Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enormous social problems and costs caused by patients suffering from dementia induce growing public interest and become a great challenge of medical science. This report attempts to give a review of recent investigations in neuropathology, genetics, neurotransmitter research, epidemiology, diagnostics and therapy of Alzheimer's dementia, the most common type of dementia. A lot of recent molecular genetic experiments and many neuropathological analogies of Alzheimer's dementia and Down's syndrome indicate a damage on the chromosome 21 as possible cause of Alzheimer's dementia. The neuropathological changes are not limited to the grey matter and cholinergic system, but the white matter and some neurotransmitter systems (noradrenaline, dopamine, serotonin and somatostatin) are affected too. Therapeutical trials to compensate these transmitter deficits show no or only poor clinical benefit. Metabolic studies show disturbances in glucose metabolism of Alzheimer brains suggesting an intraneural energy deficit may be the main damage in Alzheimer's dementia. In spite of extensive technical and psychopathometrical diagnostical attempts Alzheimer's dementia remains to be difficult to diagnose precisely clinically. Best information is given by PET.
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PMID:[Alzheimer's disease. Review of the current status of research]. 256 16

Four molecular forms of somatostatin-like immunoreactivity (SOM-LI) are present in the human temporal cortex: SOM-14, SOM-28 and high-molecular-weight forms (HMW-SOM) of 7500 and 12,000 daltons. SOM-14 and HMW-SOM are depleted in cortical tissue from cases of pre-senile Alzheimer-type dementia (ATD), but there is a disproportionate reduction in HMW-SOM. In cases of Down's syndrome (DS) with the neuropathological and neurochemical changes of ATD, the total concentration of SOM-LI was similar to that in control cases and the proportions of molecular forms present were comparable. However, there was a significant reduction in the concentration of HMW-SOM. These results show that ATD and DS may share a common abnormality in the biosynthesis and/or post-translational processing of cortical SOM.
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PMID:High-molecular-weight forms of somatostatin are reduced in Alzheimer's disease and Down's syndrome. 286 57

Hippocampal choline acetyltransferase was reduced by 89% in rats two weeks after electrolytic lesion of the septum. The hippocampal concentrations of somatostatin (SOM)-14, SOM-28 and high-molecular-weight SOM were unaltered, suggesting that the activity of hippocampal SOM neurones is not influenced by cholinergic afferents. The relevance of this finding to Alzheimer-type dementia and Down's syndrome is discussed.
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PMID:Multiple forms of somatostatin-like immunoreactivity are not influenced by cholinergic denervation of rat hippocampus. 286 60

The evidence for deficiencies in neurotransmitters in Alzheimer's disease is reviewed. Major losses occur in the subcortical afferent projection systems based on acetylcholine, noradrenaline and serotonin. Within the cortex, somatostatin containing neurones and the large pyramidal cells, presumed to use glutamate/aspartate as transmitters, are the most severely damaged cells. The anatomical distribution of cell loss is explainable if the primary site of damage lies within the cortex; nerve cells are damaged by virtue of their presence within or their connections to this region. The senile plaque may represent the site of this damage and neurofibrillary tangle formation and accumulation may lead to cell death. In patients with Down's syndrome who live past 40 years, changes in transmitters apparently identical to those in Alzheimer's disease occur. The dementia of Parkinson's disease appears related to damage to cholinergic, noradrenergic and dopaminergic systems and may reflect a failure of these subcortical regions to sufficiently "activate" an otherwise undamaged cortex.
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PMID:Neurotransmitter deficits in Alzheimer's disease and in other dementing disorders. 287 73

Molecular probes were used as markers in the backcross (Czech II X BALB/cPt) X Czech II to determine the positions of six genes on mouse chromosome 16 (MMU 16). The order of the genes mapped is (centromere), protamine-1 (Prm-1), immunoglobulin lambda 1 light chain (Igl-1), preprosomatostatin (Smst), an endogenous mouse mammary tumor virus locus (Mtv-6), and two more distal sequences, superoxide dismutase, cytoplasmic form (Sod-1), and the proto-oncogene sequence Ets-2. The largest recombination frequency between any two adjacent markers is 24 cM, and thus the position of any marker on MMU 16 that is polymorphic between these two strains can be readily determined in this backcross. A region of MMU 16 which corresponds to the Down syndrome region of human chromosome 21 is located near the distal end of the chromosome.
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PMID:Genetic mapping of Prm-1, Igl-1, Smst, Mtv-6, Sod-1, and Ets-2 and localization of the Down syndrome region on mouse chromosome 16. 288 55

The prevalence of severe dementia in the United States is about 1.3 million cases, of which at least 50 to 60% are of the Alzheimer type. Severe dementia of the Alzheimer type is found rarely in a clearly dominant pattern, although often one or more relatives are affected. Down's syndrome in adults is often associated with Alzheimer changes. The diagnosis is a clinicopathological one; there is a considerable error rate in the clinical diagnosis early in the course of the disease, especially in regard to dementia in depression. The differential diagnosis involves a great many disorders, including multi-infarct dementia, tumors, subdural hematomas, and others. Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning. The latter technique has also demonstrated that oxygen extraction is normal in Alzheimer's disease, thus excluding ischemia from possible pathogenetic factors. Morphological changes, that is, the presence of plaques and tangles, are widely distributed in neocortex, paleocortex, and many deep gray areas down through the pontine tegmentum, but largely exclude the basal ganglia, thalamus, and substantia nigra. Numerous plaques without neocortical tangles are found in many demented persons older than 75 years. A severe loss of large neocortical neurons is characteristic of the disease. The chemical nature of the paired helical filaments that make up the neurofibrillary tangle has not yet been ascertained. Neurons are markedly deficient in the basal forebrain nuclei, and this deficiency may account for the severe diminution of choline acetyltransferase and acetylcholine in the neocortex and paleocortex. Muscarinic cholinergic receptors are present in normal amounts. Norepinephrine is reduced in some cases, and somatostatin in most. Substance P is low in severe cases. The etiology of the disorder is unknown and the role of aluminum is disputed. Management of patients with Alzheimer's disease is difficult, and neuroleptics are to be used with great caution because of their side effects. Substrate therapy has not been effective; physostigmine improves memory but is not suitable for general use. Trophic factors, gangliosides, and aluminum chelation are being investigated for use in pharmacological intervention.
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PMID:Senile dementia of the Alzheimer type. 613 75

Neurochemical and histochemical techniques for characterization of neurotransmitters and their receptors in normal and pathological human brain have modified our understanding of Alzheimer's disease. From a hopeless clinico-pathological entity, it has become one of the models of possible physiopathological relations between neurotransmitter anomalies and dementia processes. Three types of neuromediator (or neuro-modulator): cholinergic, aminergic and peptidergic, appear to be affected to different degrees in 5 electively involved anatomical systems: cholinergic innominocorticoamygdalian and septohippocampic systems, noradrenergic ceruleocortical system, serotoninergic pontocortical system and cortical somatostatin and substance P systems. Critical analysis of neurochemical data shows that the biochemical nosology of Alzheimer's disease is confronted by the difficulty of constituting homogeneous series of both normal and pathological cases. Difficulties are increased when an attempt is made to establish correlations between neurotransmitter deficits and lesions or the demential process. This is the result of several factors: individual variability, difficulty in selecting valid controls, time elapsed before post-mortem sampling, imperfect understanding of the progressive topographical course of both cortical and subcortical lesions, which only now are being studied systematically and in a quantifiable manner, and finally the frequent absence of distinction between early and late forms of the disease. Truly senile forms should probably be distinguished, some authors believing them to be a particular type of aging process, from the presenile forms with more extensive biochemical changes. The constant presence of cholinergic symptoms show these to be fundamental features of the dementia but lesions of noradrenergic and serotoninergic systems also probably play an important role, and this triad is found in other dementia processes: trisomy 21, Parkinson's disease with dementia. Numerous questions concerning the neurotransmitter disorders in Alzheimer's disease remain unanswered: to what extent are the lesions due to neurone destruction? What occurs to the receptors? What factors condition severity of the disease? May the latter be directly correlated with the severity of the global dementia process or rather with the constitutive elements of the syndrome such as memory or attention disorders? What are the consequences of the peptidergic lesions? What is the sequential relation between lesions of corticopetal and intracortical afferent systems and what are their respective physiopathological significance?(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Neurotransmitter anomalies in Alzheimer's disease]. 615 May 45

Cholinergic agonists are known to potentiate GHRH-induced GH secretion, probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's disease. This may be the consequence of age-related cholinergic impairment, which, in turn, could cause somatostatinergic hyperactivity leading to GH hyposecretion. As in Down syndrome (DS) neural alterations have been reported similar to those in aging, including cholinergic impairment, we verified the GH response to GHRH (1 microgram/kg i.v. at 0 min) alone or combined with pyridostigmine (PD), a cholinesterase inhibitor (60 and 120 mg, respectively, in children and adults, orally at -60 min) in 15 DS children (13.5 +/- 0.6 years) and in 11 DS young adults (24.0 +/- 1.2 years). Fifteen normal children (11.9 +/- 0.5 years), 15 normal adults (27.3 +/- 0.9 years) and 16 normal elderly (76.3 +/- 1.5 years) were studied as controls. IGF-I levels showed an age-related reduction both in DS (children vs. adults, mean +/- SEM:354.8 +/- 44.9 vs. 204.4 +/- 29.4 micrograms/l, p < 0.02) and in controls (normal children vs. normal adults vs. normal elderly:281.4 +/- 36.3 vs. 175.4 +/- 11.2 vs. 72.5 +/- 6.6 micrograms/l, p < 0.001). The GH response to GHRH in DS children was higher than in DS adults (areas under curve: 1,197.6 +/- 241.5 vs. 434.4 +/- 83.3 micrograms/l/h, p < 0.01). On the other hand, in normal subjects the GHRH-induced GH rise was similar in children and adults (1,056.2 +/- 128.4 vs. 800.8 +/- 124.5 micrograms/l/h) and both were higher than that in elderly subjects (296.0 +/- 61.0 micrograms/l/h, p < 0.001). PD enhanced the GH response to GHRH both in DS and in normal subjects (p < 0.005). The GH response to PD+GHRH was lower in DS adults than in DS children (1,068.1 +/- 145.7 vs. 1,897.4 +/- 198.8 micrograms/l/h, p < 0.001) as well as in normal elderly subjects with respect to that in normal children and normal adults (832.3 +/- 144.7 vs. 2,172.1 +/- 156.1 and 2,347.6 +/- 322.4 micrograms/l/h, respectively, p < 0.001). The GH response to GHRH alone or combined with PD in DS adults was lower (p < 0.01) than that in normal adults and similar to that in normal elderly subjects. In conclusion, the present data demonstrate that the stimulated GH secretion in DS undergoes an accelerated age-related reduction. They also suggest the existence of a precocious impairment of central cholinergic activity in DS, which, in turn, could cause somatostatinergic hyperactivity and reduced GH secretion.
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PMID:The enhancing effect of pyridostigmine on the GH response to GHRH undergoes an accelerated age-related reduction in Down syndrome. 887 21

There are data indicating that cholinergic activity is precociously impaired in Down's syndrome (DS). On the other hand, acetylcholine as well as arginine (ARG) play a major stimulatory role in the neural control of growth hormone (GH) secretion in humans, likely acting via the inhibition of hypothalamic somatostatin release. The aim of the present study was to verify the effects of pyridostigmine (PD, 120 mg p.o.), a cholinesterase inhibitor, and ARG (0.5 g/kg i.v.) on the growth hormone-releasing hormone (GHRH) (1 microgram/kg i.v.)-induced GH rise in 15 adult patients with DS (M/F: 8/7; age 26.5 +/- 2.2 years; body mass index, BMI: 25.7 +/- 1.0 kg/m2) in which the potentiating effect of PD on GH secretion has been reported to be reduced. The results in DS were compared to those in 15 normal subjects (NS) (M/F: 8/7; age: 30.0 +/- 1.3 years; BMI: 21.4 +/- 0.4 kg/m2). Basal GH and insulin growth factor I (IGF-1) levels in DS (1.8 +/- 0.7 and 206.5 +/- 21.0 micrograms/l) were similar to those in NS (1.4 +/- 0.3 and 179.4 +/- 11.0 micrograms/l). The GH response to GHRH alone in DS (526.5 +/- 120.1 micrograms/l/h) was lower (p < 0.05) than that recorded in NS (895.4 +/- 153.7 micrograms/l/h). The GHRH-induced GH rise was potentiated by PD both in DS (1,138 +/- 184.2 micrograms/l/h; p < 0.02 vs. GHRH alone) and in NS (2,213.8 +/- 212.8 micrograms/l/h; p < 0.005 vs. GHRH alone); however, as the percent potentiating effect of PD was similar in both groups (215 and 247%, respectively) the GH response to GHRH + PD in DS was lower (p < 0.005) than that in NS. The GHRH-induced GH rise was also potentiated by ARG in both DS (2,243 +/- 362.4 micrograms/h; p < 0.001 vs. GHRH alone) and NS (2,764.3 +/- 325.7 micrograms/l/h; p < 0.005 vs. GHRH alone). As the percent potentiating effect of ARG in DS was more marked than in NS (425 vs. 308%, respectively), the GH response to GHRH + ARG became similar in both groups. No sex-related difference was found in the GH response to various stimuli both in DS and NS. In conclusion, these data demonstrate that the potentiating effect of PD but not that of ARG is impaired in adults with DS in whom a reduced somatotrope responsiveness to GHRH is present. These findings indicate that in DS the pituitary GH releasable pool is fully preserved while an impairment of the tuberoinfundibular cholinergic pathways could lead to somatostatinergic hyperactivity and low somatotrope responsiveness to GHRH.
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PMID:Further evidence of cholinergic impairment of the neuroendocrine control of the GH secretion in Down's syndrome. 952 98

Polycystic kidney diseases (autosomal dominant and autosomal recessive) are progressive renal tubular cystic diseases, which are characterised by cyst expansion and loss of normal kidney structure and function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common life- threatening, hereditary disease. ADPKD is more prevalent than Huntington's disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down's syndrome combined. Early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system (RAAS) and its potential protective effect on left ventricular hypertrophy has been one of the major therapeutic goals to decrease cardiac complications and contribute to improved prognosis of the disease. Advances in the understanding of the genetics, molecular biology and pathophysiology of the disease are likely to facilitate the improvement of treatments for these diseases. Developments in describing the role of intracellular calcium ([Ca(2+)](i)) and its correlation with cellular signalling systems, Ras/Raf/mitogen extracellular kinase (MEK)/extracellular signal-regulated protein kinase (ERK), and interaction of these pathways with cyclic adenosine monophosphate (cAMP) levels, provide new insights on treatment strategies. Blocking the vasopressin V(2) receptor, a major adenylyl cyclase agonist, demonstrated significant improvements in inhibiting cytogenesis in animal models. Because of activation of the mammalian target of rapamycin (mTOR) pathway, the use of sirolimus (rapamycin) an mTOR inhibitor, markedly reduced cyst formation and decreased polycystic kidney size in several animal models. Caspase inhibitors have been shown to decrease cytogenesis and renal failure in rats with cystic disease. Cystic fluid secretion results in cyst enlargement and somatostatin analogues have been shown to decrease renal cyst progression in patients with ADPKD. The safety and efficacy of these classes of drugs provide potential interventions for experimental and clinical trials.
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PMID:Potential pharmacological interventions in polycystic kidney disease. 1803 88


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