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)

By means of immunohistochemistry, the localization of Somatostatin (SOM)- and Substance P (SP)-ergic neuronal populations was compared to the occurrence of Glial cell line-derived neurotrophic factor (GDNF) in the human hippocampus from prenatal to adult life stages. The results obtained i) confirm previous reports on the distribution of SOM and SP; ii) show that GDNF-like immunoreactivity occurs in an ample population of hippocampal neurons, with a main location in the pyramidal cells; iii) identify regions of codistribution of either neuropeptide with GDNF-positive elements. Although coexistence of GDNF with SOM or SP was not detected, the possibility that the trophic factor may act on the neuropeptide-containing neurons can be envisaged and is worth further analysis.
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PMID:Somatostatin- and Substance P-ergic neurons and Glial cell line-derived neurotrophic factor in the human archicortex. 1172 90

Small-diameter sensory neurones found in the rat dorsal root ganglia (DRG) include cells sensitive to glial cell line-derived neurotrophic factor (GDNF), which express the inhibitory peptide somatostatin (SOM). Here we addressed the functional relationship between GDNF and sensory neurone-derived SOM. Topical application of GDNF through the rat isolated dorsal horn of the spinal cord promoted activity-induced release of SOM from central terminals of sensory neurones. Once released by sensory neurones, SOM is known to act, at least in part, by opposing the action of Substance P (SP) in neurogenic inflammation. Therefore, we evaluated GDNF ability to modulate two well-documented effects of peripherally and centrally administered SP. Local application of GDNF in the mouse air pouch reduced SP-induced leukocyte migration. This effect of GDNF was mimicked by the SOM analog octreotide (OCT) and required intact SOM neuronal pools. Intrathecal injection of GDNF activated rat lumbar dorsal horn neurones and inhibited intrathecal SP-induced thermal hypersensitivity. This effect of GDNF was reversed by the SOM antagonist c-SOM and mimicked by OCT. In conclusion we propose GDNF regulation of neuronal SOM release as a novel mechanism that, if explored, may lead to new therapeutic strategies based on local release of somatostatin.
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PMID:A novel control mechanism based on GDNF modulation of somatostatin release from sensory neurones. 1197 39

Huntington's disease is a neurodegenerative disorder characterized by a selective degeneration of striatal projection neurons, which deal with choreic movements. Neuroprotective therapy could be achieved with the knowledge of the specific trophic requirements of these neuronal populations. Thus, the induction of endogenous trophic response or the exogenous administration of neurotrophic factors may help to prevent or stop the progression of the illness. Excitotoxicity has been implicated in the etiology of Huntington's disease, because intrastriatal injection of glutamate receptor agonists reproduces some of the neuropathological features of this disorder. Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, glial cell line-derived neurotrophic factor (GDNF), neurturin, and their receptors in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults. Transplantation of cells genetically engineered to release neurotrophic factors in the striatum has been used to study the neuroprotective effects of neurotrophin and GDNF family members in the excitotoxic model of Huntington's disease. Neurotrophins (brain-derived neurotrophic factor [BDNF], neurotrophin-3, and neurotrophin-4) protected striatal projection neurons against quinolinic or kainic acid treatment. However, GDNF family members showed a more specific action. Neurturin only protected gamma-aminobutyric acid (GABA)/enkephalinergic neurons that project to the external segment of the globus pallidus, whereas GDNF exerts its effects on GABA/substance P positive neurons, which project to the substantia nigra pars compacta and the internal segment of the globus pallidus. In conclusion, the trophic requirements of each population of striatal projection neurons are due to a complex interaction between several neurotrophic factors, such as neurotrophins and GDNF family members, which can be modified, in different pathological conditions. Moreover, these neurotrophic factors may be able to provide selective protection for basal ganglia circuits, which are affected in striatonigral degenerative disorders, such as Huntington's disease or multisystem atrophy.
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PMID:Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease. 1203 Dec 78

Subsets of parasympathetic and enteric neurons require neurturin signaling via glial cell line-derived neurotrophic factor family receptor alpha2 (GFRalpha2) for development and target innervation. Why GFRalpha2-deficient (Gfra2-/-) mice grow poorly has remained unclear. Here, we analyzed several factors that could contribute to the growth retardation. Neurturin mRNA was localized in the gut circular muscle. GFRalpha2 protein was expressed in most substance P-containing myenteric neurons, in most intrapancreatic neurons, and in surrounding glial cells. In the Gfra2-/- mice, density of substance P-containing myenteric ganglion cells and nerve bundles in the myenteric ganglion cell layer was significantly reduced, and transit of test material through small intestine was 25% slower compared to wild-type mice. Importantly, the knockout mice had approximately 80% fewer intrapancreatic neurons, severely impaired cholinergic innervation of the exocrine but not the endocrine pancreas, and increased fecal fat content. Vagally mediated stimulation of pancreatic secretion by 2-deoxy-glucose in vivo was virtually abolished. Retarded growth of the Gfra2-/- mice was accompanied by reduced fat mass and elevated basal metabolic rate. Moreover, the knockout mice drank more water than wild-type controls, and wet-mash feeding resulted in partial growth rescue. Taken together, the results suggest that the growth retardation in mice lacking GFRalpha2 is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility.
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PMID:Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha2. 1295 19

We evaluated the neuroprotective potential of tachykinin peptides using a model system in which mesencephalic dopaminergic (DA) neurons die spontaneously and selectively as they mature. The three native tachykinins, substance P (SP), neurokinin (NK) A, and NKB afforded substantial protection against DA cell demise. The selective NK1 receptor antagonist [D-Pro9,[spiro-gamma-lactam] Leu10,Trp11]substance P (GR71251) was sufficient in itself to suppress the effect of SP, whereas a cotreatment with GR71251 and the NK3 receptor antagonist (R)-N-[alpha-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (SB218795) was required to prevent the effects of both NKA and NKB. Consistent with these results, D-Ala-[L-Pro9,Me-Leu8]substance P(7-11) (GR73632), a selective agonist of NK1 receptors and [pro7]-NKB, a selective agonist of NK3 receptors, conferred protection to DA neurons, whereas (Lys3, Gly8-R-gamma-lactam-Leu9)neurokinin A(3-10) (GR64349), which activates specifically NK2 receptors, did not. DA neurons rescued by tachykinins accumulated [3H]DA efficiently, which suggests that they were also totally functional. Neuroprotection by tachykinins was highly selective for DA neurons, rapidly reversed upon treatment withdrawal, and reproduced by but independent of glial cell line-derived neurotrophic factor. Survival promotion by tachykinins was abolished by blocking voltage-gated Na+ channels with tetrodotoxin or N-type voltage-gated Ca2+ channels with omega-conotoxin-MVIIA, which indicates that an increase in neuronal excitability was crucially involved in this effect. Together, these data further support the notion that the survival of mesencephalic DA neurons during development depends largely on excitatory inputs, which may be provided in part by tachykinins.
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PMID:Substance P, neurokinins A and B, and synthetic tachykinin peptides protect mesencephalic dopaminergic neurons in culture via an activity-dependent mechanism. 1607 32

Expression of the nociceptive peptide, substance P (SP) is regulated by the neurotrophin, nerve growth factor (NGF), and exogenous exposure to high levels of NGF increases its cellular content and release. NGF utilizes two receptors, the NGF-specific tyrosine kinase receptor, TrkA, and also the non-specific neurotrophin receptor, p75(NTR) (p75). The purpose of this study is to determine the relative involvement of these receptors in nociception. To investigate the role of TrkA in SP signaling, sensory neurons from adult rats were grown in vitro and exposed to a TrkA-blocking antibody. Pretreatment with the antibody inhibited NGF-induced SP elevation. Furthermore, when neurons were exposed to K252a, a relatively specific TrkA kinase inhibitor, the NGF effect on SP was also inhibited. K252a did not prevent SP up-regulation in cells exposed to forskolin or glial cell line-derived neurotrophic factor (GDNF), two agents which increase SP expression independently of TrkA. When p75 was blocked by antiserum, SP up-regulation by NGF was also inhibited. The antiserum neither impacted neuronal survival or basal levels of SP expression, nor did it inhibit SP up-regulation induced by forskolin. Two other neurotrophins, which are also ligands for p75, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) did not block NGF-induced SP up-regulation, raising the possibility that activated p75 is able to cooperate in SP regulation regardless of which neurotrophin ligand occupies it. Our data suggest that NGF up-regulation of SP expression requires the involvement of both TrkA and p75, although the specific contribution of each receptor to SP signaling remains to be determined.
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PMID:Nerve growth factor regulates substance P in adult sensory neurons through both TrkA and p75 receptors. 1630 Jul 61

In this study, we have investigated the effects of artemin (ARTN), one of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, on C-fibres following nerve injury in the adult rat. GDNF family receptor alpha (GFRalpha) 3, the ligand binding domain of the ARTN receptor, is expressed in 34% of dorsal root ganglion (DRG) cells, predominantly in the peptidergic population of C-fibres and in a proportion of the isolectin B4 (IB4)-binding population. Interestingly, only 30% of GFRalpha3-expressing DRG cells co-expressed RET (the signal transducing domain). In agreement with previous studies, treatment with ARTN prevented many of the nerve injury-induced changes in the histochemistry of both the peptidergic and the IB4-binding populations of small, but not large, diameter DRG cells. In addition, ARTN treatment maintained C-fibre conduction velocity, and C-fibre evoked substance P release within the dorsal horn following nerve injury. ARTN was also protective following capsaicin treatment, which produces selective C-fibre injury. Given the potent neurotrophic actions of ARTN on C-fibres, it may therefore provide potential for the treatment of nerve injury, particularly in the maintenance of small fibre function.
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PMID:Artemin has potent neurotrophic actions on injured C-fibres. 1711 42

Reg-2 is a secreted protein that is expressed de novo in motoneurons, sympathetic neurons, and dorsal root ganglion (DRG) neurons after nerve injury and which can act as a Schwann cell mitogen. We now show that Reg-2 is also upregulated by DRG neurons in inflammation with a very unusual expression pattern. In a rat model of monoarthritis, Reg-2 immunoreactivity was detected in DRG neurons at 1 day, peaked at 3 days (in 11.6% of DRG neurons), and was still present at 10 days (in 5%). Expression was almost exclusively in the population of DRG neurons that expresses the purinoceptor P2X(3) and binding sites for the lectin Griffonia simplicifolia IB4, and which is known to respond to glial cell line-derived neurotrophic factor (GDNF). Immunoreactivity was present in DRG cell bodies and central terminals in the dorsal horn of the spinal cord. In contrast, very little expression was seen in the nerve growth factor (NGF) responsive and substance P expressing population. However intrathecal delivery of GDNF did not induce Reg-2 expression, but leukemia inhibitory factor (LIF) had a dramatic effect, inducing Reg-2 immunoreactivity in 39% of DRG neurons and 62% of P2X(3) cells. Changes in inflammation have previously been observed predominantly in the neuropeptide expressing, NGF responsive, DRG neurons. Our results show that changes also take place in the IB4 population, possibly driven by members of the LIF family of neuropoietic cytokines. In addition, the presence of Reg-2 in central axon terminals implicates Reg-2 as a possible modulator of second order dorsal horn cells.
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PMID:Reg-2 expression in dorsal root ganglion neurons after adjuvant-induced monoarthritis. 1865 80

Rapid neck motions can load cervical nerve roots and produce persistent pain. This study investigated the cellular basis of radicular pain and mechanical implications of tissue loading rate. A range of peak loads was applied in an in vivo rat model of dorsal root compression, and mechanical allodynia (i.e. pain) was measured. Axonal damage and nociceptive mediators were assessed in the axons and cell bodies of compressed dorsal roots in separate groups of rats at days 1 and 7 after injury. In the day 7 group, damage in the compressed axons, evaluated by decreased heavy chain neurofilament immunoreactivity, was increased for compressions above a load of 34.08 mN, which is similar to the load-threshold for producing persistent pain in that model. Also, the neuropeptide substance P and glial cell line-derived neurotrophic factor and its receptor significantly decreased (p < 0.02) with increasing load in the small nociceptive neurons of the dorsal root ganglion, suggesting that axonal damage may also decrease neurotrophic support in injured nociceptive afferent fibers. In a separate study, roots were compressed at 2mm/s, and held, to develop a quasi-linear viscoelastic model that was validated through comparisons to quasistatic loading. The model demonstrated that nearly 23% less displacement was required to reach the axonal injury load threshold during dynamic loading than for quasistatic rates. Together, these studies demonstrate that nerve root compressions that produce pain symptoms are sufficient to mediate nociceptive cellular changes, and that thresholds for pain and nociceptive pathophysiology may be lower for dynamic loading scenarios.
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PMID:The role of graded nerve root compression on axonal damage, neuropeptide changes, and pain-related behaviors. 1908 57

The bone morphogenetic protein (BMP) family is a class of transforming growth factor (TGF-beta) superfamily molecules that have been implicated in neuronal differentiation. We studied the effects of BMP2 and glial cell line-derived neurotrophic factor (GDNF) on inducing differentiation of enteric neurons and the signal transduction pathways involved. Studies were performed using a novel murine fetal enteric neuronal cell line (IM-FEN) and primary enteric neurons. Enteric neurons were cultured in the presence of vehicle, GDNF (100 ng/ml), BMP2 (10 ng/ml), or both (GDNF + BMP2), and differentiation was assessed by neurite length, markers of neuronal differentiation (neurofilament medium polypeptide and beta-III-tubulin), and neurotransmitter expression [neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), choline acetyltransferase (ChAT) and Substance P]. BMP2 increased the differentiation of enteric neurons compared with vehicle and GDNF-treated neurons (P < 0.001). BMP2 increased the expression of the mature neuronal markers (P < 0.05). BMP2 promoted differentiation of NPY-, nNOS-, and TH-expressing neurons (P < 0.001) but had no effect on the expression of cholinergic neurons (ChAT, Substance P). Neurons cultured in the presence of BMP2 have higher numbers of TH-expressing neurons after exposure to 1-methyl 4-phenylpyridinium (MPP(+)) compared with those cultured with MPP(+) alone (P < 0.01). The Smad signal transduction pathway has been implicated in TGF-beta signaling. BMP2 induced phosphorylation of Smad1, and the effects of BMP2 on differentiation of enteric neurons were significantly reduced in the presence of Smad1 siRNA, implicating the role of Smad1 in BMP2-induced differentiation. The effects of BMP2 on catecholaminergic neurons may have therapeutic implications in gastrointestinal motility disturbances.
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PMID:BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway. 2000 50


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