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)

Necdin is a multifunctional signaling protein that stabilizes terminal differentiation of postmitotic neurons. The human necdin gene in chromosome 15q11-q12 is maternally imprinted, paternally transcribed, and not expressed in Prader-Willi syndrome, a human genomic imprinting-associated neurodevelopmental disorder. Although necdin-deficient mice display several abnormal phenotypes reminiscent of this syndrome, little is known about molecular mechanisms that lead to the neurodevelopmental defects. Here, we demonstrate that paternally expressed necdin is required for physiological development of nerve growth factor (NGF)-dependent sensory neurons. Mouse embryos defective in the paternal necdin allele displayed absent necdin expression in the dorsal root ganglia, in which the tropomyosin-related kinase A (TrkA) receptor tyrosine kinase and the p75 neurotrophin receptor were expressed in a normal manner. Necdin interacted with both TrkA and p75 to facilitate the association between these receptors. NGF-induced phosphorylation of TrkA and mitogen-activated protein kinase was significantly diminished in the necdin-null sensory ganglia. Furthermore, the mice lacking the paternal necdin allele displayed augmented apoptosis in the sensory ganglia in vivo and had a reduced population of substance P-containing neurons. These mutant mice showed significantly high tolerance to thermal pain, which is often seen in individuals with Prader-Willi syndrome. These results suggest that paternally expressed necdin facilitates TrkA signaling to promote the survival of NGF-dependent nociceptive neurons.
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PMID:Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival. 1604 86

Neonatal noxious insult produces a long-term effect on pain processing in adults. Rats subjected to carrageenan (CAR) injection in one hindpaw within the sensitive period develop bilateral hypoalgesia as adults. In the same rats, inflammation of the hindpaw, which was the site of the neonatal injury, induces a localized enhanced hyperalgesia limited to this paw. To gain an insight into the long-term molecular changes involved in the above-described long-term nociceptive effects of neonatal noxious insult at the spinal level, we performed DNA microarray analysis (using microarrays containing oligo-probes for 205 genes encoding receptors and transporters for glutamate, GABA, and amine neurotransmitters, precursors and receptors for neuropeptides, and neurotrophins, cytokines and their receptors) to compare gene expression profiles in the lumbar spinal dorsal horn (LDH) of adult (P60) male rats that received neonatal CAR treatment within (at postnatal day 3; P3) and outside (at postnatal 12; P12) of the sensitive period. The data were obtained both without inflammation (at baseline) and during complete Freund's adjuvant induced inflammation of the neonatally injured paw. The observed changes were verified by real-time RT-PCR. This study revealed significant basal and inflammation-associated aberrations in the expression of multiple genes in the LDH of adult animals receiving CAR injection at P3 as compared to their expression levels in the LDH of animals receiving either no injections or CAR injection at P12. In particular, at baseline, twelve genes (representing GABA, serotonin, adenosine, neuropeptide Y, cholecystokinin, opioid, tachykinin and interleukin systems) were up-regulated in the bilateral LDH of the former animals. The baseline condition in these animals was also characterized by up-regulation of seven genes (encoding members of GABA, cholecystokinin, histamine, serotonin, and neurotensin systems) in the LDH ipsilateral to the neonatally-injured paw. The largest aberration in gene expression, however, was observed during inflammation of the neonatally injured hindpaws in the ipsilateral LDH, which included thirty-six genes (encoding numerous members of glutamate, serotonin, GABA, calcitonin gene-related peptide, neurotrophin, and interleukin systems). These findings suggest that changes in gene expression may be involved in the long-term nociceptive effects of neonatal noxious insult at the spinal level.
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PMID:Neonatal local noxious insult affects gene expression in the spinal dorsal horn of adult rats. 1617 88

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

A previous phase III clinical trial failed to show significant therapeutic benefit of repeated subcutaneous nerve growth factor (NGF) administration in the treatment of diabetic neuropathy. Animal studies have since shown that site-specific viral-mediated expression of NGF in the lumbar dorsal root ganglia prevents peripheral nerve dysfunction associated with chemically induced neuropathy. Using a Herpes simplex virus expression vector, we have investigated the effect of localized NGF expression in a genetic mouse model of progressive diabetic neuropathy, the +/+ Leprdb mouse. We found that site-specific delivery of NGF initially delayed the appearance of hypoalgesia, assessed by the Hargreaves test, by 1 month and effectively attenuated this deficit for 2 months over the approximately 10 months normal life-span of these animals. Once the disease progressed into its more severe stages, NGF, although still capable of altering the electrophysiological profile of the sensory A- and C-fibers and influencing the expression of p75 and substance P in the dorsal root ganglia, could no longer maintain normal nociception. These data suggest that maximal therapeutic benefit in future NGF-based gene therapy trials will be gained from early applications of such viral-mediated neurotrophin delivery.
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PMID:HSV-1-mediated NGF delivery delays nociceptive deficits in a genetic model of diabetic neuropathy. 1642 24

Nerve growth factor (NGF), a member of the neurotrophin family, enhances synthesis of neuropeptides in sensory and sympathetic neurons. The aim of this study was to examine the effect of NGF on airway responsiveness and determine whether these effects are mediated through synthesis and release of substance P (SP) from the intrinsic airway neurons. Ferrets were instilled intratracheally with NGF or saline. Tracheal smooth muscle contractility to methacholine and electrical field stimulation (EFS) was assessed in vitro. Contractions of isolated tracheal smooth muscle to EFS at 10 and 30 Hz were significantly increased in the NGF treatment group (10 Hz: 33.57 +/- 2.44%; 30 Hz: 40.12 +/- 2.78%) compared with the control group (10 Hz: 27.24 +/- 2.14%; 30 Hz: 33.33 +/- 2.31%). However, constrictive response to cholinergic agonist was not significantly altered between the NGF treatment group and the control group. The NGF-induced modulation of airway smooth muscle to EFS was maintained in tracheal segments cultured for 24 h, a procedure that causes a significant anatomic and functional loss of SP-containing sensory fibers while maintaining viability of intrinsic airway neurons. The number of SP-containing neurons in longitudinal trunk and superficial muscular plexus and SP nerve fiber density in tracheal smooth muscle all increased significantly in cultured trachea treated with NGF. Pretreatment with CP-99994, an antagonist of neurokinin 1 receptor, attenuated the NGF-induced increased contraction to EFS in cultured segments but had no effect in saline controls. These results show that the NGF-enhanced airway smooth muscle contractile responses to EFS are mediated by the actions of SP released from intrinsic airway neurons.
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PMID:Nerve growth factor-enhanced airway responsiveness involves substance P in ferret intrinsic airway neurons. 1646 28

Biological substances with neurotrophic activities, such as nerve growth factor (NGF) and monosialoganglioside GM1, have been considered as agents for diabetic peripheral neuropathy. Because recent studies have suggested that decreased availability of these substances might contribute to the pathogenesis of diabetic peripheral neuropathy, some clinical trials of NGF for diabetic peripheral neuropathy have been conducted and have led to mixed conclusions. The major reasons were its limited delivery to the nervous system and adverse effects induced by subcutaneous injection, which was necessary because NGF is a polypeptide. The current study investigates whether an orally active sialic acid derivative, MCC-257, has neuroprotective properties in diabetic peripheral nerves. MCC-257 augmented NGF activity in cultured dorsal root ganglia and PC12 (pheochromocytoma 12) cells. Treatment with MCC-257 elevated NGF levels in the sciatic nerve, accompanied by improvement in nerve conduction velocity in streptozotocin-induced diabetic animals. More importantly, MCC-257 ameliorated small fiber dysfunctions, including thermal hypoalgesia, substance P content, and histopathological innervation in the plantar skin of diabetic animals. Thus, the orally active neurotrophin enhancer provides a new option for the clinical treatment of diabetic peripheral neuropathy.
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PMID:Orally active neurotrophin-enhancing agent protects against dysfunctions of the peripheral nerves in hyperglycemic animals. 1650 23

Maintenance of patency in distal airways is essential for gas exchange in neonatal life, and its disruption may have long-lasting effects on respiratory function. However, neural mechanisms that regulate caliber of intrapulmonary airways during early postnatal life, and their disruption by hyperoxic exposure, have not been well characterized. We have previously shown that cholinergically mediated airway contractile responses in rat pups are upregulated after hyperoxic exposure, and that increased expression of neuropeptides, such as substance P, may be contributory. More recently, we have documented impairment of neurally mediated airway relaxation in response to hyperoxic stress associated with loss of nitric oxide and prostaglandin-induced airway relaxation as well as inhibition of long chain myosin phosphatase. Our most recent data demonstrate significantly enhanced expression of the neurotrophin, brain-derived neurotrophic factor (BDNF) and its high affinity specific tyrosine kinase B (TrkB) receptor in hyperoxia-exposed airway smooth muscle. The existence of a BDNF-TrkB receptor autocrine and paracrine loops in the airways provides a basis for understanding local regulatory mechanisms of airway homeostasis. A mechanistic role for BDNF-TrkB signaling in hyperoxia-induced airway hyperreactivity in early postnatal life could serve to modulate both afferent and efferent neural pathways that result in enhanced contractile responses of immature airways exposed to hyperoxic stress. Greater insight into these neural pathways may lead to future preventive strategies for preterm infants surviving neonatal intensive care and developing chronic lung disease.
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PMID:Neonatal lung and airway injury: a role for neurotrophins. 1681 75

Nerve growth factor (NGF), a neurotrophin that regulates neuronal development, enhances production of neuropeptides that control airway caliber including substance P (SP). Little is known about the developmental interplay between neurotrophins and neuropeptides. Our goal was to assess release of NGF, SP, and vasoactive intestinal peptide (VIP) from tracheal segments of young (2-week-old) and fully-grown (13-week-old) rabbits, and ascertain location of neuropeptides in airways with mechanical denudation of epithelium and immunohistochemistry. After electrical field stimulation of nerves, bath solutions were collected and immunoassays performed to quantify NGF, SP, and VIP release. There were significant decreases in NGF, SP, and VIP release from airways in 13- versus 2-week-old rabbits. There were also significant decreases in SP and VIP release from denuded versus normal tissues at 2 weeks of age. A similar pattern for SP was seen in 13-week-old rabbits. Immunohistochemistry demonstrated increased neuropeptides in airways from younger rabbits. Although SP was seen in the epithelium and submucosal nerves in the younger group, it was localized to the latter location in fully-grown rabbits. VIP was seen in only submucosal nerves at both ages. Thus, release of NGF, SP, and VIP with neural stimulation decreases in rabbit tracheal segments with age. Decreases in SP with maturation and epithelial denudation appear related in part to decreases in epithelial SP with growth. However, decreases in VIP that occur normally and with epithelial denudation are not explained by location of VIP within the epithelium. The epithelium may be a source of factors that inhibit release of neuropeptides.
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PMID:Neuropeptide release from airways of young and fully-grown rabbits. 1706 26

Mammalian nociceptors have been classified into subclasses based on differential neurotrophin sensitivity and binding of the plant isolectin B4 (IB4). Most of the nerve growth factor-responsive IB4-negative (IB4 (-)) nociceptors contain neuropeptides such as substance P and calcitonin gene-related peptide, whereas the glial-derived neurotrophic factor-responsive IB4-positive (IB4 (+)) neurons predominantly lack such neuropeptides. We hypothesized that the differences in neuropeptide content between IB4 (+) and (-) neurons might be reflected in differences in stimulated exocytosis and/or endocytosis. To address this, we monitored the secretory activity of acutely dissociated neurons from adult rat trigeminal ganglia (TRG) using cell membrane capacitance (Cm) measurements and the fluorescent membrane-uptake marker N-(3-triethylammoniumpropyl)-4-(6-(4-(diethylamino)phenyl)hexatrienyl)pyridinium dibromide (FM4-64). Cm measurements were performed under whole-cell voltage clamp and neurons were depolarized from -75 mV to +10 mV to elicit exocytosis. Both types of TRG neurons showed similarly-sized, calcium-dependent increases in Cm, demonstrating that both IB4 (+) and (-) TRG neurons are capable of stimulated exocytosis. However, the peak Cm of IB4 (+) neurons decayed faster toward baseline than that of IB4 (-) neurons. Also, IB4 (+) neurons had stable Cm responses to repeated stimuli whereas IB4 (-) neurons loss their secretory response during repeated stimulation. These data suggested that the IB4 (+) neurons possess a faster rate of endocytosis and vesicle replenishment than IB4 (-) neurons. To test this, we measured vesicle trafficking with the fluorescent membrane dye FM4-64. FM4-64 staining showed that IB4 (-) neurons exhibit a larger pool of endocytosed vesicles than IB4 (+) neurons because the peak fluorescence increases in IB4 (-) neurons were larger but slower than in IB4 (+) neurons. However, the recycled vesicles were released faster in IB4 (+) compared with IB4 (-) neurons. Taken together these data suggest that the IB4 (+) TRG neurons have faster exocytosis and endocytosis than the IB4 (-) neurons.
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PMID:Two types of neurotransmitter release patterns in isolectin B4-positive and negative trigeminal ganglion neurons. 1710 Dec 30

There is now considerable neurobiological evidence on the pathogenesis and pathophysiology of depression. Nevertheless the underlying pathophysiology is far from fully elucidated. Norepinephrine and serotonin deficit hypotheses have been known for quite a long time. Other theories also claim a dysfunction of the dopaminergic and GABA-ergic system in depression, an altered expression of neuropeptides (e.g. of substance P), and neuroimmunologic and neuroendocrinologic mechanisms such as an overdrive of the hypothalamic-pituitary adrenal system. The neurotrophin hypothesis suggests that decreased production of neurotrophic factors and impaired neurogenesis are crucial for the pathophysiology of depression. These upcoming pathophysiological concepts have also initiated novel treatment approaches whose clinical utility still has to be demonstrated.
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PMID:[New insights into the pathogenesis and pathophysiology of depression]. 1796 Mar 53


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