Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a progressive, inherited neurodegenerative disorder that presents as polydipsia and polyuria as a consequence of a loss of secretion of the antidiuretic hormone vasopressin (VP) from posterior pituitary nerve terminals. VP gene mutations cause adFNDI. Rats expressing an adFNDI VP transgene (Cys67stop) show a neuronal pathology characterized by autophagic structures in the cell body. adFNDI has thus been added to the list of protein aggregation diseases, along with Alzheimer's, Parkinson's and Huntington's, which are associated with autophagy, a bulk process that delivers regions of cytosol to lysosomes for degradation. However, the role of autophagy in these diseases is unclear. To address the relationships between mutant protein accumulation, autophagy, cell survival, and cell death, we have developed a novel and tractable in vitro system. We have constructed adenoviral vectors (Ads) that express structural genes encoding either the Cys67stop mutant protein (Ad-VCAT-Cys67stop) or an epitope-tagged wild-type VP precursor (Ad-VCAT). After infection of mouse neuroblastoma Neuro2a cells, Ad-VCAT encoded material enters neurite processes and accumulates in terminals, while the Cys67stop protein is confined to enlarged vesicles in the cell body. Similar to the intracellular derangements seen in the Cys67stop rats, these structures are of ER origin, and colocalize with markers of autophagy. Neither Ad-VCAT-Cys67stop nor Ad-VCAT expression affected cell viability. However, inhibition of autophagy or lysosomal protein degradation, while having no effect on Ad-VCAT-expressing cells, significantly increased apoptotic cell death following Ad-VCAT-Cys67stop expression. These data suggest that activation of autophagy by the stress of the expression of an adFNDI mutant protein is a prosurvival mechanism.
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PMID:Autophagy is a prosurvival mechanism in cells expressing an autosomal dominant familial neurohypophyseal diabetes insipidus mutant vasopressin transgene. 1578 9

Corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in the stress response. The action of CRH on ACTH release is strongly potentiated by vasopressin, that is co-produced in increasing amounts when the hypothalamic paraventricular neurons are chronically activated. Whereas vasopressin stimulates ACTH release in humans, oxytocin inhibits it. ACTH release results in the release of corticosteroids from the adrenal that, subsequently, through mineralocorticoid and glucocorticoid receptors, exert negative feedback on, among other things, the hippocampus, the pituitary and the hypothalamus. The most important glucocorticoid in humans is cortisol, present in higher levels in women than in men. During aging, the activation of the CRH neurons is modest compared to the extra activation observed in Alzheimer's disease (AD) and the even stronger increase in major depression. The HPA-axis is hyperactive in depression, due to genetic factors or due to aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression. Increased production of vasopressin in depression does not only occur in neurons that colocalize CRH, but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), i.e., the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression. CRH neurons are strongly activated in depressed patients, and so is their HPA-axis, at all levels, but the individual variability is large. It is hypothesized that particularly a subgroup of CRH neurons that projects into the brain is activated in depression and induces the symptoms of this disorder. On the other hand, there is also a lot of evidence for a direct involvement of glucocorticoids in the etiology and symptoms of depression. Although there is a close association between cerebrospinal fluid (CSF) levels of CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is likely to be derived from sources other than the PVN. Furthermore, a close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. Organizing effects during fetal life as well as activating effects of sex hormones on the HPA-axis have been reported. Such mechanisms may be a basis for the higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found, e.g., in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives. In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men. This is explained by the fact that both in depressed males and females the HPA-axis is increased in activity, parallel to a diminished HPG-axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels. Sex hormone replacement therapy indeed seems to improve mood in elderly people and AD patients. Studies of rats have shown that high levels of cumulative corticosteroid exposure and rather extreme chronic stress induce neuronal damage that selectively affects hippocampal structure. Studies performed under less extreme circumstances have so far provided conflicting data. The corticosteroid neurotoxicity hypothesis that evolved as a result of these initial observations is, however, not supported by clinical and experimental observations. In a few recent postmortem studies in patients treated with corticosteroids and patients who had been seriously and chronically depressed no indications for AD neuropathology, massive cell loss, or loss of plasticity could be found, while the incidence of apoptosis was extremely rare and only seen outside regions expected to be at risk for steroid overexposure. In addition, various recent experimental studies using good stereological methods failed to find massive cell loss in the hippocampus following exposure to stress or steroids, but rather showed adaptive and reversible changes in structural parameters after stress. Thus, the HPA-axis in AD is only moderately activated, possibly due to the initial (primary) hippocampal degeneration in this condition. There are no convincing arguments to presume a causal, primary role for cortisol in the pathogenesis of AD. Although cortisol and CRH may well be causally involved in the signs and symptoms of depression, there is so far no evidence for any major irreversible damage in the human hippocampus in this disorder.
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PMID:The stress system in the human brain in depression and neurodegeneration. 1599 33

The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease (AD). Here we show that the clock genes hBmal1, hCry1, and hPer1 were rhythmically expressed in the pineal of controls (Braak 0). Moreover, hPer1 and hbeta1-adrenergic receptor (hbeta1-ADR) mRNA were positively correlated and showed a similar daily pattern. In contrast, in both preclinical (Braak I-II) and clinical AD patients (Braak V-VI), the rhythmic expression of clock genes was lost as well as the correlation between hPer1 and hbeta1-ADR mRNA. Intriguingly, hCry1 mRNA was increased in clinical AD. These changes are probably due to a disruption of the SCN control, as they were mirrored in the rat pineal deprived of SCN control. Indeed, a functional disruption of the SCN was observed from the earliest AD stages onward, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. Thus, a functional disconnection between the SCN and the pineal from the earliest AD stage onward could account for the pineal clock gene changes and underlie the circadian rhythm disturbances in AD.
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PMID:Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock". 1681 72

The pineal hormone melatonin is involved in the regulation of circadian rhythms and feeds back to the central biological clock, the hypothalamic suprachiasmatic nucleus (SCN) via melatonin receptors. Supplementary melatonin is considered to be a potential treatment for aging and Alzheimer's disease (AD)-related circadian disorders. Here we investigated by immunocytochemistry the alterations of the MT1 melatonin receptor, the neuropeptides vasopressin (AVP) and vasoactive intestinal peptide (VIP) in the SCN during aging and AD. We found that the number and density of AVP/VIP-expressing neurons in the SCN did not change, but the number and density of MT1-expressing neurons in the SCN were decreased in aged controls compared to young controls. Furthermore, both MT1-expressing neurons and AVP/VIP-expressing neurons were strongly diminished in the last neuropathological stages of AD (Braak stages V-VI), but not in the earliest stages (Braak stages I-II), compared to aged controls (Braak stage 0). Our study suggests that the MT1-mediated effects of melatonin on the SCN are disturbed during aging and even more so in late stage AD, which may contribute to the clinical circadian disorders and to the efficacy of therapeutic melatonin administration under these conditions.
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PMID:Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer's disease. 1683 2

Circadian rhythm disturbances, such as sleep disorders, are frequently seen in aging and are even more pronounced in Alzheimer's disease (AD). Alterations in the biological clock, the suprachiasmatic nucleus (SCN), and the pineal gland during aging and AD are considered to be the biological basis for these circadian rhythm disturbances. Recently, our group found that pineal melatonin secretion and pineal clock gene oscillation were disrupted in AD patients, and surprisingly even in non-demented controls with the earliest signs of AD neuropathology (neuropathological Braak stages I-II), in contrast to non-demented controls without AD neuropathology. Furthermore, a functional disruption of the SCN was observed from the earliest AD stages onwards, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. The observed functional disconnection between the SCN and the pineal from the earliest AD stage onwards seems to account for the pineal clock gene and melatonin changes and underlies circadian rhythm disturbances in AD. This paper further discusses potential therapeutic strategies for reactivation of the circadian timing system, including melatonin and bright light therapy. As the presence of melatonin MT1 receptor in the SCN is extremely decreased in late AD patients, supplementary melatonin in the late AD stages may not lead to clear effects on circadian rhythm disorders.
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PMID:Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease. 1738 38

The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRH neurons induce adrenocorticotropin (ACTH) release from the pituitary, which subsequently causes cortisol release from the adrenal cortex. The CRH neurons co-express vasopressin (AVP) which potentiates the CRH effects. CRH neurons project not only to the median eminence but also into brain areas where they, e.g., regulate the adrenal innervation of the autonomic system and affect mood. The hypothalamo-neurohypophysial system is also involved in stress response. It releases AVP from the PVN and the supraoptic nucleus (SON) and oxytocin (OXT) from the PVN via the neurohypophysis into the bloodstream. The suprachiasmatic nucleus (SCN), the hypothalamic clock, is responsible for the rhythmic changes of the stress system. Both centrally released CRH and increased levels of cortisol contribute to the signs and symptoms of depression. Symptoms of depression can be induced in experimental animals by intracerebroventricular injection of CRH. Depression is also a frequent side effect of glucocorticoid treatment and of the symptoms of Cushing's syndrome. The AVP neurons in the hypothalamic PVN and SON are also activated in depression, which contributes to the increased release of ACTH from the pituitary. Increased levels of circulating AVP are also associated with the risk for suicide. The prevalence, incidence and morbidity risk for depression are higher in females than in males and fluctuations in sex hormone levels are considered to be involved in the etiology. About 40% of the activated CRH neurons in mood disorders co-express nuclear estrogen receptor (ER)-alpha in the PVN, while estrogen-responsive elements have been found in the CRH gene promoter region, and estrogens stimulate CRH production. An androgen-responsive element in the CRH gene promoter region initiates a suppressing effect on CRH expression. The decreased activity of the SCN is the basis for the disturbances of circadian and circannual fluctuations in mood, sleep and hormonal rhythms found in depression. Neuronal loss was also reported in the hippocampus of stressed or corticosteroid-treated rodents and primates. Because of the inhibitory control of the hippocampus on the HPA-axis, damage to this structure was expected to disinhibit the HPA-axis, and to cause a positive feedforward cascade of increasing glucocorticoid levels over time. This 'glucocorticoid cascade hypothesis' of stress and hippocampal damage was proposed to be causally involved in age-related accumulation of hippocampal damage in disorders like Alzheimer's disease and depression. However, in postmortem studies we could not find the presumed hippocampal damage of steroid overexposure in either depressed patients or in patients treated with synthetic steroids.
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PMID:The stress system in depression and neurodegeneration: focus on the human hypothalamus. 1752 88

This article provides an evaluation of the dose-response features of drugs that are intended to improve memory, some of which have been used in the treatment of Alzheimer's disease (AD). A common feature of these drugs is that they act via an inverted U-shaped dose response, consistent with the hormetic dose response model. This article assesses historical foundations that lead to the development of AD drugs, their dose-response features and how the quantitative features of such dose responses affected drug discovery and development, and the successes and possible failures of such agents in preclinical and clinical settings. This story begins about 150 years ago with the discovery of an active agent in the Calabar bean plant called physostigmine, its unfolding medical applications, and its implications for dose-response relationships, memory enhancement, and improved drug discovery activities. The article also demonstrates the occurrence of U-shaped dose responses for memory with numerous endogenous agonists including neurosteroids, various peptides (e.g., vasopressin, CCK-8, neuropeptide Y), and other agents (e.g., epinephrine, antagonists for platelet activity factor and nicotinic receptors), supporting the generalizability of the hormetic biphasic dose response. Finally, the significance of the U-shaped dose response is critical for successful clinical application, since it defines the therapeutic window.
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PMID:Alzheimer's disease drugs: an application of the hormetic dose-response model. 1856 64

Amyloid beta protein (Abeta) is thought to be responsible for the loss of memory in Alzheimer's disease (AD). A significant decrease in [Arg(8)]-vasopressin (AVP) in the AD brain has been found. However, it is unclear whether the decrease in AVP is involved in Abeta-induced impairment of memory and whether AVP can protect against Abeta-induced neurotoxicity. The present study examines the effects of intracerebroventricular (i.c.v.) injection of AVP on hippocampal long-term potentiation (LTP), a synaptic model of memory, and investigates the potential protective function of AVP in Abeta-induced LTP impairment. The results showed that (1) i.c.v. injection of different concentrations of AVP or Abeta(25-35) did not affect the baseline field excitatory postsynaptic potentials (fEPSPs); (2) AVP administration alone induced a significant increase in HFS-induced LTP, while Abeta(25-35) significantly suppressed HFS-induced LTP; (3) Abeta(25-35)-induced LTP suppression was significantly prevented by the pretreatment with AVP; (4) paired-pulse facilitation did not change after separate application or co-application of AVP and Abeta(25-35). These results indicate that AVP can potentiate hippocampal synaptic plasticity and dose-dependently prevent Abeta(25-35)-induced LTP impairment. Thus, the present study provides further insight into the mechanisms by which Abeta impairs synaptic plasticity and suggests an important approach in the treatment of AD.
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PMID:Arginine vasopressin prevents amyloid beta protein-induced impairment of long-term potentiation in rat hippocampus in vivo. 1905 64

Aging itself is considered as a major risk factor of dementia. The prevalence of the Alzheimer's disease (AD) is increasing exponentially after the age of 65 and doubles every 5 years. The major aim of our present research was to examine the effect of aging on the transcription of certain genes associated with neurodegenerative disorders in the rat brain. The influence of the vasopressin (VP) hormone was also examined in the same experimental paradigm. Age dependent transcriptional changes of the following four genes were examined in the cerebral cortex: the first was the gene of the amyloid precursor protein (APP) which is abnormally cleaved to toxic beta-amyloid fragments. These aggregated peptides are the major components of the senile plaques in the AD brain. The second one was the mitogen-activated protein kinase (MAPK1) gene. The MAPK is involved in the abnormal hyperphosphorylation of the tau-protein which results in aggregated neurofibrillary tangles. The beta-actin gene was the third one. The protein product of this gene is considered to be involved in synaptogenesis, neuronal plasticity and clinical conditions like depression and AD. The last one was the gene of the tryptophan 2,3-dioxygenase (TDO2) enzyme. The activity of this enzyme is considered as a rate limiting factor in the metabolism of the neuro-immune modulator quinolinic acid (QUIN). The transciptional activity of young (2.5 months) and aged (13 months) Brattleboro rats with or without VP expression were compared by means of real time PCR technique. The cortical transciptional activity of the APP and TDO2 genes were increased in the aged animals as compared with the activity of the young ones, and this effect was independent on the presence of the VP. Our results indicate the importance of certain age dependent transcriptional changes might influence the mechanism of AD and other neurodegenerative disorders.
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PMID:[The transcription of the amyloid precursor protein and tryptophan 2,3-dioxygenase genes are increased by aging in the rat brain]. 1983 74

Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
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PMID:GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity. 2005 51


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