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)

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50-90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium.
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PMID:Nerve growth factor and diabetic neuropathy. 1466 49

1. Diabetic neuropathy is one of the most frequent complications of diabetes mellitus. However, the mechanisms underlying these disorders are not yet well defined and it has been reported that currently available analgesics have hardly any ameliorating effect on painful diabetic neuropathy. 2. The purpose of the present study was to evaluate the antinociceptive effect of oxcarbazepine (OCBZ), a keto derivative of carbamazepine (CBZ), in animal models generally used in pain research and in rats and mice with streptozotocin (STZ)-induced diabetes. In addition, we compared the effect of OCBZ with those of CBZ, mexiletine and morphine. 3. Diabetes was induced by injection of STZ at a dose of 300 mg/kg (i.p.) in mice and 50 mg/kg (i.v.) in rats. Experiments were conducted 2 weeks after STZ injection and those animals with a serum glucose level above 400 mg/dL were used for data analysis. Antinociceptive effects of the drugs were evaluated by the paw withdrawal test (normal, STZ-induced diabetic and carrageenin-injected rats), tail-flick test (normal and STZ-induced diabetic mice) and nociceptive behaviour (formalin-injected mice). 4. In the present study, diabetic mice showed thermal hyperalgesia and diabetic rats exhibited mechanical hyperalgesia. From these results, the STZ-induced diabetic animals used in the present study were found to be suitable for research on painful diabetic neuropathy. In STZ-induced diabetic animals, the antinociceptive effects of OCBZ, CBZ and mexiletine were facilitated, whereas the effect of morphine was attenuated, compared with effects in normal animals. 5. Oxcarbazepine inhibited the formalin-induced biphasic pain responses and increased the nociceptive threshold in the case of carrageenin-induced hyperalgesia. In view of these results, inhibition of substance P-mediated pain transmission may be involved in the antinociceptive action of OCBZ. 6. These results indicate that OCBZ has an analgesic action and is a possible therapeutic agent for the treatment of neuropathic pain, such as occurs in painful diabetic neuropathy.
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PMID:Oxcarbazepine antinociception in animals with inflammatory pain or painful diabetic neuropathy. 1475 85

We examined the effects of C-peptide replacement on unmyelinated fiber function in the hind paw, sural nerve C-fiber morphometry, sciatic nerve neurotrophins, and the expression of neurotrophic receptors and content of neuropeptides in dorsal root ganglia in type 1 diabetic BB/Wor-rats. C-peptide replacement from onset of diabetes had no effect on hyperglycemia, but it significantly prevented progressive thermal hyperalgesia and prevented C-fiber atrophy, degeneration, and loss. These findings were associated with preventive effects on impaired availability of nerve growth factor and neurotrophin 3 in the sciatic nerve and significant prevention of perturbed expression of insulin, insulin growth factor-1, nerve growth factor, and neurotrophin 3 receptors in dorsal root ganglion cells. These beneficial effects translated into prevention of the decreased content of dorsal root ganglia nociceptive peptides such as substance P and calcitonin gene-related peptide. From these findings we conclude that replacement of insulinomimetic C-peptide prevents abnormalities of neurotrophins, their receptors, and nociceptive neuropeptides in type 1 BB/Wor-rats, resulting in the prevention of C-fiber pathology and nociceptive sensory nerve dysfunction. The data indicate that perturbed insulin/C-peptide action plays an important pathogenetic role in nociceptive sensory neuropathy and that C-peptide replacement may be of benefit in treating painful diabetic neuropathy in insulin-deficient diabetic conditions.
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PMID:C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. 1549 55

We examined the utility of herpes simplex virus (HSV) vector-mediated gene transfer of vascular endothelial growth factor (VEGF) in a mouse model of diabetic neuropathy. A replication-incompetent HSV vector with VEGF under the control of the HSV ICP0 promoter (vector T0VEGF) was constructed. T0VEGF expressed and released VEGF from primary dorsal root ganglion (DRG) neurons in vitro, and following subcutaneous inoculation in the foot, expressed VEGF in DRG and nerve in vivo. At 2 weeks after induction of diabetes, subcutaneous inoculation of T0VEGF prevented the reduction in sensory nerve amplitude characteristic of diabetic neuropathy measured 4 weeks later, preserved autonomic function measured by pilocarpine-induced sweating, and prevented the loss of nerve fibers in the skin and reduction of neuropeptide calcitonin gene-related peptide and substance P in DRG neurons of the diabetic mice. HSV-mediated transfer of VEGF to DRG may prove useful in treatment of diabetic neuropathy.
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PMID:HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy. 1592 Apr 61

Progressive loss of pain perception and cutaneous nerve fibers are frequently observed in diabetic patients. We evaluated the feasibility of using thy1-YFP mice that express the yellowish-green fluorescent protein (YFP) in all of their sensory/motor neurons for noninvasive monitoring of cutaneous nerve fiber loss during diabetes. Fluorescent fibers in skin sections from the leg of thy1-YFP mice stained positive for the neuron-specific protein gene product 9.5 (PGP9.5), indicating that the cutaneous fluorescent fibers are indeed nerve fibers. In diabetic thy1-YFP mice, significant small cutaneous nerve fiber loss in the leg was observed at 3 months following the onset of diabetes, but loss of heat-induced pain perception occurred as early as 1 month following the onset of diabetes, indicating that functional impairment of sensory nerves precedes cutaneous nerve fiber loss. Immunostaining of skin sections of mice killed at 6 months following the onset of diabetes showed that parallel to the loss of small fluorescent nerve fibers, there was a significant decrease in fibers stained positive for calcitonin gene-related peptide, substance P, and purinoreceptor subtype in diabetic thy1-YFP mice. These mice will be useful for noninvasive monitoring of cutaneous nerve fiber degeneration and loss of heat-induced pain perception during diabetes and for the assessment of efficacy of therapeutic treatment of diabetic neuropathy.
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PMID:Noninvasive monitoring of diabetes-induced cutaneous nerve fiber loss and hypoalgesia in thy1-YFP transgenic mice. 1624 33

Epidemiological studies confirm frequent appearance of pain symptoms in depressive patients and a marked prevalence of depression in pain conditions. These observations seem to point at a close intertwining between mood regulation and pain perception. In the pathogenesis of both depression and pain symptoms, an important role has been attributed to disturbances of serotonergic and noradrenergic neurotransmission as well as to neuropeptides such as opioids and substance P. In mood regulation as well as in the perception and emotional dimension of pain stimuli, such brain structures as the amygdala, anterior cingulate cortex and prefrontal cortex are of main significance. The action of antidepressant drugs results in a normalization of the activity of those neurotransmitter systems and brain structures. It was found that dual action antidepressants (i.e. influencing both serotonergic and noradrenergic system) such as tricyclic antidepressants and new generation drugs (venlafaxine, milnacipram, duloxetine, mirtazapine) exert a stronger antidepressant effect and possess a broader therapeutic spectrum, including also an effect on pain symptoms. These drugs have been also increasingly used for the treatment of pain symptoms in somatic illnesses (e.g. diabetic neuropathy, fibromyalgia).
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PMID:[Depression and pain: novel clinical, neurobiological and psychopharmacological data]. 1635 93

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

We investigated the ability of Neotrofin, an agent that enhances endogenous nerve growth factor (NGF) levels, to prevent phenotypic, functional and structural changes that occur in the peripheral nerve of streptozotocin-diabetic rats. Eight weeks of Neotrofin treatment prevented depletion of NGF protein in plantar foot skin and sciatic nerve of diabetic rats and increased NGF protein in associated skeletal muscles. These effects were accompanied by maintenance of normal nerve levels of the neuropeptides substance P and calcitonin gene related peptide. Thermal hypoalgesia and conduction slowing of large sensory fibres in diabetic rats were ameliorated by Neotrofin treatment, whereas there was no effect on conduction slowing in large motor fibres or on reduced myelinated fibre axonal calibre. Enhancing endogenous production of neurotrophic factors using small molecules may be an alternative to either exogenous treatment with neurotrophic factors or gene therapy as a therapeutic approach to treating diabetic neuropathy.
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PMID:Protection of sensory function in diabetic rats by Neotrofin. 1650 5

Autonomic neuropathy affecting the gastrointestinal system is a major presentation of diabetic neuropathy. Changes in the innervation of gastric mucosa or muscle layers can contribute to gastrointestinal symptoms. The present study investigated this issue by quantitatively analyzing the immunohistochemical patterns of the gastric innervation in rats with streptozotocin (STZ)-induced diabetes. In control rats, calcitonin gene-related peptide (CGRP) and substance P (SP) (+) nerve fibers appeared in the gastric mucosa and muscle layers. Double immunohistochemical staining showed that immunoreactivities for SP and CGRP were co-localized with a pan-neuronal marker protein gene product 9.5. Both SP (+) nerve fibers (p<0.001) and CGRP (+) nerve fibers (p<0.005) were decreased in the gastric mucosa within 4 weeks of diabetes; the reduction persisted throughout 24 weeks. Diabetic rats treated with insulin did not show decrease of SP or CGRP (+) fibers in the mucosa 4 weeks after STZ injection (p>0.05). There was no significant change in SP (+) nerve fibers (p>0.05) or CGRP (+) nerve fibers (p>0.05) of the gastric muscle layers. Reverse transcription-polymerase chain reaction (RT-PCR) showed that the expression levels of SP and CGRP mRNA in the thoracic dorsal root ganglia were similar between diabetic and control animals (p>0.05). Qualitative and quantitative ultrastructural examinations on the gastric mucosa documented unmyelinated nerve degeneration. These results suggest the existence of gastric sensory neuropathy in STZ-induced diabetes, and this pathology provides a foundation for understanding diabetic gastropathy.
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PMID:Depletion of peptidergic innervation in the gastric mucosa of streptozotocin-induced diabetic rats. 1867 69

C57BLKS db/db (db/db) mice develop a neuropathy with features of human type 2 diabetic neuropathy. Here, we demonstrate that these mice develop transient mechanical allodynia at the early stage of diabetes. We hypothesized that nerve growth factor (NGF), which enhances the expression of key mediators of nociception (i.e. substance P [SP] and calcitonin gene-related peptide), contributes to the development of mechanical allodynia in these mice. We found that NGF, SP, and calcitonin gene-related peptide gene expression is upregulated in the dorsal root ganglion (DRG) of db/db mice before or during the period that they develop mechanical allodynia. There were more small- to medium-sized NGF-immunopositive DRG neurons in db/db mice than in control db+ mice; these neurons also expressed SP, consistent with its role in nociception. Nerve growth factor expression in the hind paw skin was also increased in a variety of dermal cell types and nerve fibers, suggesting the contribution of a peripheral source of NGF to mechanical allodynia. The upregulation of NGF coincided with enhanced tropomyosin-related kinase A receptor phosphorylation in the DRG. Finally, an antibody against NGF inhibited mechanical allodynia and decreased the numbers of SP-positive DRG neurons in db/db mice. These results suggest that inhibition of NGF action is a potential strategy for treating painful diabetic neuropathy.
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PMID:Nerve growth factor mediates mechanical allodynia in a mouse model of type 2 diabetes. 1981 94


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