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)

This study examined the effects of nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 on substance P levels in dorsal root ganglia of the quail shortly after ganglia formation (stage 26, embryonic day 4.5), during the middle of development (stage 33, embryonic day 7.5) and during late development (stage 44, embryonic day 14). It has already been shown that nerve growth factor increases levels of substance P during the middle and late stages of development, and that messenger RNA for the neurotrophin receptors, trkA, trkB and trkC is present at all of these stages. Dorsal root ganglia were isolated, rinsed with defined medium to dilute endogenous neurotrophins and exposed to one of the neurotrophins for either 4 or 20 h. Substance P levels were quantitated using enzyme immunoassay. None of the neurotrophins had any effect on substance P levels in dorsal root ganglia obtained at stage 26 after either a 4 or 20 h exposure time. Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 all significantly increased levels of substance P after either a 4 h or 20 h incubation in ganglia obtained at stages 33 and 44. The effects of nerve growth factor and neurotrophin-3 were specific: increases in substance P were completely blocked by simultaneous exposure to antibodies against either nerve growth factor or neurotrophin-3. The absence of any effect of neurotrophins on substance P expression during early development was unexpected, since dorsal root ganglia exhibit substantial levels of substance P and receptors for the neurotrophins are present and are apparently functional. It was also surprising that brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 induced increases in substance P levels during the middle and late stages of development, since substance P was thought to be exclusively localized to small TrkA neurons in dorsal root ganglia. However, immunocytochemical examination of dorsal root ganglia at stages 33 and 44 revealed substance P-like immunoreactivity in larger neurons as well as in small neurons. The results of this study have shown that different cellular responses to neurotrophins, such as effects on survival and/or peptide expression, may be acquired with differing temporal patterns not strictly related to expression of their receptors. Further, the regulation of neuropeptide synthesis in dorsal root ganglia is not due to any one neurotrophic factor. and the factors that regulate expression during early development are still unknown.
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PMID:Differential regulation of substance P by all members of the nerve growth factor family of neurotrophins in avian dorsal root ganglia throughout development. 921 78

Ginsenoside Rb1 (Rb1), a saponin of North American ginseng (Panax quinquefolium L.), has been found to exert beneficial effects on memory and learning, putatively through its actions on the cholinergic system. In situ hybridization studies show that Rb1 increases the expression of choline acetyltransferase and trkA mRNAs in the basal forebrain and nerve growth factor mRNA in the hippocampus. Other neurotrophins (brain-derived neurotrophic factor, neurotrophin-3), genes encoding neuropeptides (preproenkephalin, preprotachykinin) and amyloid protein precursor were also studied, but no significant change was observed. These findings support the specificity of the effects of Rb1 on certain aspects of the cholinergic and neurotrophic systems.
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PMID:Ginsenoside Rb1 regulates ChAT, NGF and trkA mRNA expression in the rat brain. 922 15

A better understanding of the mechanisms of nerve regeneration could improve the outcome of surgical nerve repair. We have previously shown that axonal regeneration is increased by nerve growth factor. Neurotrophin-3 (NT-3) belongs to the same family as nerve growth factor but acts on a distinct neuron subpopulation. As little is known about its role following nerve injury, we have investigated the effect of NT-3 delivered via fibronectin mats, previously shown to support nerve regeneration comparable to nerve grafts. NT-3 stimulation (0.1-1000 ng/ml) of neurite extension from embryonic chick dorsal root ganglia in vitro has shown that fibronectin can bind and release bioactive NT-3. Fibronectin mats impregnated with NT-3 (500 ng/ml) were grafted into 1 cm sciatic nerve defects in adult Lewis rats. Plain mats were used as controls. Computerized quantification of penetration distance, volume of axonal regeneration and myelinated fibre counts was undertaken using immunostaining for axonal markers (growth-associated protein 43, calcitonin gene-related peptide, substance P, vasoactive intestinal peptide and neuropeptide tyrosine), or S100 or thionine blue staining up to 8 months postoperatively. The maximal effect of NT-3 occurred at day 15, when for GAP43-immunostained axons both penetration distance (NT-3, 6.10 +/- 0.42 mm; control, 4.11 +/- 0.41 mm; P < 0.01) and staining area (NT-3, 0.137 +/- 0.012 mm2; control, 0.077 +/- 0.018 mm2; P < 0.05) were significantly increased. Similar results were found for each neuronal subpopulation investigated. By 8 months after repair, the NT-3 group supported a significantly greater number of myelinated axons (NT-3, 7003 +/- 402; control, 4932 +/- 725; P < 0.05) of similar diameter and g-ratio to controls. These results demonstrate the contribution of NT-3 to the increase of nerve regeneration promoted by growth factors.
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PMID:Neurotrophin-3 delivered locally via fibronectin mats enhances peripheral nerve regeneration. 924 Mar 96

In rodent models of diabetes, there are expression deficits in nerve growth factor (NGF) and in mRNA for its high-affinity receptor, trkA, leading to decreased retrograde axonal transport of NGF and decreased support of NGF-dependent sensory neurons, with reduced expression of their neuropeptides, substance P and calcitonin gene-related peptide (CGRP). Treatment of diabetic rats with intensive insulin normalized these deficits, and treatment with exogenous NGF caused dose-related increases, giving levels of NGF and neuropeptides that were greater than those of controls. Neurotrophin-3 (NT-3) mRNA was also deficient in leg muscle from diabetic rats, and administration of recombinant NT-3 to diabetic rats increased the conduction velocity of sensory nerves without affecting motor conduction velocity. In regenerating nerves after experimental crush injury, expression of NGF in the nerve trunk is increased in diabetes to a greater extent than in controls, but this is offset by a greater reduction in the neuronal expression of trkA in dorsal root ganglia of diabetic rats. Nonetheless, targeted administration of exogenous NGF via impregnated conduits stimulated regeneration in both control and diabetic rats. These findings implicate deficient neurotrophic support in diabetic neuropathy and suggest that its correction should be a paramount therapeutic target.
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PMID:Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors. 928 98

The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 micrograms) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor D1 and D2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [3H]choline and [3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventricular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 micrograms/day) over a two-week period did not afford notable improvement compared to the single injection of 10 micrograms. In contrast, continuous infusion of brain-derived neurotrophic factor (10 micrograms/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 micrograms/day) delivery into the striatum significantly increased [3H]GABA uptake, but only modestly affected [3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.
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PMID:Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease. 933 Mar 71

Acute superfusion of nerve growth factor (NGF; 1-100 ng/ml) through a naive rat spinal cord preparation did not alter basal or electrically evoked release of substance P-like immunoreactivity (SP-LI). In contrast, neurotrophin-3 (NT-3; 1-100 ng/ml), although not modifying SP-LI basal outflow, dose-dependently inhibited the electrically evoked, but not capsaicin (10 nM)-induced, release of the peptide. This NT-3 (10 ng/ml)-induced inhibition persisted even in the presence of 100 ng/ml NGF in the perfusion fluid and was still significant when the evoked release of SP-LI was enhanced by a prolonged in vivo treatment with NGF. Co-superfusion with naloxone (0.1 microM), but not CGP 36742 (100 microM), a GABAB antagonist, prevented NT-3 (10 ng/ml) inhibition of SP-LI release. Basal and electrically evoked release of SP-LI from the rat spinal cord in vitro was not modified 24 hr after single systemic injection of either NGF (1 mg/kg) or NT-3 (10 mg/kg). At these time intervals from administration, NGF had induced thermal and mechanical hyperalgesia in the rat hindpaw, and NT-3 had induced mechanical, but not thermal, hypoalgesia. NT-3 administered six times over a 2 week period (at 1 mg/kg) did not alter thermal threshold but significantly reduced electrically evoked release of SP-LI from the spinal cord. An identical treatment regimen with 1 mg/kg NGF induced a significant increase in evoked release of SP-LI. However, this was not associated with a significant hyperalgesia. Although finding that NGF-induced hyperalgesia does not clearly correlate with changes in the release of SP-LI in the spinal cord, this study shows that NT-3 is an inhibitor of SP-LI release and suggests that this mechanism may be responsible for NT-3-induced antinociception.
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PMID:Nerve growth factor- and neurotrophin-3-induced changes in nociceptive threshold and the release of substance P from the rat isolated spinal cord. 933 18

In addition to the known retrograde transport of neurotrophins, it is now evident that endogenous brain-derived neurotrophic factor (BDNF) is transported in the anterograde direction in peripheral and central neurons. We used a double-ligation procedure that distinguishes between anterograde and retrograde flow to quantify the anterograde transport of endogenous neurotrophins and neuropeptides in the peripheral nervous system before and after axotomy. BDNF accumulation proximal to the ligation (anterograde transport) was twice that distal to the ligation (retrograde direction). Anterograde transport of nerve growth factor and neurotrophin-3 was not evident. Furthermore, BDNF anterograde transport increased 3.5-fold within 24 hr after sciatic nerve injury or dorsal rhizotomy. Anterograde transport of substance P and calcitonin gene-related peptide decreased after peripheral nerve lesion, demonstrating that there was no generalized increase in anterograde transport. To determine the source of the anterogradely transported BDNF, we performed in situ hybridization in a variety of tissues before and after axotomy. Expression of BDNF mRNA in proximal nerve segments did not change with treatment, showing that the increased accumulation of BDNF was not a result of increased local synthesis. BDNF mRNA and protein were expressed by dorsal root ganglion sensory neurons but not by motor neurons. BDNF mRNA expression was increased 1 d after nerve injury, and BDNF protein was also increased twofold to threefold, suggesting that sensory neurons are the major contributing source of the increased BDNF traffic in the sciatic nerve. Our results suggest that increased anterogradely transported BDNF plays a role in the early neuronal response to peripheral nerve injury at sites distal to the cell body.
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PMID:Axotomy upregulates the anterograde transport and expression of brain-derived neurotrophic factor by sensory neurons. 959 14

The impact of the nerve growth factor (NGF) family of neurotrophins and their receptors was examined on the cutaneous innervation in the mystacial pads of mice. Ten sets of unmyelinated and thinly myelinated sensory and autonomic innervation were evaluated that terminated in the epidermis, upper dermis, and upper part of the intervibrissal hair follicles. Mystacial pads were analyzed from newborn to 4-week-old mice that had homozygous functional deletions of the genes for NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), tyrosine kinase (trk) A, trkB, trkC, or p75. Mystacial pads were also analyzed in adult transgenic mice that had overproduction of NGF, BDNF, or NT-3 driven by a keratin promoter gene. The innervation was revealed by using immunofluorescence and immunocytochemistry with antibodies for protein gene product (PGP) 9.5, calcitonin gene-related product (CGRP), substance P (SP), galanin (GAL), neuropeptide Y (NPY), tyrosine hydroxylase (TH), and a neurofilament protein. The cumulative results indicated that NGF/trkA signaling plays a major role in the outgrowth and proliferation of sensory axons, whereas NT-3/ trkA signaling plays a major role in the formation of sensory endings. TrkC is also essential for the development of three sets of trkA-dependent sensory innervation that coexpress CGRP, SP, and GAL. Another set of sensory innervation that only coexpressed CGRP and SP was solely dependent upon NGF and trkA. Surprisingly, most sets of trkA-dependent sensory innervation are suppressed by trkB perhaps interacting with p75. BDNF and NT-4 appear to mediate this suppressing effect in the upper dermis and NT-4 in the epidermis. In contrast to sensory innervation, sympathetic innervation to the necks of intervibrissal hair follicles depends upon NGF/trkA signaling interacting with p75 for both the axon outgrowth and ending formation. Although NT-3/trkA signaling is essential for the full complement of sympathetic neurons, NT-3 is detrimental to the formation of sympathetic terminations to the necks of hair follicles. TrkB signaling mediated by BDNF but not NT-4 also suppresses these sympathetic terminations. One sparse set of innervation, perhaps parasympathetic, terminating at the necks of hair follicles is dependent solely upon NT-3 and trkC. Taken together, our results indicate that the innervation of the epidermis, upper dermis, and the upper portion of hair follicles is regulated by a competitive balance between promoting and suppressing effects of the various neurotrophins.
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PMID:Differential dependency of unmyelinated and A delta epidermal and upper dermal innervation on neurotrophins, trk receptors, and p75LNGFR. 964 Mar 32

In rats with streptozotocin-induced diabetes, we measured increased (by 61%; P < 0.05) mRNA for nerve growth factor (NGF) in the iris together with increased (by 82%; P < 0.05) mRNA for preprotachykinin (the substance P precursor) in the trigeminal ganglion, suggesting that increased NGF was driving increased substance P gene expression. In other diabetic rats, these changes were prevented by treatment with either an antioxidant (butylated hydroxytoluene; 1% by diet) or an aldose reductase inhibitor (ARI) (sorbinil; 25 mg/kg/day p.o.) and the sorbinil treatment was associated with significant inhibition of polyol pathway intermediates in both lens and sciatic nerve. This suggests that polyol pathway activity in the lens may translate to oxidative stress-driving stimulation of NGF gene expression in the iris. The change is selective for NFG, because expression of the analogous neurotrophin, neurotrophin-3 (NT-3), was unaltered in the same irises. These changes suggest that oxidative stress and/or inflammation can drive up NGF expression in diabetes--a mechanism that might participate in iritis.
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PMID:Stimulation of nerve growth-factor and substance P expression in the iris-trigeminal axis of diabetic rats--involvement of oxidative stress and effects of aldose reductase inhibition. 974 8

Peripheral nerve transection induces significant changes in neuropeptide expression and content in injured primary sensory neurons, possibly due to loss of target derived neurotrophic support. This study shows that neurotrophin-3 (NT-3) delivery to the injured nerve influences neuropeptide Y (NPY) expression within dorsal root ganglia (DRG) neurons. NT-3 was delivered by grafting impregnated fibronectin (500 ng/ml; NT group) in the axotomised sciatic nerve. Animals grafted with plain fibronectin mats (FN) or nerve grafts (NG) were used as controls. L4 and L5 DRG from operated and contralateral sides were harvested between 5 and 240 d. Using immunohistochemistry and computerised image analysis the percentage, diameter and optical density of neurons expressing calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and NPY were quantified. Sciatic nerve axotomy resulted in significant reduction in expression of CGRP and SP, and significant upregulation of VIP and NPY (P < 0.05 for ipsilateral vs contralateral DRG). By d 30, exogenous NT-3 and nerve graft attenuated the upregulation of NPY (P < 0.05 for NT and NG vs FN). However, NT-3 administration did not influence the expression of CGRP, SP or VIP. The mean cell diameter of NPY immunoreactive neurons was significantly smaller in the NT-3 group (P < 0.05 for NT vs FN and NG) suggesting a differential influence of NT-3 on larger neurons. The optical densities of NPY immunoreactive neurons of equal size were the same in each group at any time point, indicating that the neurons responding to NT-3 downregulate NPY expression to levels not detectable by immunohistochemistry. These results demonstrate that targeted administration of NT-3 regulates the phenotype of a NPY-immunoreactive neuronal subpopulation in the dorsal root ganglia, a further evidence of the trophic role of neurotrophins on primary sensory neurons.
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PMID:NT-3 modulates NPY expression in primary sensory neurons following peripheral nerve injury. 982 42


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