5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's disease

OBJECTIVE: To investigate the association between 5-HT(2A) receptor polymorphism and neuropsychiatric (NP) symptoms in Chinese elderly with Alzheimer's disease (AD). METHODS: This case-control study evaluated Chinese subjects with AD first presented to an university affiliated psychogeriatric clinic. Eighty-seven subjects with NINCDS-ADRDA diagnosis for probable and possible AD were recruited consecutively from the psychogeriatric clinics of the Prince of Wales Hospital in Hong Kong. 5-HT(2A) receptor polymorphisms were examined by polymerase chain reaction (PCR), enzyme digestion and gel electrophoresis. NP symptoms were assessed by the Chinese version of the Neuropsychiatric Inventory (NPI). RESULTS: The genotype frequencies were significantly different in subjects with regards to the presentation of delusions, aggression, aberrant motor behavior and apathy (Pearson Chi Squares, p < 0.05). If only homozygote states were included, there were significantly fewer subjects of CC genotype with delusion (Pearson chi square, p < 0.05). CONCLUSIONS: Specific NP symptoms in AD were significantly associated with 5-HT(2A) receptor polymorphisms. Possible ethnic differences in the behavioral expression of 5-HT(2A) receptor polymorphisms are worthy of further exploration.     

Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT(6) receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT(6) receptor blockade might eventually play in the treatment of schizophrenia.     

A crustacean serotonin receptor: cloning and distribution in the thoracic ganglia of crayfish and freshwater prawn

Serotonin (5-HT) is involved in regulating important aspects of behavior and a variety of systemic physiological functions in both vertebrates and invertebrates. These functions are mediated through binding to 5-HT receptors, of which approximately 13 have been characterized in mammals. In crustaceans, important model systems for the study of the neural basis of behaviors, 5-HT is also linked with higher-order behaviors, associated with different 5-HT receptors that have been identified at the physiological and pharmacological levels. However, no crustacean 5-HT receptors have been identified at the molecular level. We have cloned a putative 5-HT(1) receptor (5-HT(1crust)) from crayfish, prawn, and spiny lobster and have raised antibodies that recognize this protein in all three organisms. 5-HT(1crust) immunoreactivity (5-HT(1crust)ir) was observed surrounding the somata of specific groups of neurons and as punctate staining within the neuropil in all thoracic ganglia of crayfish and prawn. In the crayfish, 5-HT(1crust)ir was also found in boutons surrounding the first and second nerves of each ganglion and on the 5-HT cells of T1-4. In the prawn, 5-HT(1crust)ir was also found in axons that project across the ganglia and along the connectives. We found examples of colocalization of 5-HT(1crust) with 5-HT, consistent with the short-term modulatory role of 5-HT, as well as cases of serotonergic staining in the absence of a 5-HT(1crust) signal, which might imply that other 5-HT receptors are found at these locations. We also observed receptors that did not possess counterpart 5-HT staining, suggesting that these may also mediate long-term neurohormonal functions of serotonin.     

Apoptosis inducing effects of 6-Methoxydihydrosanguinarine in HT29 colon carcinoma cells

6-methoxydihydrosanguinarine (6ME), a benzophenanthridine alkaloid derived from the methanol extracts of Hylomecon hylomeconoides, showed a dose-dependent effect at 1-10 microM on causing apoptotic cell death in HT29 colon carcinoma cells (IC50 = 5.0+/-0.2 microM). Treatment of HT-29 cells with 6ME resulted in the formation of internucleosomal DNA fragmentation. Treatment of the cells with 6ME caused activation of caspase-3, -8 and 9 protease and subsequent proteolytic cleavage of poly(ADP-ribose)polymerase. 6ME increased the expression of p53 and Bax and decreased the expression of Bid. These results indicate that p53 and proapoptotic Bcl-2 family proteins might participate in the antiproliferative activity of 6ME in HT29 cells.     

The effects of age and hyperhomocysteinemia on the redox forms of plasma thiols

We assayed the redox forms of cysteine (reduced [CSH], oxidized [CSSC], and bound to protein [CS-SP]), cysteinylglycine (CGSH; cysteinylgycine disulfide [CGSSGC] and cysteinylglycine-protein mixed disulfide [CGS-SP]), glutathione (GSH; glutathione disulfide [GSSG] and glutathione-protein mixed disulfide [GS-SP]), homocysteine (Hcy; homocystine [HcyS] and homocystine-protein mixed disulfides [bHcy]), and protein sulfhydryls in the plasma of healthy subjects (divided into 8 groups ranging in age from birth to 70 years) and patients with mild hyperhomocysteinemia associated with cardiovascular disease (heart-transplant patients) or vascular atherosclerosis, with or without renal failure. In healthy individuals, levels of disulfides and protein-mixed disulfides were more abundant than those of thiols, and those of protein-thiol mixed disulfides were higher than disulfides. Concentrations of CSH, GSH, and CGSH in the various groups had profiles characterized by a maximum over time. The concentration of Hcy was unchanged up to the age of 30 years, after which it increased. CSSC concentration increased gradually with age, whereas concentrations of the other disulfides were essentially unchanged. By contrast, the concentrations of all protein-thiol mixed disulfides, especially those with CSH, increased gradually with age. Ranks of distribution of the reduced forms changed with age (at birth, CSH > CGSH > GSH > Hcy; in 1- to 2-year-olds, CSH > GSH > CGSH > Hcy; and in 51- to 70-year-olds, CSH > CGSH = GSH > Hcy), whereas those of disulfides and protein-thiol mixed disulfides were substantially unchanged (in all age groups, CSSC > CGSSGC > GSSG = HcyS and CS-SP > CGS-SP > bHcy > GS-SP). In patients with pathologic conditions, plasma levels of disulfide forms CSSC, HcyS, CS-SP, and bHcy were significantly increased, whereas other redox forms of thiols were unchanged or showed variations opposite (increasing or decreasing) to control values. Maximal increases in disulfides and protein-thiol mixed disulfides were associated with renal failure. Our data suggest that increases in plasma bHcy concentrations in subjects with pathologic conditions were more likely the result of activation of thiol-disulfide exchange reactions between free reduced Hcy and CS-SP than of a direct action of reactive oxygen species.     

超声内镜诊治上消化道早期癌21例

目的探讨超声内镜诊断和治疗上消化道早期肿瘤的可靠性。方法超声内镜诊断上消化道早期肿瘤,有手术或内镜切除标本可证实诊断的21例,并对其中12例有适应证的患者进行超声内镜指导下的早癌切除术。结果超声内镜诊断早期癌的准确性66%,12例内镜切除的早期癌切除完全,仅个别少量出血并发症。结论超声内镜对上消化道早期癌的诊断有较高敏感性,部分类型的早期癌在超声内镜指导下行内镜切除术安全、可行。     

A comparison of electrophoretic methods for isoenzyme characterization of trypanosomatids. I: Standard stocks of Trypanosoma cruzi zymodemes from northeast Brazil

An investigation of the relative merits of cellulose acetate electophoresis (CAE) and starch-gel electrophoresis (SGE) was made for 18 enzymes of T. cruzi using standard stocks of zymodemes Z1, Z2 and Z3. The 18 enzymes were those shown previously to be the most suited to routine screening of T. cruzi on starch-gel, namely, aspartate aminotransferase (E.C.2.6.1.1. ASAT); alanine aminotransferase (E.C.2.6.1.2. ALAT); phosphoglucomutase (E.C.-2.7.5.1. PGM); glucosephosphate isomerase (E.C.-5.3.1.9. GPI); malate dehydrogenase (oxaloacetate decarboxylating) (NADP⁺) (E.C. 1.1.1.40. ME); glucose-6-phosphate dehydrogenase (E.C.1.1.1.49 G6PD); malate dehydrogenase (E.C. 1.1.1.37. MDH); aconitate hydratase (E.C.4.2.1.3. ACON); isocitrate dehydrogenase (NADP⁺) (E.C.1.1.1.42. ICD); alcohol dehydrogenase (NADP⁺) (E.C.-1.1.1.2. ADH); lactate dehydrogenase (E.C.1.1.1.27. LDH); aminopeptidase (cytosol) (E.G.3.4.11.1. PEP); pyruvate kinase (E.C.2.7.1.40. PK); phosphoglycerate kinase (E.C.2.7.2.3. PGK); enolase (E.C.4.2.1.11. ENO); hexokinase (E.C.2.7.1.1. HK); mannose phosphate isomerase (E.C.5.3.1.8. MPI); and glutamate dehydrogenase (E.C.1.4.1.2. GD). Of these MDH and PEP failed to give satisfactory patterns on CAE. The cellulose acetate zymograms of the other 16 enzymes were as good as, and in some cases better than, those of starch. Increased CAE resolution for ME and G6PD enabled all three zymodemes to be distinguished. Single CAE bands replaced double SGE bands in some cases, and vice versa, without affecting the zymodeme classification. It was concluded that CAE and SGE were both suitable for isoenzyme characterization and were complementary to each other. CAE characterization of T. cruzi was recommended for use in field work and simple laboratories because of its simplicity, transportability, low maintenance requirements and low capital expenditure. Isoelectric focusing (IEF) of ASAT, ALAT, GPI and PGM on Ampholine PAG plates gave poor results, in our hands, and was considered impracticable for routine characterization of T. cruzi.     

Influence of forced swimming-induced stress on the anxiolytic-like effect of 5HT<Subscript>1A</Subscript> agents in mice

RATIONALE: Stress has been related to both anxiety and mood disorders. Forced swimming (FS) is a type of stress that is able to modify the activity of serotonin (5-HT) and GABA in the central nervous system. 5-HT(1A) compounds have been shown to be anxiolytic in a variety of behavioral models and in clinical studies. OBJECTIVE: The main purpose of the present study was to analyze the effect of FS on the anxiolytic-like actions of three 5-HT(1A) compounds. METHODS: Stressed (ST) and unstressed (UST) mice were evaluated in the exploratory behavior test (EBT) or burying behavior test (BBT). In addition, the action of increasing doses of the 5-HT(1A) compounds buspirone, 8-OH-DPAT and indorenate in ST and UST mice was analyzed using the EBT. A spontaneous ambulatory behavior test was carried out immediately after the anxiety tests. RESULTS: One session of FS induced anxiolytic-like behavior in mice tested in both the EBT and the BBT. This effect of FS was blocked by a previous administration of either picrotoxin or WAY 100635. The 5-HT(1A) compounds produced a clear anxiolytic-like effect in UST animals. By contrast, with low doses of either 8-OH-DPAT (0.01 mg/kg), buspirone (0.03 mg/kg) or indorenate (0.3, 0.6 mg/kg) ST mice showed a decrease in the anti-anxiety-like effect observed after FS. No change in ambulation that could mask the results of the anxiety test was registered. CONCLUSIONS: The present data provide evidence that FS induces changes in the effect of 5-HT(1A) agents. The participation of the 5-HT and/or GABA systems in these stress-induced effects is discussed.