神经肽Y拮抗去甲肾上腺素在杏仁核的心血管效应

为了解杏仁内侧核内神经肽Ｙ（ＮＰＹ）和去甲肾上腺素（ＮＡ）的相互关系，向杏仁内侧核（ＭＡＮ）内微量注射ＮＰＹ，或微电泳ＮＰＹ，观察神经元单位放电和测量动脉血压，并在血压改变的条件下测量血浆中ＮＡ含量。结果发现，ＮＰＹ可以对抗ＮＡ的升压作用，微电泳ＮＰＹ到ＭＡＮ也得到相同结论。向ＭＡＮ注入ＮＰＹ后血浆中ＮＡ的含量明显减少，这可能是ＮＰＹ拮抗ＮＡ作用的原因之一。     

Influence of cysteamine and cysteine on open-field behaviour,and on brain concentrations of catecholamines,somatostatin, neuropeptide Y,and corticotropin releasing hormone in the rat

Summary Cysteamine (1.95 or 3.90 mM/kg) administered subcutaneously (sc) markedly decreased the open-field activity of the rats, while the structurally related amino acid cysteine had only minor influence. Cysteamine (1.95 or 3.90 mM/kg) reduced the noradrenaline and increased the dopamine and dihydroxyphenyl acetic acid (DOPAC) levels in the hypothalamus. In striatum the drug decreased both the noradrenaline (1.95 or 3.90 mM/kg) and dopamine (3.90 mM/kg) levels without influencing the DOPAC content. Neither the hypothalamic nor the striatal catecholamines are influenced by administration of equimolar doses of cysteine.Cysteamine (1.95 or 3.90 mM/kg) decreased the somatostatin levels both in the hypothalamus and in the striatum without influencing neuropeptide Y (NPY) and corticotropin releasing hormone (CRH) concentrations. Cysteine administered in equimolar doses did not influence the peptide levels in these brain structures.These data suggest that the cysteamine-induced behavioural changes are related to the decrease of brain noradrenaline and somatostatin concentrations. The structurally related amino acid cystein does not influence the behaviour or the central monoaminergic and peptidergic concentrations in the hypothalamus and striatum of rats.     

Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas

Numerous peptide receptors are overexpressed in human cancer, permitting in vivo tumor targeting. Among such receptors, those for the neurotransmitter neuropeptide Y (NPY) are overexpressed in various tumors. Since NPY can play a role in the kidney, NPY receptor expression and/or endogenous production of peptides of the NPY family (NPY, PYY, PP) were evaluated in 40 renal cell carcinomas (RCCs) and 18 nephroblastomas. NPY receptor protein expression was investigated by in vitro autoradiography using (125)I-labeled PYY in competition with NPY receptor subtype-selective analogs. NPY, PYY and PP production was assessed immunohistochemically. Fifty-six percent of RCCs expressed the Y1 receptor subtype in moderate density, and 80% of nephroblastomas expressed Y1 and Y2 subtypes in moderate to high density. Y1 was also highly expressed in intratumoral blood vessels. In selected cases, NPY was observed in nerve fibers in close association with intratumoral blood vessels and in the vicinity of tumor cells, while no PYY or PP was detected immunohistochemically in these sites. NPY receptors on renal tumor cells and tumor blood vessels may therefore be the molecular targets of endogenous NPY released by intratumoral nerve fibers. With regard to clinical applications, NPY receptors may act as in vivo targets for receptor-directed therapy of RCCs and nephroblastomas for which alternative therapeutic approaches are still required.     

神经肽Y、丹参多酚酸盐对癫痫大鼠海马FOS蛋白表达的影响及作用探讨

目的探讨NPY及丹参多酚酸盐干预对大鼠海马FOS蛋白的表达影响研究及作用探讨。方法采用匹鲁卡品诱发癫痫状态模型,随机分为丹参多酚酸盐干预组、NPY干预组、盐水干预组和对照组,观察各组大鼠的行为学改变,用免疫组织化学法标记显示各组癫痫发作脑内海马FOS蛋白的表达变化。结果在海马门区、CA3区、CA1区有FOS阳性细胞表达,干预方法不同,海马FOS阳性细胞数表达不同,NS、NPY、丹参多酚酸盐干预组FOS阳性细胞数高于对照组,差异有统计学意义（P〈0.05）。结论丹参多酚酸盐和NPY可能通过某种机制抑制了FOS的表达,在一定程度上起到了抗癫痫作用。     

The role of NPY in hypothalamic mediated food intake

Neuropeptide Y (NPY) is a highly conserved neuropeptide with orexigenic actions in discrete hypothalamic nuclei that plays a role in regulating energy homeostasis. NPY signals via a family of high affinity receptors that mediate the widespread actions of NPY in all hypothalamic nuclei. These actions are also subject to tight, intricate regulation by numerous peripheral and central energy balance signals. The NPY system is embedded within a densely-redundant network designed to ensure stable energy homeostasis. This redundancy may underlie compensation for the loss of NPY or its receptors in germline knockouts, explaining why conventional knockouts of NPY or its receptors rarely yield a marked phenotypic change. We discuss insights into the hypothalamic role of NPY from studies of its physiological actions, responses to genetic manipulations and interactions with other energy balance signals. We conclude that numerous approaches must be employed to effectively study different aspects of NPY action.     

Identification of positions in the human neuropeptide Y/peptide YY receptor Y2 that contribute to pharmacological differences between receptor subtypes

The members of the neuropeptide Y (NPY) family are key players in food-intake regulation. In humans this family consists of NPY, peptide YY (PYY) and pancreatic polypeptide (PP) which interact with distinct preference for the four receptors showing very low sequence identity, i.e. Y1, Y2, Y4 and Y5. The binding of similar peptides to these divergent receptors makes them highly interesting for mutagenesis studies. We present here a site-directed mutagenesis study of four amino acid positions in the human Y2 receptor. T^3.40 was selected based on sequence alignments both between subtypes and between species and G^2.68, L^4.60 and Q^6.55 also on previous binding studies of the corresponding positions in the Y1 receptor. The mutated receptors were characterized pharmacologically with the peptide agonists NPY, PYY, PYY(3-36), NPY(13-36) and the non-peptide antagonist BIIE0246. Interestingly, the affinity of NPY and PYY(3-36) increased for the mutants T^3.40I and Q^6.55A. Increased affinity was also observed for PYY to Q^6.55A. PYY(3-36) displayed decreased affinity for G^2.68N and L^4.60A whereas binding of NPY(13-36) was unaffected by all mutations. The antagonist BIIE0246 showed decreased affinity for T^3.40I, L^4.60A and Q^6.55A. Although all positions investigated were found important for interaction with at least one of the tested ligands the corresponding positions in hY1 seem to be of greater importance for ligand binding. Furthermore these data indicate that binding of the agonists and the antagonist differs in their points of interaction. The increase in the binding affinity observed may reflect an indirect effect caused by a conformational change of the receptor. These findings will help to improve the structural models of the human NPY receptors.     

Treatment Strategies Targeting Excess Hippocampal Activity Benefit Aged Rats with Cognitive Impairment

Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long–Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13–36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication.     

Calretinin immunoreactivity in the brain of the zebrafish, Danio rerio: distribution and comparison with some neuropeptides and neurotransmitter-synthesizing enzymes. II. Midbrain, hindbrain, and rostral spinal cord

The distribution of calretinin (CR) in the brainstem and rostral spinal cord of the adult zebrafish was studied by using immunocytochemical techniques. For analysis of some brainstem nuclei and regions, CR distribution was compared with that of complementary markers (choline acetyltransferase, glutamic acid decarboxylase, tyrosine hydroxylase, neuropeptide Y). The results reveal that CR is a marker of various neuronal populations distributed throughout the brainstem, including numerous cells in the optic tectum, torus semicircularis, secondary gustatory nucleus, reticular formation, somatomotor column, gustatory lobes, octavolateral area, and inferior olive, as well as of characteristic tracts of fibers and neuropil. These results indicate that CR may prove useful for characterizing a number of neuronal subpopulations in zebrafish. Comparison of the distribution of CR observed in the brainstem of zebrafish with that reported in an advanced teleost (the gray mullet) revealed a number of similarities, and also some interesting differences. Our results indicate that many brainstem neuronal populations have maintained the CR phenotype in widely divergent teleost lines, so CR studies may prove very useful for comparative analysis.