神经元烟碱受体介导的钙信号及其调节作用

神经元烟碱受体广泛地分布于中枢神经系统并参与脑内信号传导系统的调节过程.烟碱受体对钙离子通透的特点在其中发挥了重要的作用.这种激活烟碱受体产生的由钙离子介导的复杂的信息传递或许与学习记忆的提高、药物成瘾或神经保护机制有密切的关系.     

淀粉样前体蛋白(APP)分泌的神经及药物调节

综述了多种神经递质通过兴奋受体参与APP的分泌过程。这些受体包括M1、M3、5 HT2 、5 HT1C,代谢型谷氨酸受体及肽能加压素和缓激肽受体。脑片实验同样表明内源性神经递质和神经调质可调节APP在哺乳动物脑中的代谢。进一步明确神经递质在AD中的作用 ,有利于研究开发出更多的针对不同受体亚型或递质系统的药物 ,使AD的治疗途径进一步拓宽     

先天免疫受体介导的神经炎症在神经系统疾病中的作用

神经退行性疾病、精神疾病和脑损伤等多种神经系统疾病的发生与神经炎症密切相关。先天免疫受体是脑内免疫防御的第一道防线,在神经炎症和神经系统疾病的发生发展过程中起到至关重要的作用。本综述重点围绕参与神经免疫的先天免疫受体,从先天免疫受体类型、功能作用和分子机制等几方面,详细阐述先天免疫受体介导的神经炎症在神经系统疾病中的功能作用和分子机制。同时,简要概述目前治疗神经退行性疾病药物的研究进展,以及靶向神经炎症的药物开发和临床治疗的可行性。     

新促智药茴拉西坦(Aniracetam)

1引言某些调查显示至2000年随着普通人群的平均寿命逐年增加，60岁以上老人的百分比将达到30风预计将来中枢神经系统退化性疾病等慢性病将会增加，约25％老年人的认知功能会出现障碍。谷氨酸是参与记忆过程的主要神经递质，实验研究显示，由于它的各种受体功能协调的结果，产生记忆和神经保护作用（见表）。表中枢神经系统中的谷氨酸受体及其功能菌拉西坦是2一毗咯烷酮的衍生物，对参与神经保护和记忆过程的受体具有特殊的作用。本品由意大利和日本的Roche药厂生产。国内无锡市第四制药厂正试制中2作用机制在鼠海马切片中，发现首拉西坦（1…     

脑内胶质细胞源性神经营养因子及其受体复合物研究进展

胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)在脑内广泛分布,通过其受体复合物介导激活细胞内信号转导通路,发挥维持神经元功能和损伤修复等作用。胶质细胞源性神经营养因子家族受体α(GD-NF family receptorα,GFRα)和RET是其受体复合物的主要成员。GDNF和其受体复合物可能参与多种脑部病变的病理生理过程,是潜在的治疗靶点之一。     

胆碱能抗炎通路α7烟碱型乙酰胆碱受体的最新研究进展

α7nAChR(α7 nicotinic acetylcholine receptor)属于烟碱型乙酰胆碱受体（nAChRs）,是机体胆碱能抗炎通路的关键受体,在免疫系统的神经调控中发挥重要作用。近期研究发现,α7nAChR还参与调节免疫以外的多种生理病理过程,如非酒精性脂肪肝、血管新生、保护心脏等。此外,α7nAChR在神经退行性疾病等与能量代谢紧密关联。本文综述α7nAChR在治疗炎症、改善能量代谢中发挥的作用,以及α7nAChR参与治疗的新方向。     

白三烯受体拮抗剂ONO-1078对内皮素-1诱导的大鼠局灶性脑缺血的保护作用

目的观察白三烯受体拮抗剂ONO-1078对内皮素-1诱导的大鼠局灶性脑缺血的保护作用。方法向大脑中动脉附近微量缓慢注射内皮素-1(120 pmol,6 μL,>6 min),诱导大鼠局灶性脑缺血模型,在注射内皮素-1前1 h ip ONO-1078(0.1 mg·kg^-1)。观察神经症状、脑水肿程度、脑梗死体积、纹状体和皮层的存活神经元数的变化。结果 脑内微量注射内皮素-1引起动物出现明显神经症状、脑梗死、脑水肿及皮层和纹状体的存活神经元减少。预先ip ONO-1078显著抑制脑水肿,减小脑梗死体积,增加纹状体和皮层的存活神经元数,可减轻神经症状,但无显著意义。结论ONO-1078对内皮素-1诱导的脑缺血损伤有保护作用,白三烯参与了脑缺血后的组织损伤过程。     

梓醇对L-谷氨酸损伤PC12细胞的保护作用

梓醇是地黄中含量较高的活性成分,研究表明其对动物模型及培养细胞有明显神经保护作用[1～3].本室研究发现,梓醇可保护Aβ25～35损伤PC12细胞及脑内注射Aβ25～35拟AD小鼠的胆碱能神经系统功能,改善AD的病理变化,但其作用机制不明,既不是胆碱酯酶抑制剂,也不是M受体激动剂或阻断剂[4].兴奋性神经递质谷氨酸(glutamate,Glu)神经毒性在AD发病过程中起重要作用[5],梓醇的神经保护作用是否与影响L-Glu的毒性作用有关,本文利用PC12细胞对此进行了研究.     

尤瑞克林的临床应用进展

尤瑞克林即人尿激肽原酶(HUK),为组织型激肽原酶,能裂解激肽原,产生激肽。激肽与激肽受体结合可发挥脑保护作用。其作用机制可能有以下几方面:(1)组织型激肽原酶是一种丝氨酸蛋白水解酶,可使激肽原释放具有舒张血管效应的激肽。可选择性扩张缺血脑组织微血管,具有改善局部脑血流量,减少缺血半暗带作用。(2)具有一定的神经保护作用:HUK通过抑制神经细胞凋亡,促进脑缺血后神经干细胞增殖、迁移,     

NMDA受体的作用位点研究

N-甲基-D-天冬氨酸(NMDA)受体是离子型谷氨酸受体家族中的重要一员,是神经系统发育以及神经毒性的核心。NMDA受体通道大分子上存在着许多独立的结合位点。(1)谷氨酸(Glu)作用位点:Glu作为NMDA受体经典的激动剂,高浓度Glu的作用于NMDA受体识别部位,使细胞膜去极化,离子通道开放;低浓度的Glu则不能使NMDA门控的离子通道打开,需要甘氨酸(Gly)的参与。(2) Gly作用位点:Gly受体和NMDR有相同的分布,并对NMDA受体激活有增强作用。Gly能增加Glu与NMDA识别位点的亲和力,使通道开放频率增加4～6倍。研究表明NMDA受体被Glu激活前,需要Gly的结合,Gly起着NMDA受体协同激动剂的作用。(3)Mg2+作用位点:Mg2+是兴奋性氨基酸受体NMDA非竞争性阻断剂和Ca2+拮抗剂。NMDA受体通道的开放受配体和膜电位的双重控制。在静息态的膜蛋白条件下,Mg2+等镶嵌在通道深部,阻挡胞内外离子交换,这时即使Glu和Gly结合到NMDA受体,Mg2+也会阻断离子的流出。细胞去极化时Mg2+被电场力移开,离子得以流动,Mg2+的抑制作用逐渐减小并消失,故Mg2+是调节NMDA受体的重要位点。(4) Zn2+作用位点:Zn2+可以非竞争性地拮抗NMDA受体的反应。升高Gly的浓度不能翻转Zn2+的抑制作用,表明Zn2+有单独的结合位点。Zn2+对NMDA受体的抑制作用需要两个结合位点参与,其一是高亲和力、非电压依赖性结合位点,其二是低亲和力呈电压依赖性的结合位点。(5)多胺作用位点:多胺对NMDA的电流有多重影响。多胺的增强效应可分为:非Gly依赖性刺激作用(饱和Glu和Gly会引起全细胞电流增加);Gly依赖性刺激作用(在Gly浓度亚饱和的情况下,精胺能增加NMDA受体与Gly的亲和力,对NMDA电流有刺激效应)。多胺的抑制效应也可分为电压依赖性通道抑制作用,以及Glu受体亲和力降低作用。其中,Gly是Glu为开放受体通道所必需的,多胺对通道开放起正性调节作用,而Zn2+和Mg2+则起负性调节作用。此外,这些位点之间还存在着复杂的交互作用,NMDA受体通道是由复杂多样的因子所调节的。NMDA受体是学习记忆相关神经网络中一个相对中心的关键位点,中枢系统中广泛参与学习记忆、突触可塑性、缺血性脑损伤及神经退行性疾病等多种生理病理过程。本文以NMDA受体的作用位点为切入点,阐明NMDA受体的调节作用,以期为神经系统相关疾病的研究提供理论指导。     

Effects of an endothelin B receptor agonist on secretory phospholipase A2-IIA-induced apoptosis in cortical neurons

Endothelin (ET), a vasoconstrictive peptide, acts as an anti-apoptotic factor, and endothelin receptor B (ETB receptor) is associated with neuronal survival in the brain. Human group IIA secretory phospholipase A2 (sPLA2-IIA) is expressed in the cerebral cortex after brain ischemia and causes neuronal cell death via apoptosis. In primary cultures of rat cortical neurons, we investigated the effects of an ETB receptor agonist, ET-3, on sPLA2-IIA-induced cell death. sPLA2-IIA caused neuronal cell death in a concentration- and time-dependent manner. ET-3 significantly prevented neurons from undergoing sPLA2-IIA-induced cell death. These agonists reversed sPLA2-IIA-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Before cell death, sPLA2-IIA potentiated the influx of Ca2+ into neurons. Blockers of the L-type voltage-dependent calcium channel (L-VSCC) not only suppressed the Ca2+ influx, but also exhibited neuroprotective effects. As well as L-VSCC blockers, ET-3 significantly prevented neurons from sPLA2-IIA-induced Ca2+ influx. An ETB receptor antagonist, BQ788, inhibited the effects of ET-3. The present cortical cultures contained few non-neuronal cells, indicating that the ETB receptor agonist affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that the ETB receptor agonist rescues cortical neurons from sPLA2-IIA-induced apoptosis. Furthermore, the present study suggests that the inhibition of L-VSCC contributes to the neuroprotective effects of the ETB receptor agonist.     

Neuregulin-1 exerts protective effects against neurotoxicities induced by C-terminal fragments of APP via ErbB4 receptor

Neuregulin-1 (NRG1) plays important roles in the development and plasticity of the brain, and it is also reported to have potent neuroprotective properties. We previously reported that NRG1 has neuroprotective actions against Swedish amyloid precursor protein-induced neurotoxicity. In addition to the amyloid beta peptide, other metabolites of amyloid precursor protein (APP) such as the C-terminal fragments of APP (APP-CTs) have been reported to possess cytotoxic effects in neuronal cells. In this study, we investigated whether NRG1 exerts neuroprotective effects against APP-CTs and attempted to determine its neuroprotective mechanisms. NRG1 attenuated the neurotoxicities induced by the expression of APP-CTs in neuronal cells. NRG1 also reduced the accumulation of reactive oxygen species and attenuated mitochondrial membrane potential loss induced by APP-CTs. In addition, NRG1 upregulated the expression of the anti-apoptotic protein Bcl-2. This effect was blocked by the inhibition of ErbB4, a key NRG1 receptor. Taken together, these results demonstrate the neuroprotective potential of NRG1 in Alzheimer's disease.     

A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke

Repinotan HCl (repinotan, BAYx3702), a highly selective 5-HT1A receptor agonist with a good record of safety was found to have pronounced neuroprotective effects in experimental models that mimic various aspects of brain injury. Repinotan caused strong, dose-dependent infarct reductions in permanent middle cerebral artery occlusion, transient middle cerebral artery occlusion, and traumatic brain injury paradigms. The specific 5-HT1A receptor antagonist WAY 100635 blocked these effects, indicating that the neuroprotective properties of repinotan are mediated through the 5-HT1A receptor. The proposed neuroprotective mechanisms of repinotan are thought to be the result of neuronal hyperpolarization via the activation of G protein-coupled inwardly rectifying K+ channels upon binding to both pre- and post-synaptic 5-HT1A receptors. Hyperpolarization results in inhibition of neuron firing and reduction of glutamate release. These mechanisms, leading to protection of neurons against overexcitation, could explain the neuroprotective efficacy of repinotan per se, but not necessarily the efficacy by delayed administration. The therapeutic time window of repinotan appeared to be at least 5 h in in vivo animal models, but may be even longer at higher doses of the drug. Experimental studies indicate that repinotan affects various mechanisms involved in the pathogenesis of brain injury. In addition to the direct effect of repinotan on neuronal hyperpolarization and suppression of glutamate release this compound affects the death-inhibiting protein Bcl-2, serotonergic glial growth factor S-100beta and Nerve Growth Factor. It also suppresses the activity of caspase-3 through MAPK and PKCalpha; this effect may contribute to its neuroprotective efficacy. The dose- and time-dependent neuroprotective efficacy of repinotan indicates that the drug is a promising candidate for prevention of secondary brain damage in brain-injured patients suffering from acute ischemic stroke. Unfortunately, however, the first, randomized, double blind, placebo-controlled clinical trial did not demonstrate the efficacy of repinotan in acute ischemic stroke.     

Sodium channel blocking activity of AM-36 and sipatrigine (BW619C89): in vitro and in vivo evidence

Sodium channel blockers are neuroprotective against cerebral ischemia in animal models. A novel neuroprotective compound AM-36, when screened for activity at the most common receptor and ion channel binding sites, revealed activity at site 2 Na+ channels. Studies then investigated this Na+ channel blocking activity in vitro and in vivo relative to other Na+ channel blockers, including the neuroprotective agent sipatrigine (BW619C89). AM-36 inhibited batrachotoxinin (BTX)-sensitive Na+ channel binding in rat brain homogenates with an IC50 of 0.28 microM. Veratridine (100 microM)-induced neurotoxicity in murine cerebellar granule cells was completely inhibited by AM-36 (1.7 microM) compared to only partial inhibition by sipatrigine (26 microM). Veratridine-stimulated glutamate release, as measured through a microdialysis probe in the cortex of anesthetised rats, was inhibited by 90% by superfusion of AM-36 (1000 microM). In the endothelin-1 (ET-1) model of middle cerebral artery occlusion (MCAo) in conscious rats, both AM-36 (6 mg/kg i.p.) and sipatrigine (10 mg/kg i.p.) 30 min post-MCAo significantly reduced cortical, but not striatal infarct volume. As the refractiveness of the striatum is likely to be dependent on the route and time of drug administration, AM-36 (1 mg/kg i.v.) was administered 3 or 5 h after MCAo and significantly reduced both cortical and striatal infarct volumes. The present studies demonstrate Na+ channel blocking activity of AM-36 both in vitro and in vivo, together with significant neuroprotection when administration is delayed up to 5 h following experimental stroke.     

Interleukin-6 enhances expression of adenosine A(1) receptor mRNA and signaling in cultured rat cortical astrocytes and brain slices.

The inhibitory neuromodulator adenosine is released in the brain in high concentrations under conditions of exaggerated neuronal activity such as ischemia and seizures, or electroconvulsive treatment. By inhibiting neural overactivity, adenosine counteracts seizure activity and promotes neuronal survival. Since stimulation of adenosine A(2b) receptors on astrocytes induces increased synthesis and release of interleukin-6, which also exerts neuroprotective effects, we hypothesized that the effects of interleukin-6 and of adenosine might be related. We report here that stimulation with interleukin-6 of cultured astrocytes, of cultured organotypic brain slices from newborn rat cortex, and of freshly prepared brain slices from rat cortex induces a concentration- and time-dependent upregulation of adenosine A(1) receptor mRNA. This increased adenosine A(1) receptor mRNA expression is accompanied in astrocytes by an increase in adenosine A(1) receptor-mediated signaling via the phosphoinositide-dependent pathway. Since upregulation of adenosine A(1) receptors leads to increased neuroprotective effects of adenosine, we suggest that the neuroprotective actions of interleukin-6 and adenosine are related and might be mediated at least in part through upregulation of adenosine A(1) receptors. These results may be of relevance for a better understanding of neuroprotection in brain damage but also point to a potential impact of neuroprotection in the mechanisms of the antidepressive effects of chronic carbamazepine, electroconvulsive therapy, and sleep deprivation, which are all accompanied by adenosine A(1) receptor upregulation.     

海风藤酮治疗脑梗死的活体磁共振成像与波谱研究

目的研究血小板活化因子(PAF)受体拮抗剂海风藤酮治疗脑梗死的作用机制,并与传统的PAF受体拮抗剂银杏苦内酯相比较。方法采用磁共振成像与波谱技术原位动态观察海风藤酮对活体鼠脑组织损害程度、神经递质方面的影响。分别对缺血再灌注组及海风藤酮、银杏苦内酯治疗组鼠脑组织缺血、水肿及氮-乙酰天门冬氨酸(NAA)与乳酸(Lac)等代谢产物变化进行观察和比较。结果在缺血60m in再灌注1、3、6 h海风藤酮均能减小高信号区的体积,有效减少脑缺血后Lac/(PCr+Cr)比值的上升和NAA/(PCr+Cr)比值的下降,与银杏苦内酯治疗组差异无显著性(P>0.05),与缺血再灌组相比较差异有显著性(P<0.01)。结论海风藤酮与传统的PAF受体拮抗剂银杏苦内酯均具有明显的缺血后脑保护作用,磁共振成像与波谱技术可为缺血再灌注后神经脑保护剂作用机制的研究提供精确的神经影像学信息。     

Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice

Background and purpose:

Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy.

Experimental approach:

Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB₁, CB₂ and TRPV1 receptor agonist); HU308 (CB₂ receptor agonist), SR141716A (CB₁ receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB₂ receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively.

Results:

Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin.

Conclusions:

Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.     

Akt is a molecular target for signal transduction therapy in brain ischemic insult

Growth factors including insulin-like growth factor-1 (IGF-1) promote cell survival in ischemic brain injury. Stimulation of IGF-1 receptor coupled with tyrosine kinase activates phosphatidylinositol 3-kinase and subsequently, protein kinase B (Akt) in hippocampal neurons. Here we introduce a new approach of signal transduction therapy for brain damage occurring in ischemic insult. As has been shown for IGF-1, intracerebroventricular injection of sodium orthovanadate, a protein tyrosine phosphatase inhibitor, prior to ischemic insult blocked delayed neuronal death in the CA1 region. The neuroprotective effects of orthovanadate and IGF-1 were associated with an increased Akt activity in the CA1 region. We discuss here potential targets for Akt relevant to such neuroprotective activity. Our findings lead to the conclusion that Akt activity is a potential target for neuroprotective drugs in brain ischemic insult and other episodes of excitotoxic neuronal apoptosis such as seizure and Huntington's and Parkinson's diseases.     

Microglial SK3 and SK4 Currents and Activation State are Modulated by the Neuroprotective Drug, Riluzole

Microglia monitor the CNS for ‘danger’ signals after acute injury, such as stroke and trauma, and then undergo complex activation processes. Classical activation of microglia can produce neurotoxic levels of glutamate and immune mediators (e.g., pro-inflammatory cytokines, reactive oxygen and nitrogen species), while alternative activation up-regulates anti-inflammatory molecules and is thought to resolve inflammation and protect the brain. Thus, pharmacological strategies to decrease classical- and/or promote alternative activation are of interest. Here, we assessed actions of the neuroprotective drug, riluzole, on two Ca²⁺-activated K⁺ channels in microglia — SK3 (KCa2.3, KCNN3) and SK4 (KCa3.1, KCNN4) — and on classical versus alternative microglial activation. Riluzole is used to treat amyotrophic lateral sclerosis, and is in clinical trials for several other CNS disorders, where it has been presumed to target neurons and reduce glutamate-mediated toxicity. We show that simply elevating intracellular Ca²⁺ to micromolar levels in whole-cell recordings does not activate SK channels in a cell line derived from primary rat microglia (MLS-9). In intact cells, riluzole raised cytoplasmic Ca²⁺, but it was marginal (~200 nM) and transient (2 min). Surprisingly then, in whole cell recordings, riluzole rapidly activated SK3 and SK4 channels for as long as it was present, and did not require elevated intracellular Ca²⁺. We then used primary rat microglia to analyze expression of several activation markers and inflammatory mediators. Riluzole decreased classical LPS-induced activation, and increased some aspects of IL-4-induced alternative activation. These actions on microglia suggest an additional mechanism underlying the neuroprotective actions of riluzole.     

Mechanisms of Chronic Nicotine Treatment–Induced Enhancement of the Sensitivity of Cortical Neurons to the Neuroprotective Effect of Donepezil in Cortical Neurons

We have previously shown that chronic donepezil treatment induces nicotinic acetylcholine receptor up-regulation and enhances the sensitivity of the neurons to the neuroprotective effect of donepezil. Further analyses revealed that the nicotinic receptor is involved in this enhancement. In this study, we examined whether nicotinic receptor stimulation is sufficient to make neurons more sensitive to donepezil. We treated primary cultures of rat cortical neurons with nicotine and confirmed that chronic nicotine treatment induced nicotinic receptor up-regulation and made the neurons more sensitive to the neuroprotective effects of donepezil. Analyses with receptor antagonists and kinase inhibitors revealed that the effects of chronic nicotine treatment are mediated by nicotinic receptors and their downstream effectors including phosphatidylinositol 3-kinase. In contrast to chronic donepezil treatment that enhanced the level of nicotine-induced Ca²⁺ influx, chronic nicotine treatment did not significantly alter the level of Ca²⁺ influx.