Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunohistochemistry was used to analyse 18- and 26-month-old transgenic mice overexpressing the human beta-amyloid precursor protein under the platelet-derived growth factor-beta promoter with regard to presence and distribution of neuropeptides. In addition, antisera/antibodies to tyrosine hydroxylase, acetylcholinesterase, amyloid peptide, glial fibrillary acidic protein and microglial marker OX42 were used. These mice have been reported to exhibit extensive amyloid plaques in the hippocampus and cortex [Masliah et al. (1996) J. Neurosci. 16, 5795-5811]. The most pronounced changes were related to neuropeptides, whereas differences between wild-type and transgenic mice were less prominent with regard to tyrosine hydroxylase and acetylcholinesterase. The main findings were of two types; (i) involvement of peptide-containing neurites in amyloid beta-peptide positive plaques, and (ii) more generalized changes in peptide levels in specific layers, neuron populations and/or subregions in the hippocampal formation and ventral cortices. In contrast, the parietal and auditory cortices were comparatively less affected. The peptide immunoreactivities most strongly involved, both in plaques and in the generalized changes, were galanin, neuropeptide Y, cholecystokinin and enkephalin. This study shows that there is considerable variation both with regard to plaque load and peptide expression even among homozygotes of the same age. The most pronounced changes, predominantly increased peptide levels, were observed in two 26-month-old homozygous mice, for example, galanin-, enkephalin- and cholecystokinin-like immunoreactivities in stratum lacunosum moleculare, and galanin, neuropeptide Y, enkephalin and dynorphin in mossy fibers. Many peptides also showed elevated levels in the ventral cortices. However, decreases were also observed. Thus, galanin-like immunoreactivity could not any longer be detected in the diffusely distributed (presumably noradrenergic) fiber network in all hippocampal and cortical layers, and dynorphin-like immunoreactivity was decreased in stratum moleculare, cholecystokinin-like immunoreactivity in mossy fibers and substance P-like immunoreactivity in fibers around granule cells. The significance of generalized peptide changes is at present unclear. For example, the increase in the mainly inhibitory peptides galanin, neuropeptide Y, enkephalin and dynorphin and the decrease in the mainly excitatory peptide cholecystokinin in mossy fibers (and of substance P fibers around granule cells) indicate a shift in balance towards inhibition of the input to the CA3 pyramidal cell layer. Moreover, it may be speculated that the increase in levels of some of the peptides represents a reaction to nerve injury with the aim to counteract, in different ways, the consequences of injury, for example by exerting trophic actions. Further studies will be needed to establish to what extent these changes are typical for Alzheimer mouse models in general or are associated with the V717F mutation and/or the platelet-derived growth factor-beta promoter.
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PMID:Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein--initial observations. 1100 66

Immunoreactivities of total apolipoprotein E (ApoE-IR), amyloid beta peptide(1-42) (Abeta42-IR), interleukin-6 (IL-6-IR), substance P (SPIR) and total tau protein (TTIR) were measured in lumbar cerebrospinal fluid samples of patients with Alzheimer's disease (AD), non-Alzheimer's dementias (NAD), neurological disorders without cognitive impairment (OND) and controls without central nervous system disease using sensitive and specific enzyme immunoassay methods. TTIR was highly significantly increased (P < 0,001) and Abeta42-IR was significantly decreased (P < 0,001 vs. OND/CO, P < 0,03 vs. NAD) in the AD cohort compared with the other diagnostic groups. Significant increases in AD were also found for ApoE-IR (P < 0,001) and IL-6 (P < 0,03), but there was a considerable overlap between groups. In the total AD cohort, SPIR was not significantly changed, but AD patients with late disease onset (>65 years) showed significantly higher values than both early onset patients (<65 years) and controls (P < 0,05). Discriminant function analysis showed that Abeta42-IR (cut-off value 375pg/ml) and TTIR (cut-off value 440 pg/ml) levels contributed most to the group classification of patients. At 85% sensitivity for AD and 100% specificity for controls, the combined evaluation of Abeta42-IR and TTIR in this cross-sectional study resulted in a graph separating AD from non-AD patients with increased specificity of 91% and 75% for AD versus OND and NAD, respectively.
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PMID:Clinical significance of neurobiochemical profiles in the lumbar cerebrospinal fluid of Alzheimer's disease patients. 1131 76

The brain tissue has a large oxidative capacity, but its ability to combat oxidative stress is limited. In aging brain tissue the oxidative stress increases due to decreased activity of antioxidant enzymes and increased oxidative stress leading to neurodegeneration associated with excitotoxicity. The aim of the present study was to determine the effect of neuropeptides, neurokinin B (NKB) and amyloid beta protein fragment Abeta (25-35) and neurotransmitters N-methyl D-aspartate (NMDA) and Glutamate on rat brain synaptosomes of different age groups. Aging brain functions were assessed by measuring the activities of superoxide dismutase (Mn-SOD) and monoamine oxidase (MAO) and intrasynaptosomal [Ca(2+)](i )levels in presence of neuropeptides and neurotransmitters. Increase in age decreased the SOD and MAO enzyme activities; Abeta (25-35) addition further had damaging/toxic effects on the enzymes, whereas NKB alone and in combination with amyloid lowered the toxic effects caused by Abeta (25-35) addition, which was concentration (peptide) and age dependent. Oxidative stress and excitotoxicity are major consequences associated with the age, [Ca(2+)](i )was increased with the age and the neuropeptides and neurotransmitters elicited significant modulatory effects on it. Our study elucidates an increased activity of SOD, decreased activity of MAO and restoration of [Ca(2+)](i) levels in the presence of NKB and suggests an antioxidant, neuromodulatory and neuroprotective role of tachykinin peptide NKB against the beta amyloid induced toxicity.
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PMID:Neuroprotective role of neurokinin B (NKB) on beta-amyloid (25-35) induced toxicity in aging rat brain synaptosomes: involvement in oxidative stress and excitotoxicity. 1651 16

Neprilysin (NEP) is a neutral endopeptidase with diverse physiological roles in the body. NEP's role in degradation of diverse classes of peptides such as amyloid beta, natriuretic peptide, substance P, angiotensin, endothelins, etc., is associated with pathologies of alzheimer's, kidney and heart diseases, obesity, diabetes and certain malignancies. Hence, the functional inhibition of NEP in the above systems can be a good therapeutic target. In the present study, in-silico drug repurposing approach was used to identify NEP inhibitors. Molecular docking was carried out using GLIDE tool. 2934 drugs from the ZINC12 database were screened using high throughput virtual screening (HTVS) followed by standard precision (SP) and extra precision (XP) docking. Based on the XP docking score and ligand interaction, the top 8 hits were subjected to free ligand binding energy calculation, to filter out 4 hits (ZINC000000001427, ZINC000001533877, ZINC000000601283, and ZINC000003831594). Further, induced fit docking-standard precision (IFD-SP) and molecular dynamics (MD) studies were performed. The results obtained from MD studies suggest that ZINC000000601283-NEP and ZINC000003831594-NEP complexes were most stable for 20ns simulation period as compared to ZINC000001533877-NEP and ZINC000000001427-NEP complexes. Interestingly, ZINC000000601283 and ZINC000003831594 showed similarity in binding with the reported NEP inhibitor sacubitrilat. Findings from this study suggest that ZINC000000601283 and ZINC000003831594 may act as NEP inhibitors. In future studies, the role of ZINC000000601283 and ZINC000003831594 in NEP inhibition should be tested in biological systems to evaluate therapeutic effect in NEP associated pathological conditions.
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PMID:Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study. 3283 16


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