Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia?

Cognitive impairment is a key feature of schizophrenia and may be the most important determinant of outcome in schizophrenia. This impairment is diffuse and may reflect abnormalities in frontal cortex, hippocampus and other brain regions. While deficits in glutamatergic, GABAergic, dopaminergic and cholinergic impairment have received the most attention as the basis of this impairment, there are many reasons for considering the role of serotonin (5-HT) in contributing to these deficits. This may be via its influence on dopaminergic, cholinergic, glutamatergic and GABAergic function, as well as various growth factors that have been implicated in schizophrenia. Of the 14 known serotonin receptors, the 5-HT(1A) receptor is a key candidate for mediating at least some of the influence 5-HT has on cognition. 5-HT(1A) receptors are upregulated in postmortem specimens from patients with schizophrenia, suggesting a deficit in 5-HT(1A) function in this disorder. Atypical but not typical antipsychotic drugs stimulate the efflux of dopamine from cortex by a 5-HT(1A)-dependent mechanism. A series of studies from this laboratory involving the 5-HT(1A) partial agonists tandospirone and buspirone have reported a modest ability of these agents to improve some domains of cognition in patients receiving typical or atypical antipsychotic drugs. Preclinical studies have been mixed in regard to the ability of 5-HT(1A) partial agonists to improve cognition in various paradigms; some studies report that 5-HT(1A) antagonists are effective to improve cognition. Aripiprazole, clozapine, olanzapine, perospirone, quetiapine risperidone, and ziprasidone are examples of atypical antipsychotic drugs which are either direct or indirect 5-HT(1A) agonists which have been shown to improve cognitive function in patients with schizophrenia. Further study is needed to determine the role of the 5-HT(1A) receptor to improve cognitive function in schizophrenia.     

5—羟色氨酸(5—HTP)治疗忧郁症(综述)

关于情感性精神病的发病机理,目前流行二种生化学说,即儿茶酚胺学说和5-羟色胺学说。这二种学说统称为生物胺学说,虽然解释部分情感性精神病的发病机理,但都有不全之处。忧郁症的5-羟色胺学说认为:当脑内的5-羟色胺含量减少时,可发生忧郁症。而使用5-羟色胺的前体5-羟色氨酸(5-HTP),     

Immunohistochemical Distribution of Somatostatin and Somatostatin Receptor Subtypes (SSTR1–5) in Hypothalamus of ApoD Knockout Mice Brain

In the present study, the expression of somatostatin (SST) and somatostatin receptor subtypes (SSTR1-5) was determined in the hypothalamus of wild-type (wt) and apolipoprotein D knockout (ApoD(-/-)) mice brain. SST-like immunoreactivity, while comparable in most regions of hypothalamus, diminished significantly in arcuate nucleus of ApoD(-/-) mice. SSTR1 strongly localized in all major hypothalamic nuclei as well as in the median eminence and ependyma of the third ventricle of wt mice brain. SSTR1-like immunoreactivity increases in hypothalamus except in paraventricular nucleus of ApoD(-/-) mice. SSTR2 was well expressed in most of the hypothalamic regions whereas it decreases significantly in ventromedial and arcuate nucleus of ApoD(-/-) mice. SSTR3 and SSTR4-like immunoreactivity increases in ApoD(-/-) mice in all major nuclei of hypothalamus, median eminence, and ependymal cells of third ventricle. SSTR5 is well expressed in ventromedial and arcuate nucleus whereas weakly expressed in paraventricular nucleus. In comparison to wt, ApoD(-/-) mice exhibit increased SSTR5-like immunoreactivity in paraventricular nuclei and decreased receptor expression in ventromedial hypothalamus and arcuate nucleus. In conclusion, the changes in hypothalamus of ApoD(-/-) mice may indicate potential role of ApoD in regulation of endocrine functions of somatostatin in a receptor-dependent manner.     

Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder?

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition for which strong evidence of a genetic component and serotonergic system involvement exists. Recent studies have shown that sumatriptan, a selective ligand of the serotonin (5-HT)(1Dbeta) autoreceptor, modifies OCD symptoms. The aim of this study was to investigate the presence of linkage disequilibrium between the 5-HT(1Dbeta) receptor gene, which has a variant caused by a silent G to C substitution at nucleotide 861 of the coding region, and OCD. METHOD: DNA was collected from 67 probands who met DSM-IV criteria for OCD and from their living parents or siblings. Transmission Disequilibrium Test/sib-Transmission Disequilibrium Test analyses were then conducted with the DNA data. RESULTS: Thirty-two families were informative for the analysis, which showed a preferential transmission of the G allele to the affected subjects. CONCLUSIONS: If the results are confirmed, there may be important implications for the 5-HT(1Dbeta) receptor gene in the pathogenesis and treatment of OCD.     

Control of dorsal raphé 5-HT function by multiple 5-HT(1) autoreceptors: parallel purposes or pointless plurality?

The serotonergic cells of the dorsal raphé nucleus innervate much of the forebrain and are thought to be involved in the mechanism of action of antidepressants. Dysfunction of these cells might be involved in the neural mechanisms underlying depression and suicide. The traffic in pathways emanating from the dorsal raphé nucleus is controlled by 5-HT(1) autoreceptors. Until recently it was thought that the autoreceptors in the dorsal raphé nucleus were solely of the 5-HT(1A) subtype. In this article, we discuss evidence that the situation is more complex and that multiple 5-HT(1) subtypes govern different aspects of 5-HT function in the dorsal raphé nucleus presenting new therapeutic opportunities.     

The up-regulation of metabotropic glutamate receptor 5 (mGluR5) in Down’s syndrome brains

We investigated the expression of metabotropic glutamate receptor 5 (mGluR5), a subtype of group I mGluRs, in the cerebral cortex of cases with Down’s syndrome (DS), using immunohistochemistry and immunoblotting with this receptor. The up-regulation of mGluR5 was observed in DS by immunohistochemistry, and atrophic pyramidal neurons were immunolabelled in elderly DS cases. Western blotting confirmed the increased expression in DS brains. Since group I mGluR regulates the metabolism of amyloid precursor protein (APP) and accelerates its processing into non-amyloidogenic APP, the overexpression of mGluR5 may be related to the pathological state of APP metabolism in DS. Received: 9 February 1998 / Revised: 1 September 1998 / Accepted: 14 September 1998     

Effect of cytidine(5′)diphosphocholine (CDP-Choline) on the total urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) by rats and humans

Summary We examined the effects of orally administered cytidine(5)-diphosphocholine (CDP-choline) on the total levels of 3-methoxy-4-hydroxyphenyl-glycol (MHPG) in human and rat urine. Four subjects who had been on a low-choline diet (less than 1 gm/day) for 24 hours received three doses of CDP-choline (2 gm each) at 8 a.m., 10 a.m., and noon; urines were collected at two-hour intervals after each dose. Rats received water for three days; then CDP-choline (100 mg/kg) or equimolar doses of choline for five days; then water again for three more days. Twenty-four hour urine samples were collected on each day of the study. The levels of MHPG in human urine increased by 45–68% when subjects were receiving CDP-choline (p<0.01). CDP-choline, but not choline, also elevated urinary MHPG significantly in rats (p<0.01). These data suggest that CDP-choline enhances norepinephrine release, and that this action may be mediated by more than just its choline content.     

帕金森病(PD)治疗进展(1)

1　前言帕金森病 (ＰＤ)是一种常见的中枢神经系统慢性退行性疾病。病理改变主要为脑干的黑质、蓝斑和纹状体等处的多巴胺能神经元缺失 ,胶质增生及细胞内有Ｌｅｗｙ包含体为特征。生化研究可见在尾一壳核处多巴胺活性明显降低。ＰＤ是影响人类影响、发生残障的主要病症之一 ,其发生率随年龄增加而增加。具有病程长、致残率高之特点 ,严重影响病人的生活质量。对ＰＤ的治疗 ,一直受到神经病学界之关注。2　现有的几种治疗方案2 1　模拟　通过模拟失去的神经递质来活化丢失部位神经元的靶位点。如在治疗ＰＤ时使用多巴胺前体或多巴胺受体激…     

Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1)

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the APP processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.     

Antibody-Mediated Inhibition of Integrin α5β1 Blocks Neurotoxic Prion Peptide PrP(106-126)-Induced Activation of BV2 Microglia

Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The identification of cell surface molecules that mediate the prion protein (PrP) synthetic peptide interaction with microglia is of great significance as it represents potential target molecules to modulate the events leading to the pathophysiology of prion diseases. Here, we carried out in vitro experiments to investigate the involvement of α5β1 integrin in neurotoxic prion peptide PrP(106-126)-induced activation of BV2 microglia. The results showed that the exposure to PrP(106-126) upregulated the mRNA expression of proinflammatory factors (IL-1 β, IL-6, and iNOS) and NALP3 inflammasome components (NALP3 and ASC), increased the release of iNOS and its product nitric oxide, and stimulated NF-κB activation. Blockade of α5β1 integrin with monoclonal antibody BMC5 prior to PrP(106-126) treatment abrogated the upregulation of the mRNA expression of IL-1 β, IL-6, iNOS, and ASC, but had no effect on the mRNA expression of NALP3, blocked the release of iNOS and nitric oxide, and inhibited NF-κB activation. These results suggest that α5β1 integrin is involved in the PrP(106-126)-induced microglial activation through the participation in the activation of NF-κB and NALP3/ASC inflammasome. Our study unveils a previously unidentified role of α5β1 integrin as an intermediate signaling molecule in neurotoxic prion peptides-microglia interactions and identifies a potential molecular target for the modulation of prion-induced microglial activation.     

Involvement of 5-HT(2A) receptor and α(2)-adrenoceptor blockade in the asenapine-induced elevation of prefrontal cortical monoamine outflow

The psychotropic drug asenapine is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Asenapine exhibits higher affinity for several 5-HT receptors and α(2)-adrenoceptors than for D(2) receptors. Noteworthy, blockage of both the 5-HT(2A) and α(2)-adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D(2) receptor antagonists. Previous results show that asenapine, both systemically and locally, increases dopamine, noradrenaline, and serotonin release in the medial prefrontal cortex (mPFC), and that the increased dopamine release largely depends on an intracortical action. Using reverse microdialysis in freely moving rats, we here assessed the potency of low concentrations of asenapine to cause a pharmacologically significant blockage in vivo of 5-HT(2A) receptors and α(2)-adrenoceptors within the mPFC, and thus its ability to affect cortical monoamine release by these receptors. Intracortical administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT(2A/2C) receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT(2A) antagonist M100907. Application of clonidine, an α(2)-adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective α(2)-adrenoceptor antagonist idazoxan blocked, whereas asenapine partially blocked clonidine-induced cortical dopamine and noradrenaline decrease. The effects of asenapine and idazoxan on clonidine-induced serotonin decrease were less pronounced. Our results propose that low concentrations of asenapine in the mPFC exhibit a pharmacologically significant 5-HT(2A) and α(2) receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder.     

Sequence Analysis of 5′ Regulatory Regions of the Machado–Joseph Disease Gene (ATXN3)

Machado–Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)_n expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expression of ATXN3 could contribute to the explanation of different ages at onset in patients displaying similar CAG repeat sizes. Variation in 5′ regulatory regions of the ATXN3 gene may have the potential to influence expression levels and, ultimately, modulate the MJD phenotype. The main goal of this work was to analyze the extent of sequence variation upstream of the ATXN3 start codon. A fragment containing the core promoter and the 5′ untranslated region (UTR) was sequenced and analyzed in 186 patients and 59 controls (490 chromosomes). In the core promoter, no polymorphisms were observed. In the 5′ UTR, only one SNP (rs3814834) was found, but no improvements on the explanation of onset variance were observed, when adding its allelic state in a linear model. Accordingly, in silico analysis predicted that this SNP lays in a nonconserved position for CMYB binding. Therefore, no functional effect could be predicted for this variant.     

Effects of insulin-like growth factor-1 (IGF-1) receptor signaling on rates of apoptosis in retina of dopamine beta hydroxylase (Dbh−/−) knockout mice

We have investigated whether insulin-like growth factor-1 (IGF-1) receptor signaling alters rates of apoptosis in dopamine beta-hydroxylase (Dbh^?/?) knockout mice. Retinal lysates from Dbh^?/? and their heterozygote littermates (Dbh^+/?) were used to examine the role of norepinephrine in the regulation of IGF-1 receptor signaling and apoptosis in the retina. Western blot analysis was done for protein levels of total and phosphorylated IGF-1 receptor, insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and Akt. A caspase 3 ELISA and dopamine ELISA were done on retinal lysates. To verify which regions of the retina were undergoing apoptosis, TUNEL labeling was performed. No changes in dopamine were noted between the KO and heterozygote mice. IGF-1 receptor phosphorylation was significantly decreased in Dbh^?/? mice as compared to their heterozygote littermates (P < 0.05 vs. heterozygous mice). IRS-1 protein phosphorylation was significantly decreased in KO mice (P < 0.05 vs. heterozygous mice), while no significant changes were noted in IRS-2 protein phosphorylation. Akt protein phosphorylation was also reduced in the KO mice, likely leading to increased cleaved caspase 3 levels. The increase in apoptosis in the Dbh^?/? mice occurred predominantly in the inner retina. Our results suggest that IGF-1 receptor signaling is reduced in the retina of mice with dysfunctional adrenergic receptor signaling. The data also indicate that IGF-1 receptor signaling occurs primarily through IRS-1, rather than IRS-2. The reduction in Akt phosphorylation, likely through reduced IGF-1 receptor signaling, could explain the increase in cleaved caspase 3, leading to apoptosis. These results suggest that alterations in adrenergic receptor signaling modulate IGF-1 receptor signaling, which can regulate apoptosis in the retina.     

糖尿病性神经病(DN)与前列腺素 E_1(PGE_1)

DN 在糖尿病并发症中发生率最高,临床征象多样,病因不明。作者就DN 之血管病因及PGE_1药理和临床疗效作了探讨。据报告,多数病例腓神经活检发现神经内小血管壁有PAS 染色阳性物质沉着,内膜肥厚,腔径狭窄,肾病或视网膜病有相同之微血管病变。现已被认为,除特殊DN 病型外,是糖尿病特有的代谢障碍之基础。电镜发现,远端对称性多神经病变,其神经毛细血管内皮细胞增生,     

脊髓小脑性共济失调(附1家系5代6例报道)

脊髓小脑性共济失调(SCA)较少见。本研究介绍1家系5代6人发病,现报道并分析如下:1资料与方法1.1临床资料先证者(Ⅲ2),男,51岁,工人。因行走不稳6年,于2012年7月25日以"脑梗死后遗症"收住院(住院号12023042)。患者自觉2006年开始感左下肢无力,僵硬,行走不稳,易跌倒,逐渐加重;2010年开始感左上肢也出现无     

Non-proteolytic effect of β-site APP-cleaving enzyme 1 (BACE1) on sodium channel function

The β-site APP-cleaving enzyme 1 (BACE1) is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease. Here, we elaborate on the recent finding that auxiliary subunits of voltage-gated sodium channels (β2 and β4) are BACE substrates. BACE1 produced complex effects on sodium channel gating that could be only partially explained by β2/β4 cleavage. To characterize the unexpected non-proteolytic effect of BACE1, we examined HEK cells co-transfected with only Nav1.2 and either normal or catalytically inactive BACE1. Both BACE1 variants produced virtually identical effects on sodium channel gating, which would lead to enhanced cellular excitability. The non-proteolytic BACE1 effect on Nav1.2 current was confirmed in murine neuroblastoma cells, which express sodium channels endogenously, but lack β2 and β4. Our study reveals an important facet of BACE1 function that should help to decipher the role of BACE1 in normal and demented brain.     

脉络丛癌(附5例报告)

目的　探讨脉络丛癌的诊断和治疗。方法　分析我院诊治的 5例脉络丛癌临床资料。结果　临床表现为进行性颅高压征 ,影像学表现不典型 ;免疫组化特异性不高 ;随访均未见复发。结论　脉络丛癌在成年人临床诊断困难 ,治疗以手术为主 ,力争肿瘤全切除     

POEMS综合征(附5例报告)

POEMS综合征是一组多系统损害的症候群。临床主要表现为：多发性周围神经病（P，polyneuropathy）、脏器肿大（O，organomegaly）、内分泌病变（E，endocrinopathy）、M蛋白（M，Mprotein）、皮肤改变（S，skinehanges）．1965年Crow首先报道一例骨髓瘤伴发多系统损害病例，1968年日本学者Fukase又发现一类似病例。1984年日本学者TakaoNakanishi总结分析102例类似病例，并把本病命名为Crow-Fukase综合征。随着对本病的认识，国内陆续有报道病例，但本病仍属临床少见病，现将我科收治的5例报告如下。临床资料一般资料男性4例，女性1…