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)

Neurotrophin-3-deficient (NT-3-deficient) mice were generated by gene targeting. Mutant mice displayed severe movement defects of the limbs, and most died shortly after birth. Substantial portions of peripheral sensory and sympathetic neurons were lost while motor neurons were not affected. Significantly, spinal proprioceptive afferents and their peripheral sense organs (muscle spindles and Golgi tendon organs) were completely absent in homozygous mutant mice. This correlated with a loss of parvalbumin and carbonic anhydrase-positive neurons in the dorsal root ganglion. No gross abnormalities were seen in Pacinian corpuscles, cutaneous afferents containing substance P and calcitonin gene-related peptide, and deep nerve fibers in the joint capsule and tendon. Importantly, the number of muscle spindles in heterozygous mutant mice was half of that in control mice, indicating that NT-3 is present at limiting concentrations in the embryo.
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PMID:Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. 751 2

Adult rat dorsal root ganglion sensory neurons in culture require nerve growth factor for synthesis of substance P and calcitonin gene-related peptide but express vasoactive intestinal peptide independently of nerve growth factor. In contrast, the same neurons from newborn rats do not express detectable vasoactive intestinal polypeptide when cultured with nerve growth factor. To further explore the mechanisms regulating neuropeptide expression in these cells, I compared the effects of nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, ciliary neurotrophic factor and leukaemia inhibitory factor on substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and somatostatin expression in rat dorsal root ganglion cultures. As with neurons from adult animals, newborn rat sensory neurons required nerve growth factor for synthesis of substance P and calcitonin gene-related peptide. This effect was independent of neuronal survival since most neurons capable of expressing these peptides appeared to survive without added neurotrophic factors. Neurons surviving in the absence of nerve growth factor also expressed vasoactive intestinal polypeptide, suggesting that nerve growth factor suppresses vasoactive intestinal polypeptide expression in immature neurons. However, nerve growth factor withdrawal after eight days' culture failed to cause vasoactive intestinal polypeptide induction which therefore appears to depend on other factors also. Neither ciliary neurotrophic factor nor leukaemia inhibitory factor affected peptide levels when used alone, but both inhibited nerve growth factor-stimulated expression of substance P and calcitonin gene-related peptide in adult rat neurons. They also stimulated vasoactive intestinal polypeptide expression in newborn rat neurons in the presence of nerve growth factor but not to such high levels as those seen under conditions of nerve growth factor deprivation. Neither brain-derived neurotrophic factor nor neurotrophin-3 affected peptide expression significantly. Somatostatin was defected in adult rat neurons, but was unaffected by neurotrophic factors. No somatostatin was detected in newborn rat neurons. These results suggest that in immature animals at least, the increased expression of vasoactive intestinal polypeptide seen in sensory neurons following peripheral nerve injury in vivo, could result from deprivation of target-derived nerve growth factor in combination with increased availability of ciliary neurotrophic factor or leukaemia inhibitory factor from the injured nerve.
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PMID:Neuropeptide expression by newborn and adult rat sensory neurons in culture: effects of nerve growth factor and other neurotrophic factors. 751 8

Neurotrophins, which are structurally related to nerve growth factor, have been shown to promote survival of various neurons. Recently, we found a novel activity of a neurotrophin in the brain: Brain-derived neurotrophic factor (BDNF) enhances expression of various neuropeptides. The neuropeptide differentiation activity was then compared among neurotrophins both in vivo and in vitro. In cultured neocortical neurons, BDNF and neurotrophin-5 (NT-5) remarkably increased levels of neuropeptide Y and somatostatin, and neurotrophin-3 (NT-3) also increased these peptides but required higher concentrations. At elevating substance P, however, NT-3 was as potent as BDNF. In contrast, NGF had negligible or no effect. Neurotrophins administered into neonatal brain exhibited slightly different potencies for increasing these neuropeptides: The most marked increase in neuropeptide Y levels was obtained in the neocortex by NT-5, whereas in the striatum and hippocampus by BDNF, although all three neurotrophins increased somatostatin similarly in all the brain regions examined. Overall spatial patterns of the neuropeptide induction were similar among the neurotrophins. Neurons in adult rat brain can also react with the neurotrophins and alter neuropeptide expression in a slightly different fashion. Excitatory neuronal activity and hormones are known to change expression of neurotrophins. Therefore, neurotrophins, neuronal activity, and hormones influence each other and all regulate neurotransmitter/peptide expression in developing and mature brain. Physiological implication of the neurotransmitter/peptide differentiation activities is also discussed.
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PMID:Regulation of neuropeptide expression in the brain by neurotrophins. Potential role in vivo. 757 4

Disruption of dopaminergic neurotransmission in the striatum by neurotoxic lesions of the substantia nigra leads to increases in glutamic acid decarboxylase and proenkephalin messenger RNA expression, and to decreases in preprotackykinin (the precursor molecule for substance P) messenger RNA expression in the two populations of striatal medium-sized spiny projection neurons. These cells also express TrkB, the neurotrophin receptor for brain-derived neurotrophic factor and neurotrophin 4/5, and TrkC, the receptor for neurotrophin-3. Since there is some indication that exogenous brain-derived neurotrophic factor can exert neuromodulatory effects in the basal ganglia, we studied the effects of repeated intrastriatal injections of the four members of the neurotrophin family of neural growth factors, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 on the expression of striatal neurotransmitter-related genes in the unilaterally 6-hydroxydopamine-lesioned rat using in situ hybridization histochemistry. We found that 4 micrograms/day of brain-derived neurotrophic factor or neurotrophin-4/5 when injected intrastriatally for eight consecutive days led to a normalization of the denervation-induced decrease of preprotachykinin messenger RNA when compared to animals injected with equivalent doses of nerve growth factor, neurotrophin-3, or vehicle. Neurotrophin-4/5 alone also normalized expression of messenger RNA encoding the 67 x 10(3) mol. wt isoform of glutamate decarboxylase, while none of the neurotrophins had a significant effect on preproenkephalin messenger RNA expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Brain-derived neurotrophic factor and neurotrophin-4/5 modify neurotransmitter-related gene expression in the 6-hydroxydopamine-lesioned rat striatum. 761 69

The most common form of peripheral neuropathy is that associated with diabetes mellitus. In rodent models of diabetes there are expression deficits in nerve growth factor (NGF) and in 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 which 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. 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:Neurotrophins and peripheral neuropathy. 873 Jul 85

During development, many neurons in the dorsal root ganglia require neurotrophin-3 for survival. However, it is not known precisely which subpopulations of sensory neurons, other than the proprioceptive afferents, are neurotrophin-3 dependent in vivo. In this study, using a battery of neurochemical markers that label different subpopulations of dorsal root ganglion neurons, we found a widespread, about 60-65% loss of cells in most subpopulations in neurotrophin-3 deficient mice. Intermediate losses were found in the heterozygous mutant mice consistent with a gene dosage effect. In agreement with this, the cell size distribution between the homozygous mutant and wild type mice was virtually identical. The loss of small neurons containing calcitonin gene-related peptide, substance P and thiamine monophosphatase activity suggests that many unmyelinated primary afferents are also lost in the mutant animals. The fact that many different sensory neuron subpopulations are lost to the same extent in neurotrophin-3 deficient mice is consistent with the proposed early role of neurotrophin-3 during neurogenesis. Interestingly, calretinin immunoreactive neurons, which contribute a minor subpopulation, were not affected suggesting that neurotrophin-3 independent regulation of neurogenesis occurs in addition to prominent neurotrophin-3 dependent mechanisms.
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PMID:Most classes of dorsal root ganglion neurons are severely depleted but not absent in mice lacking neurotrophin-3. 880 9

Syntheses of substance P, somatostatin, and calcitonin gene-related peptide in sensory neurons have been suggested to be regulated by neurotrophic factors retrogradely transported from target tissues. In this study, we re-examined this idea by investigating the coexpression of neurotrophin receptor (trk family proto-oncogene) messenger RNAs, and preprotachykinin-A (a precursor peptide of substance P), alpha-calcitonin gene-related peptide and somatostatin messenger RNAs in lumbar dorsal root ganglion neurons by means of in situ hybridization histochemistry in rats. Approximately 35-40%, 5% and 15-20% of sensory neurons displayed signals for trkA, trkB, and trkC messenger RNAs, respectively. Approximately 28% of dorsal root ganglion neurons were positive for preprotachykinin-A messenger RNA, and were divided into two groups; those labeled strongly and those labeled weakly by in situ hybridization. All the strongly-labeled neurons (78% of preprotachykinin-A-positive cells) expressed trkA messenger RNA at the same time, while the weakly-labeled neurons did not. Thirty-seven per cent of dorsal root ganglion neurons expressed alpha-calcitonin gene-related peptide messenger RNA, and most of these neurons (84%) also expressed trkA messenger RNA. No or few preprotachykinin-A messenger RNA- and/or alpha-calcitonin gene-related peptide messenger RNA-expressing neurons were also positive for trkB or trkC messenger RNAs. Nine per cent of dorsal root ganglion neurons expressed somatostatin messenger RNA, and these neurons lacked all three trk messenger RNAs. Furthermore, most of these neurons (about 90%) showed positive, albeit weak, signals for preprotachykinin-A and alpha-calcitonin gene-related peptide messenger RNAs. The results suggest that expression of preprotachykinin-A and alpha-calcitonin gene-related peptide messenger RNAs is mediated by nerve growth factor via trkA receptor but not by brain-derived neurotrophic factor or neurotrophin-3, and that somatostatin gene transcription is not regulated by any member of the neurotrophin family in rat sensory neurons.
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PMID:Coexpression of preprotachykinin-A, alpha-calcitonin gene-related peptide, somatostatin, and neurotrophin receptor family messenger RNAs in rat dorsal root ganglion neurons. 884 23

Adult sensory neurons differ chemically, morphologically, and functionally, but the factors that generate their diversity remain unclear. For example, neuropeptides are generally found in small neurons, whereas abundant neurofilament is common in large neurons. Neurons containing the neuropeptides calcitonin gene-related peptide (CGRP) or substance P were quantified using immunohistochemistry in rat lumbar dorsal root ganglion (DRG) at times before and after sensory neurons contact central and peripheral targets in vivo. No neurons in the newly formed DRG expressed neuropeptide or neuropeptide mRNA, but neuropeptides were detectable about the time that axons connect with peripheral targets. To determine the requirement for target in neuropeptide regulation, embryonic DRG neurons were isolated at times before central and peripheral connections had formed, placed in culture, and immunocytochemically assayed for CGRP and substance P. Cultured neurons expressed neuropeptides with a time course and in proportions similar to those in vivo. Thus, some neurons in the embryonic DRG seem to be intrinsically specified to later express CGRP and substance P. The percentage of CGRP-immunoreactive neurons was not changed by cell density, non-neuronal cells, neurotrophins in addition to nerve growth factor (NGF), or antibody inactivation of neurotrophin-3 in the presence of NGF. To test the role of extrinsic cues on CGRP expression, DRG neurons were co-cultured with potential target tissues. Co-culture with a rat epidermal or smooth muscle cell line increased the proportion of CGRP-containing neurons, whereas primary skeletal muscle and 3T3 cells had no effects. Thus, multiple appropriate sensory neuron phenotypes arise in a regulated fashion in cultured neurons isolated before target connections have formed, and some candidate target tissues can modulate that intrinsic expression pattern.
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PMID:The generation of neuronal heterogeneity in a rat sensory ganglion. 909 99

Spinal cord projections from transected sciatic nerves treated with different neurotrophins were investigated in the adult rat following injections of choleragenoid into the proximal stump of the injured nerve. Transganglionically transported choleragenoid labelled primary afferent fibres in all spinal cord dorsal horn laminae except the outer part of lamina II (II(o)), which is almost devoid of labelling. Transection of the sciatic nerve, however, resulted in intense transganglionic choleragenoid labelling in lamina II(o) and in lamina I. In this study, the sciatic nerve was transected bilaterally and 4erve growth factor (6 or 24 microg), brain-derived neurotrophic factor (20 microg), neurotrophin-3 (27 microg) or cytochrome C (8 microg; control substance) was applied unilaterally during postoperative survival times of eight, 16 and 32 days. The animals received bilateral injections of choleragenoid into the injured nerve two days before they were killed. The effect of the axotomy and neurotrophin treatment was evaluated by analysing the extent of choleragenoid and substance P immunoreactivity in the somatotopically appropriate spinal cord dorsal horn regions. At eight days' postoperative survival, laminae I and II(o) on the transected, non-treated side showed much more intense choleragenoid-like immunoreactivity compared to the contralateral transected, nerve growth factor-treated (6 and 24 microg) side. A similar situation was also found in cases treated with the higher dose (24 microg) at 16 days but to a lesser degree when the lower (6 microg) dose was used. After 32 days' survival, there was no detectable side difference in the choleragenoid labelling pattern. At 16 days' survival, the mean area of choleragenoid-positive ganglion cell body profiles in the L5 dorsal root ganglion of the transected, non-treated side was significantly smaller than the mean area of the transected, nerve growth factor-treated (24 microg) neurons. An axotomy-induced depletion of substance P-like immunoreactivity was seen from eight days' survival and onwards, whereas on the nerve growth factor-treated side a clearcut substance P depletion was not observed until 32 days. Brain-derived neurotrophic factor, neurotrophin-3 and cytochrome C had no detectable effects on the distribution of choleragenoid labelling or substance P-like immunoreactivity in the dorsal horn following sciatic nerve transection. In conclusion, peripheral nerve injury-induced expansion of primary afferent choleragenoid labelling in the spinal cord dorsal horn is counteracted by treating the axotomized nerve with nerve growth factor.
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PMID:Effects of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 on the laminar distribution of transganglionically fransported choleragenoid in the spinal cord dorsal horn following transection of the sciatic nerve in the adult rat. 915 64

The role of neurotrophin-3 (NT3) during sensory neuron development was investigated in transgenic mice overexpressing NT3 under the control of the promoter and enhancer regions of the nestin gene, an intermediate filament gene widely expressed in the developing nervous system. Most of these mice died during the first postnatal day, and all showed severe limb ataxia suggestive of limb proprioceptive dysfunction. Tracing and histological analyses revealed a complete loss of spindles in limb muscles, absence of peripheral and central Ia projections, and lack of cells immunoreactive to parvalbumin in the dorsal root ganglion (DRG). Despite these deficits, there was no neuronal loss in the DRG of these mice. At birth, transgenic DRG showed increased neuron numbers, and displayed a normal proportion of neurons expressing substance P, calcitonin gene-related peptide and the NT3 receptor trkC. Transgenic dorsal roots exhibited an increased number of axons at birth, indicating that all sensory neurons in transgenic mice projected to the dorsal spinal cord. Despite the absence of central Ia afferents reaching motorneurons, several sensory fibers were seen projecting towards ectopic high levels of NT3 in the midline of transgenic spinal cords. These findings suggest novel roles for NT3 in differentiation of proprioceptive neurons, target invasion and formation of Ia projections which are independent from its effects on neuronal survival.
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PMID:Limb proprioceptive deficits without neuronal loss in transgenic mice overexpressing neurotrophin-3 in the developing nervous system. 921 2


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