Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotrophin-3 (NT-3) binds to multiple trks, not only its initially identified receptor trkC. Recent studies in our laboratory show that NT-3 negatively regulates nociceptive phenotype associated with the trkA subpopulation. Due to the extensive overlap in trkA and trkC expression it is uncertain whether there is a direct influence of NT-3 on trkA in adult sensory neurons. Thus, the aim of this study was to examine whether NT-3 might alter trkA and associated neuronal phenotype outside of the trkC subpopulation. The effect of a seven-day intrathecal infusion of NT-3 on intact, uninjured adult rat dorsal root ganglion neurons was investigated. Serial sections were processed for receptor radioautography or in situ hybridization to identify and colocalize neurons expressing high-affinity nerve growth factor (NGF) binding sites, substance P (SP), trkC, or trkA mRNAs and to examine the influence of NT-3 on these populations. NT-3 does not appear to alter trkC expression, but evokes a notable reduction in trkA, high-affinity NGF binding sites, and SP levels. It is unlikely that signalling by trkC greatly influences this response because the down-regulation of SP occurs most notably in trkA neurons that lack trkC. Moreover, we have shown here that message levels of two trkA isoforms are differentially modulated by NT-3; infusion results in greater down-regulation of the noninsert containing isoform. These findings suggest a clinically relevant role for NT-3 as an antagonist to NGF, but also raise the caution that not just trkC-positive neurons are influenced following exposure to the neurotrophin.
...
PMID:Neurotrophin-3 down-regulates trkA mRNA, NGF high-affinity binding sites, and associated phenotype in adult DRG neurons. 1451 33

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50-90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium.
...
PMID:Nerve growth factor and diabetic neuropathy. 1466 49

A contributing role of neurogenic inflammation has provided a new dimension in understanding the pathogenesis of various cutaneous and systemic inflammatory diseases such as atopic dermatitis, urticaria, rheumatoid arthritis, ulcerative colitis and bronchial asthma. Several critical observations, such as (i) psoriasis resolves at sites of anaesthesia, (ii) neuropeptides are upregulated, and (iii) there is a marked proliferation of terminal cutaneous nerves in psoriatic plaques, encouraged us to search for a mechanism of neural influence in inflammation and inflammatory diseases. In immunohistochemical studies, we found that keratinocytes in lesional and nonlesional psoriatic tissue express high levels of nerve growth factor (NGF) and that there is a marked upregulation of NGF receptors, p75 neurotrophin receptor (p75NTR) and tyrosine kinase A (TrkA), in the terminal cutaneous nerves of psoriatic lesions. As keratinocytes of psoriatic plaques express increased levels of NGF, it is likely that murine nerves will promptly proliferate into the transplanted plaques on a severe combined immunodeficient mouse. Indeed, we have noted marked proliferation of nerve fibers in transplanted psoriatic plaques compared with the few nerves in transplanted normal human skin. By double label immunofluorescence staining, we have further demonstrated that in these terminal cutaneous nerves there is a marked upregulation of neuropeptides, such as substance P and calcitonin gene-related protein. These observations, as well as recent findings about NGF-induced chemokine expression in keratinocytes, further substantiate a role of the NGF-p75NTR-TrkA system in the inflammatory process of psoriasis. Currently, we are evaluating antagonists to selected neuropeptides and NGF/receptors, with the expectation of identifying pharmacological agents to counter neurogenic inflammation in psoriasis.
...
PMID:Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis. 1469 78

During metamorphosis, the frog intestine goes through a dramatic shortening with extensive apoptosis and regeneration in the epithelial layer and connective tissue. Our aim was to study changes in the enteric nervous system represented by one inhibitory (vasoactive intestinal polypeptide; VIP) and one excitatory (substance P, neurokinin A; SP/NKA) nerve population and concomitant changes in neurotrophin receptor occurrence during this development in the gut of Xenopus laevis adults and tadpoles at different stages of metamorphosis (NF stages 57-66). Sections were incubated with antibodies against the neurotrophin Trk receptors and p75NTR, and the neurotransmitters VIP and SP/NKA. Trk-immunoreactive nerves increased dramatically but transiently in number during early metamorphic climax. Nerves immunoreactive for p75NTR were present throughout the gut, decreased in number in the middle intestine during climax, and increased in the large intestine during late metamorphosis. The percentage of VIP-immunoreactive nerves did not change during metamorphosis. SP/NKA-immunoreactive nerves were first apparent at NF stages 61-62 in the middle intestine and increased in the stomach and large intestine during metamorphosis. Endocrine cells expressing SP/NKA increased in number in stomach, proximal, and middle intestine during metamorphic climax. Thus, neurotrophin receptors are expressed transiently in neurons of the enteric nervous system during metamorphosis in Xenopus laevis and SP/NKA innervation is more abundant in the intestine of the postmetamorphic frog than in the tadpole.
...
PMID:Neurotrophin receptors and enteric neuronal development during metamorphosis in the amphibian Xenopus laevis. 1498

To evaluate the possible role of neuropeptide immunoreactive primary sensory neurons on the development of nociceptive dysfunction in diabetes, the absolute numbers of immunoreactive substance P and calcitonin gene-related peptide (CGRP) dorsal root ganglion (DRG) cell bodies were estimated in diabetic and nondiabetic BALB/C (p75(+/+)) and p75 receptor knockout (p75(-/-)) mice with unilateral sciatic nerve crush. The total numbers of immunoreactive substance P A-cells, substance P B-cells, CGRP A-cells, and CGRP B-cells in L5DRG were estimated using semithick consecutive sections and the optical fractionator. After 4 weeks of streptozotocin-induced diabetes, the number of immunoreactive CGRP A-cells was reduced from 692 +/- 122 to 489 +/- 125 (P = 0.004) in p75(+/+) mice on the noncrushed side. In p75(-/-) mice, there was no such effect of diabetes on the immunoreactive CGRP A-cell number. In p75(+/+) and p75(-/-) mice, there was no effect of diabetes on the immunoreactive CGRP B-cell number, nor was there any effect of diabetes on the immunoreactive substance P B-cell number. Sciatic nerve crush was associated with a substantial loss of L5DRG B-cells in diabetic and nondiabetic p75(+/+) mice and with substantial loss of immunoreactive substance P cells in diabetic p75(+/+) mice. In diabetic and nondiabetic p75(-/-) mice, there was no crush effect on neuropeptide expression. It is concluded that experimental diabetes in the mouse is associated with loss of immunoreactive CGRP primary sensory neurons of the A-cell phenotype, that this loss could play a role for the touch-evoked nociception in the model, and that the neuronal immunoreactive CGRP abnormality possibly is mediated by activation of the p75 neurotrophin receptor.
...
PMID:Selective loss of calcitonin gene-related Peptide-expressing primary sensory neurons of the a-cell phenotype in early experimental diabetes. 1544 99

In the present study, the co-localisation of substance P (SP) with the vanilloid receptor TRPV1 and the neurotrophin receptor tyrosine kinase trkA was analysed in airway-specific murine dorsal root ganglion (DRG) neurons. DRG neurons labelled with Fast Blue were predominantly found at the segmental levels T2-T5. Immunoreactivity for the receptor TRPV1 was localized to 12% of Fast Blue labelled DRG neurons. Double-labelling immunohistochemistry revealed that a substantial number of them also co-express SP (7.6 +/- 1.1% (mean +/- S.E.M.)), whereas neurons with immunoreactivity for TRPV1 only were found in 4.4 +/- 1.3% of the retrogradely labelled neuronal population. Further analysis of retrogradely labelled neurons showed that their majority expressed trkA (62.8 +/- 1.4%), neurofilament protein 68-kDa (64.8 +/- 1.5%) or glutamate alone (19.5 +/- 1.9%). SP was always expressed in trkA-positive neurons. Based on the extent of co-localization of SP with the receptors TRPV1 and trkA in DRG airway neurons, the present study indicates that the DRG pathway may have effects on the magnitude of neurogenic inflammation in airway diseases such as asthma.
...
PMID:Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung. 1552 99

Viral infections are major causes of cough. Virus-induced changes in airway sensory nerve function include increased tachykinin expression and, more specifically, expression of tachykinins by Adelta fibers. This change may be mediated by neurotrophins produced in response to viral infection. At the same time, activity of neutral endopeptidase, an enzyme that is important in degrading and inactivating tachykinins, is decreased by airway viral infections. Viral infections can activate eosinophils, releasing proteins that can cause tachykinin release. Moreover, expression of the NK1 receptor is increased by viral infections of the lungs. The expression of M2 muscarinic receptors, which normally decrease the sensitivity of sensory nerves, is decreased by viral infections. So it is possible that viral infections (1) increase expression of tachykinins (by causing neurotrophin expression), (2) increase release of tachykinins (by causing release of eosinophil proteins), (3) decrease degradation of tachykinins (by decreasing neutral endopeptidase activity), (4) increase expression of the NK1 receptor (again mediated by neurotrophins), and (5) increase the sensitivity of airway afferents (by decreasing M2 muscarinic receptor expression). All these changes may potentiate the tachykininergic input into the cough reflex, and may provide new therapeutic targets for controlling virus-induced cough.
...
PMID:Pathophysiology of airway viral infections. 1556 71

Little is known about postnatal enteric nervous system (ENS) development, but some reports suggest that the postnatal bowel may contain neural stem cells. Therefore, we created an in vitro model of desegregation using an enzymatic and mechanical tissue technique. This approach yielded a group of cells from the small intestine of lactating and adult mice, which ex vivo attach to the culture dish; actively proliferate; and express nestin, vimentin, and the pro-neural transcription factors neurogenin-2 (ngn-2), Sox-10, and Mash-1. In the conditions grown, double immunostains suggest that they differentiate into various cell types, particularly neurons, smooth muscle, and glia including 04 protein-positive cells. They also express the neurotrophic-protein tyrosine kinase (Trk) receptors TrkA, TrkB, and TrkC; the low-affinity neurotrophin receptor p75NTR; and the glial-derived neurotrophic factor receptors (GFR)alpha-1, GFRalpha-2, and GFRalpha-3. The neurons expressed several sensory and motor neurotransmitters present in the central and enteric nervous systems, including calcitonin gene-related peptide, neuropeptideY, peptideYY, substance P, vasoactive intestinal polypeptide, and galanin; along with glia, these neurons formed elaborate intercellular connections. They also express c-KIT, CD34, CD20, and CD45RO, suggesting they either have a hematogenous origin or may differentiate toward hematogenous lines. These findings suggest that these cells may be enteric neural stem cells (ENSCs); may normally be present in the small intestine; and may have the capacity to proliferate and differentiate into neurons, glia, and smooth muscle. Further identification and purification of intestinal ENSCs will provide a means to study the regulation of their differentiation and should give insight into the mechanisms involved in development and remodeling of the ENS. The possible therapeutic application of postnatal stem cells such as ENSCs needs to be evaluated, including their use for transplantation in the central nervous system.
...
PMID:Cultured nestin-positive cells from postnatal mouse small bowel differentiate ex vivo into neurons, glia, and smooth muscle. 1557 54

The pivotal role of nerve growth factor in inducing hyperalgesia and central sensitization has been emphasized in experimental pain models. Higher nerve growth factor levels have recently been found in the cerebrospinal fluid of patients with chronic daily headache. These levels were significantly correlated with the cerebrospinal fluid levels of substance P and calcitonin gene-related peptide, supporting the involvement of this neurotrophin in enhancing the production of the two sensory neuropeptides of the trigemino-vascular system in chronic daily headache. This may, in part, account for the long-lasting sensitization and activation of this system, which could contribute to headache chronicity. More recent research has shown a significant correlation between the higher cerebrospinal fluid levels of nerve growth factor and those of another neurotrophin, the brain-derived neurotrophic factor, as well as glutamate in chronic daily headache patients. These findings suggest the potential involvement of nerve growth factor-mediated upregulation of brain-derived neurotrophic factor in persistent head pain. Therefore, nerve growth factor appears to indirectly exert its effect through enhancing glutamatergic transmission involved in the processing of head pain via brain-derived neurotrophic factor. Based on these data, a potential application can be hypothesized for novel strategies targeting neurotrophins (nerve growth factor and brain-derived neurotrophic factor) and their receptors to chronic daily headache. To date, the majority of the molecules discovered in this regard have been scarcely or never proved in animal pain models and are far from clinical use in chronic pain, including chronic daily headache. If this approach is to be developed in the near future, research should be focused on identifying strategies with few central side effects and specific selective action on central sites involved in chronic head pain and more generally in chronic pain conditions. This will represent a very difficult challenge, taking into account the pleiotropic effect of nerve growth factor and the wide range of intracellular signalling pathways activated by this neurotrophin which are not limited to the nociceptive system.
...
PMID:Nerve growth factor and chronic daily headache: a potential implication for therapy. 1585 22

Acute or chronic stress can alter hippocampal structure, cause neuronal damage, and decrease hippocampal levels of the neurotrophin brain-derived neurotrophic factor (BDNF). The tachykinin substance P and its neurokinin-1 (NK-1) receptor may play a critical role in neuronal systems that process nociceptive stimuli; their importance in stress-activated systems has recently been demonstrated by the antidepressant-like actions of NK-1 receptor antagonists. However, the functional similarities between neurokinin receptors in the hippocampus and those in sensory systems are poorly understood, as is the significance of hippocampal NK-1 receptor in the context of chronic pain. Therefore, we investigated the effects of immobilization stress or inflammatory stimuli on NK-1 receptor and BDNF gene expression in the rat hippocampus. Rats received an acute or chronic immobilization stress, or an acute (formalin) or chronic (complete Freund's adjuvant) inflammatory stimulus to the right hind paw. Subsequently hippocampal volume and specific gravity were measured and NK-1 receptor and BDNF mRNA levels quantified using ribonuclease protection assays. Results showed that either stress or pain down-regulates expression of both NK-1 receptor and BDNF genes in the hippocampus. Hippocampal volume was increased by either pain or stress; this may be due to edema (decreased specific gravity). Thus, BDNF and NK-1 receptor gene plasticity may reflect sensory activation or responses to neuronal injury. These data may provide useful markers of hippocampal activation during chronic pain, and suggest similarities in the mechanisms underlying chronic pain and depression.
...
PMID:Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. 1596 88


<< Previous 1 2 3 4 5 6 7 8 Next >>

---