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

The broad-spectrum antagonist of neuropeptide receptor, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P, induced apoptosis selectively in human small cell lung carcinoma (SCLC) cells, which express gastrin-releasing peptide receptor, but not in other types of tumor cells as well as normal cells. The addition of gastrin-releasing peptide or bombesin and the inhibitor of caspase-3 suppressed [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P-induced apoptosis. Moreover, [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P-induced apoptosis was not suppressed by Bcl-2 over-expression. Thus, blockage of gastrin-releasing peptide receptor-mediated signaling may provide a novel therapeutic option in SCLC which has become resistant to conventional chemotherapeutic agents.
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PMID:Bcl-2-independent induction of apoptosis by neuropeptide receptor antagonist in human small cell lung carcinoma cells. 1106 32

Neutrophil apoptosis is an important event in the resolution of inflammation. The role of substance P (SP) in neutrophil apoptosis has not been previously investigated. We found that substance P delays apoptosis in neutrophils. Human neutrophils were isolated and cultured up to 24 hours. Apoptosis was detected by light and electron microscopy, as well as DNA-fragmentation assays. Substance P delayed the spontaneous apoptosis of neutrophils at 6, 12, 18 and 24 hours in a dose-dependent fashion in the range of 10-100 microM. Whereas the both peptide neurokinin-1 (NK-1) receptor antagonists [D-Pro(2), D-Trp(7,9)]-SP and GR 82334 inhibited the substance P effect on neutrophils, the nonpeptide NK(1) receptor antagonist L-703.606 itself, an analogue of CP-96,345, induced apoptosis of neutrophils. Surprisingly, the effect of L-703.606 could be prevented by substance P. Western blotting results showed that the neuropeptide substance P inhibited the spontaneous apoptosis-associated caspase-3 activation in the same concentration range as described above. Parallel the inhibition of cleavage of focal adhesion kinase (FAK), a substrate of caspases could be observed by substance P. In conclusion, our results extend the range of biological effects of the neuropeptide substance P and provide new insight to the role of this tachykinin in the modulation of the inflammatory response by the nervous system.
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PMID:Delay of neutrophil apoptosis by the neuropeptide substance P: involvement of caspase cascade. 1131 37

The bone marrow (BM), which is the major site of immune cell development in the adult, responds to different stimuli such as inflammation and hemorrhagic shock. Substance P (SP) is the major peptide encoded by the immune/hemopoietic modulator gene, preprotachykinin-1 (PPT-I). Differential gene expression using a microarray showed that SP reduced hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA levels in BM stroma. Because long-term hypoxia induced the expression of PPT-I in BM mononuclear cells, we used timeline studies to determine whether PPT-I is central to the biologic responses of BM stroma subjected to 30-min hypoxia (pO(2) = 35 mm Hg) followed by reoxygenation. HIF-1alpha mRNA and protein levels were increased up to 12 h. At this time, beta-PPT-I mRNA was detected with the release of SP at 16 h. SP release correlated with down-regulation of HIF-1alpha to baseline. A direct role for SP in HIF-1alpha expression was demonstrated as follows: 1) transient knockout of beta-PPT-I showed an increase in HIF-1alpha expression up to 48 h of reoxygenation; and 2) HIF-1alpha expression remained baseline during reoxygenation when stroma was subjected to hypoxia in the presence of SP. Reoxygenation activated the PPT-I promoter with concomitant nuclear translocation of HIF-1alpha that can bind to the respective consensus sequences within the PPT-I promoter. SP reversed active caspase-3, an indicator of apoptosis and erythropoiesis, to homeostasis level after reoxygenation of hypoxic stroma. The results show that during reoxgenation the PPT-I gene acts as a negative regulator on the expression of HIF-1alpha and active caspase-3 in BM stroma subjected to reoxygenation.
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PMID:Induction of hypoxia-inducible factor-1alpha and activation of caspase-3 in hypoxia-reoxygenated bone marrow stroma is negatively regulated by the delayed production of substance P. 1159 89

All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of G(alphaq) and G(alpha12,13). Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting G(alphaq) and stimulating G(alpha12,13). However, these SPDs had low potency and short half-lives. In this report we show that a bradykinin antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric bradykinin antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two antagonists. CU201 inhibited intracellular Ca2+ release in response to bradykinin, indicating blockage of the G(alphaq) signal, and stimulated c-Jun kinases, indicating stimulation of the G(alpha12,13) pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a "biased agonist" mechanism. 1193 11

Previously, we have shown that primary afferent neurons are necessary for disease activity in immune-mediated liver injury in mice. These nerve fibers are detectable by substance P (SP) immunocytochemistry in the portal tract of rodent liver. Antagonists of the neurokinin-1 receptor (NK-1R), which is the prime receptor of SP, prevented liver damage by suppressing the synthesis of proinflammatory cytokines. Here, we investigated the influence of primary afferent nerve fibers, SP, and NK-1 receptor antagonists on hepatocyte apoptosis in vivo induced by administration of activating anti-CD95 monoclonal antibody (mAb) to mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment prevented CD95-mediated activation of caspase-3, measured as enzymatic activity in liver homogenates or by demonstration of hepatocellular immunoreactivity for active caspase-3 in liver slices, and liver damage. This effect was reversed by administration of SP to anti-CD95 mAb-treated mice depleted from primary afferent neurons. The presence of the NK-1R on mouse hepatocytes was demonstrated by immunocytochemistry and flow cytometry. Intraperitoneal pretreatment with the NK-1 receptor antagonists (2S,3S)-cis-2-(diphenylmethyl)-N-([2-methoxyphenyl]-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) or (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperadine (L-733,060) dose dependently protected mice from CD95-mediated liver injury. Similar results were obtained when apoptotic liver damage was induced by administration of tumor necrosis factor-alpha to d-galactosamine-sensitized mice. In conclusion, SP, probably by binding to its receptor on hepatocytes, might aggravate apoptotic signals in these cells. Because NK-1 receptor antagonists not only suppress the proinflammatory cytokine response in the liver but also prevent liver cell apoptosis in vivo, they might be suitable drugs for treatment of immune-mediated liver disease.
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PMID:Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage. 1461 92

Parkinson's disease (PD) is a basal ganglia disorder. Motor symptoms develop insidiously following substantial neurodegeneration of the dopamine (DA) neurons in the nigrostriatal system and produce slowed, infrequent movements, postural instability, and gait changes. A thorough understanding of neurochemical compensations occurring in the striatum during early stages of PD is crucial in identifying components that are altered initially as the DA is depleted. Producing an incomplete lesion of the nigrostriatal DA system in rats would mimic the principal early neurochemical features of human PD. We infused 6-hydroxydopamine unilaterally into the substantia nigra to reach a target of approximately 50% depletion in striatal DA at 4 weeks. This was evaluated by HPLC analysis of tissue DA content and monitored behaviorally by forepaw use reflecting asymmetries in striatal DA levels. DA loss was assessed by using tyrosine hydroxylase immunohistochemical staining, and the data were conjoined with the behavioral assessments. We found that activated caspase-3, its actin cleavage product fractin, and components of the apoptosome were increased significantly in DA-depleted striatum. Thus mobilization of the intrinsic programmed cell death pathway occurred, without cell loss. Elevations in apoptogenic proteins were pronounced in enkephalinergic striatopallidal neurons compared with the substance P-containing striatonigral neurons. Our findings suggest that cellular homeostatic imbalances that accompany even mild striatal DA depletion take time to develop, differentially affect the striatal output pathways, and may be an important feature of early-stage PD. These observations could be capitalized upon to develop therapeutic interventions in the preclinical phases of the disorder.
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PMID:Partial dopamine loss enhances activated caspase-3 activity: differential outcomes in striatal projection systems. 1618 Feb 25

Several groups have reported apoptosis of dorsal root ganglion (DRG) cells as a prominent feature of diabetic polyneuropathy (DPN), although this has been controversial. Here, we examined subacute (4-month) type 1 diabetic BB/Wor rats with respect to sensory nerve functions, DRG and sural nerve morphometry, pro- and antiapoptotic proteins, and the expression of neurotrophic factors and their receptors. Sensory nerve conduction velocity was reduced by 13% and was accompanied by significant hyperalgesia. The numbers of DRG neurons including substance P-and calcitonin gene-related peptide-positive neurons were not altered, although they showed significant atrophy. Sural nerve morphometry showed decreased numbers of myelinated and unmyelinated fibers. Active caspase-3 and Bax expressions were increased, whereas antiapoptotic Bcl-xl and heat shock protein (HSP) 27 expressions in DRGs were increased. Nerve growth factor (NGF) contents in sciatic nerves and the expression of NGF receptor TrkA in DRGs were decreased. Immunohistochemistry showed increased numbers of active caspase-3-, HSP70-, and HSP27-positive neurons. Examinations of DRGs revealed no structural evidence of apoptosis but rather progressive hydropic degenerative changes. We conclude that apoptotic stress is induced in DRGs but is counterbalanced by survival elements in subacute type 1 diabetic BB/Wor rats and that distal nerve fiber loss reflects a dying-back phenomenon caused by impaired neurotrophic support.
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PMID:Apoptotic stress is counterbalanced by survival elements preventing programmed cell death of dorsal root ganglions in subacute type 1 diabetic BB/Wor rats. 1624 57

P2X(7) is a receptor for extracellular nucleotides expressed by different normal cell types. P2X(7) triggering may result in stimulation of cell proliferation or induction of apoptosis depending on the level of activation. P2X(7) expression and function in B-cell chronic lymphocytic leukemia has been shown to correlate with disease severity. Here, we have asked the question of whether P2X(7) is expressed and functional in neuroblastoma, a pediatric tumor of neuroectodermal origin. P2X(7) was detected both in primary neuroblastoma tumors and in neuroblastoma cell lines. In the latter cells, P2X(7) stimulation by ATP was found to trigger (a) increased intracellular calcium fluxes, (b) plasma membrane depolarization, and (c) formation of a nonselective plasma membrane permeable pore. In contrast to the usual response typically observed in the majority of cell types, P2X(7) in vitro stimulation did not induce caspase-3 activation or apoptosis of neuroblastoma cells but rather supported their proliferation. Growth stimulation was partially due to substance P release from nucleotide-activated neuroblastoma cells. Therefore, neuroblastoma cells seem to have molded P2X(7) function to their advantage in two ways (i.e., by silencing P2X(7) proapoptotic activity and by coupling P2X(7) stimulation to release of locally acting trophic factors).
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PMID:The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. 1642 24

Excitotoxic damage appears to be a critical factor in the formation of perinatal brain lesions associated with cerebral palsy (CP). When injected into newborn mice, the glutamatergic analogue, ibotenate, produces cortical lesions and white matter cysts that mimic human perinatal brain lesions. Neuropeptides are neuronal activity modulators and could therefore modulate glutamate-induced lesions. However, neuropeptides are rapidly degraded by peptidases. Racecadotril, which is rapidly metabolized to its active metabolite thiorphan, is a neutral endopeptidase (NEP) inhibitor used in clinical practice for diarrhoea with a remarkable safety profile. This study aimed to test the original hypothesis that thiorphan could be neuroprotective against ibotenate-induced lesions in newborn mice. Intraperitoneal administration of thiorphan reduced ibotenate-induced cortical lesions by up to 57% and cortical caspase-3 cleavage by up to 59%. This neuroprotective effect was long-lasting and was still observed when thiorphan was administered 12 h after the insult, showing a remarkable window for therapeutic intervention. Further supporting the neuroprotective effect of pharmacological blockade of NEP, mouse pups with a genetic deletion of NEP displayed a significantly reduced size of the ibotenate-induced cortical grey matter lesion when compared with wild-type animals. Thiorphan effects were mimicked by substance P (SP) and, in a less potent manner, by neurokinin A. Thiorphan effects were inhibited by blockers of NK1 and NK2 receptors. Real-time reverse transcription-polymerase chain reaction, autoradiography and immunohistochemistry confirmed the expression of NK1 and NK2 receptors in the neonatal murine neocortex. These data demonstrate that thiorphan prevents neonatal excitotoxic cortical damage, an effect largely mediated by SP. Thiorphan could represent a promising drug for the prevention of CP, which remains a challenging disease. In a broader context, these results also raise potential implications for the prevention of neurodegenerative diseases involving glutamate-mediated excitotoxic neuronal death.
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PMID:Thiorphan, a neutral endopeptidase inhibitor used for diarrhoea, is neuroprotective in newborn mice. 1702 11

In the current study, we have evaluated the ability of substance P (SP) and other neurokinin 1 receptor (NK1) agonists to protect, in a dose- and time-dependent manner, primary cultures of rat cerebellar granule cells (CGCs) from serum and potassium deprivation-induced cell death (S-K5). We also established the presence of SP high affinity NK1 transcripts and the NK1 protein localization in the membrane of a sub-population of CGCs. Moreover, SP significantly and dose-dependently reduced the Akt 1/2 and Erk1/2 dephosphorylation induced by S-K5 conditions, as demonstrated by Western blot analysis. Surprisingly, in SP-treated CGCs caspase-3 activity was not inhibited, while the calpain-1 activity was moderately reduced. Corroborating this result, SP blocked calpain-mediated cleavage of tau protein, as demonstrated by the reduced appearance of a diagnostic fragment of 17 kDa by Western blot analysis. In addition, SP induced a significant reduction of the delayed rectifier K+ currents (Ik) in about 42% of the patched neurons, when these were evoked with depolarizing potential steps. Taken together, the present results demonstrate that the activation of NK1 receptors expressed in CGCs promote the neuronal survival via pathways involving Akt and Erk activation and by inhibition of Ik which can contribute to the neuroprotective effect of the peptide.
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PMID:Substance P provides neuroprotection in cerebellar granule cells through Akt and MAPK/Erk activation: evidence for the involvement of the delayed rectifier potassium current. 1739 81


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