treatment was studied using Western blot assay. Twenty-nine primary cultures from 36 patients were established. GHR and IGF-1R were expressed in tumor tissue. The promotion of cell growth by GH compared to control was most prominent at 100 ng/mL, while inhibition by tamoxifen was concentration dependent. IGF-1 was more effective in promoting growth in CP cell cultures with high IGF-1R expression, and it increased phosphorylation of Akt protein. Primary cell cultures can be established in more than 80% of fresh CP specimens. GH and its endogenous mediator, IGF-1, promotes CP cell growth in vitro, while tamoxifen inhibits growth.