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)

Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p less than 0.01). CBF returned to preischemic levels approximately 45 min after reperfusion and was reduced to approximately 65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p less than 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p less than 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 nM; 50 microliters) to the middle or posterior temporal branch of the MCA 10-14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (PaCO2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.
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PMID:Chronic trigeminal ganglionectomy or topical capsaicin application to pial vessels attenuates postocclusive cortical hyperemia but does not influence postischemic hypoperfusion. 170 54

The levels of substance P (SP) in rat brains were assayed in 64 rats. Bilateral common carotid artery ligation was done in 49 rats. Half an hour before ligation, 25 rats were given 10 g/kg of RSM; 24 rats were given the same volume of normal saline as controls. Sham operation was done in 15 rats. Half an hour and 3 hours after cerebral ischemia, the rats were quickly decapitated. SP concentration was assayed in the cerebral cortex, caudate nucleus and brain stem. In saline-treated animals, the SP level of caudate nucleus at 3-hour group was significantly decreased as compared with the 0.5-hour group and sham-operated group respectively. No significances were found among RSM-treated groups and sham-operated groups. The SP levels were shown: brain stem greater than caudate nucleus greater than cerebral cortex. The preliminary results suggest that SP may be involved in the pathophysiologic procedures of cerebral ischemia and RSM may attenuate the dysfunction of SP during cerebral ischemia.
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PMID:The effect of radix Salviae Miltiorrhizae (RSM) on substance P in cerebral ischemia--animal experiment. 171 33

The influence of neuroeffector mechanisms in the regulation of postischemic cerebral blood flow was investigated by microsphere determination in 8 cats after chronic unilateral vascular deafferentation by trigeminal ganglionectomy. The animals were subjected to 90 min of reperfusion following 10 min of global ischemia induced by 4-vessel occlusion and systemic hypotension. Cortical hyperemia 30 min after reperfusion was attenuated by up to 48% in cortical gray matter ipsilateral to the side of trigeminal ganglionectomy (p less than 0.01). Axon reflex mechanisms involving the release of neuropeptides from peripheral sensory nerve fibers, such as substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A (NKA), mediate this response. SP and NKA cause vasodilation by endothelium-dependent mechanisms (endothelium-dependent relaxing factor), whereas CGRP relaxes vascular smooth muscle by direct receptor interactions. Studies were therefore undertaken to determine the extent to which endothelium-dependent mechanisms mediate the hyperemia following global cerebral ischemia. In 7 intact cats, the postischemic response of pial arterioles to the topical application of acetylcholine (ACh; 10(-7) M), an endothelial-dependent vasodilator, was measured using a closed cranial window technique. Although ACh increased pial arteriolar caliber by 17% under resting conditions, the same dose elicited a vasoconstrictor response (87% of pre-ACh diameter 30 min after reperfusion) for the first 60 min of reperfusion after 10 min of ischemia. ACh-induced vasodilation was restored by 75 min (105%), but was less than control even at 120 min (109 vs. 117%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postischemic cerebral blood flow and neuroeffector mechanisms. 200 79

Substance P (SP) has been implicated in immune responses and could increase glutamate release, and inflammatory reactions are known to be able to potentiate ischemic damage. We have previously found that SP was over-expressed in cerebral ischemia and speculated that SP may play a role in exacerbating ischemic damage. In this study, we examined whether a neurokinin-1 (NK-1) receptor antagonist, SR140333, would have an effect on brain ischemia. Intra-cerebroventricular (i.c.v.) administration of SR140333 (30 micrograms) markedly reduced (37.1 +/- 7.8%, p < 0.001) infarct volume measured 24 h after focal cerebral ischemia in the rat. The SR140333-treated group also exhibited a significantly improved neurological function reflected by the neurological deficit score. The results represented the first demonstration that a NK-1 receptor antagonist may be a novel type of drug for treatment of cerebral ischemia.
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PMID:Neurokinin-1 receptor antagonist SR140333: a novel type of drug to treat cerebral ischemia. 924 95

To test the hypothesis of an involvement of tachykinins in destabilization and hyperexcitation of neuronal circuits, gliosis, and neuroinflammation during cerebral ischemia, we investigated cell-specific expressional changes of the genes encoding substance P (SP), neurokinin B (NKB), and the tachykinin/neurokinin receptors (NK1, NK2, and NK3) after middle cerebral artery occlusion (MCAO) in the rat. Our analysis by quantitative in situ hybridization, immunohistochemistry, and confocal microscopy was concentrated on cerebrocortical areas that survive primary infarction but undergo secondary damage. Here, SP-encoding preprotachykinin-A and NK1 mRNA levels and SP-like immunoreactivity were transiently increased in GABAergic interneurons at 2 d after MCAO. Coincidently, MCAO caused a marked expression of SP and NK1 in a subpopulation of glutamatergic pyramidal cells, and in some neurons SP and NK1 mRNAs were coinduced. Elevated levels of the NKB-encoding preprotachykinin-B mRNA and of NKB-like immunoreactivity at 2 and 7 d after MCAO were confined to GABAergic interneurons. In parallel, the expression of NK3 was markedly downregulated in pyramidal neurons. MCAO caused transient NK1 expression in activated cerebrovenular endothelium within and adjacent to the infarct. NK1 expression was absent from activated astroglia or microglia. The differential ischemia-induced plasticity of the tachykinin system in distinct inhibitory and excitatory cerebrocortical circuits suggests that it may be involved in the balance of endogenous neuroprotection and neurotoxicity by enhancing GABAergic inhibitory circuits or by facilitating glutamate-mediated hyperexcitability. The transient induction of NK1 in cerebrovenular endothelium may contribute to ischemia-induced edema and leukocyte diapedesis. Brain tachykinin receptors are proposed as potential drug targets in stroke.
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PMID:Adaptive plasticity in tachykinin and tachykinin receptor expression after focal cerebral ischemia is differentially linked to gabaergic and glutamatergic cerebrocortical circuits and cerebrovenular endothelium. 1115 66

Tackykinins are involved in the inflammatory process of a large number of diseases. The role of the tachykinins in ischemic brain injury was evaluated by the serum levels of Substance P (SP), one of the most known tachykinins and detected by a competitive enzyme immunoassay. The study was performed in 15 human females and 3 human males with typical manifestation of complete stroke (12 cases) or transient ischemic attack (6 cases). The mean SP level in the serum of patients with transient ischemic attack (0.53+/-0.25 ng/ml) and of patients with complete stroke (0.31+/-0.14 ng/ml), showed significantly higher values than in controls (0.10+/-0.02 ng/ml). Moreover, in transient ischemic attack, the SP values were significantly higher than in cerebral complete stroke. But SP levels, based on the timings of classification of patients (i.e. before 12 hours: 0.34+/-0.15 ng/ml vs. 12 to 24 hours: 0.26+/-0.11 ng/ml) with brain injury, did not show any significant difference. Both values anyway were significantly higher than in controls. Our original results demonstrate the SP increase during cerebral ischemia. Further studies are necessary to verify if SP has an effective physiopathological role in the neurological ischemic damage, or if it is only a concomitant phenomenon. Our data, if confirmed, will be particularly important, not only to improve the knowledge of cerebral ischemic injury, but also for diagnosis and therapeutic approaches.
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PMID:The role of substance P in cerebral ischemia. 1257 34

We investigated the effects of PACAP treatment, and endogenous PACAP deficiency, on infarct volume, neurological function, and the cerebrocortical transcriptional response in a mouse model of stroke, middle cerebral artery occlusion (MCAO). PACAP-38 administered i.v. or i.c.v. 1 h after MCAO significantly reduced infarct volume, and ameliorated functional motor deficits measured 24 h later in wild-type mice. Infarct volumes and neurological deficits (walking faults) were both greater in PACAP-deficient than in wild-type mice, but treatment with PACAP reduced lesion volume and neurological deficits in PACAP-deficient mice to the same level of improvement as in wild-type mice. A 35,546-clone mouse cDNA microarray was used to investigate cortical transcriptional changes associated with cerebral ischemia in wild-type and PACAP-deficient mice, and with PACAP treatment after MCAO in wild-type mice. 229 known (named) transcripts were increased (228) or decreased (1) in abundance at least 50% following cerebral ischemia in wild-type mice. 49 transcripts were significantly up-regulated only at 1 h post-MCAO (acute response transcripts), 142 were up-regulated only at 24 h post-MCAO (delayed response transcripts) and 37 transcripts were up-regulated at both times (sustained response transcripts). More than half of these are transcripts not previously reported to be altered in ischemia. A larger percentage of genes up-regulated at 24 hr than at 1 hr required endogenous PACAP, suggesting a more prominent role for PACAP in later response to injury than in the initial response. This is consistent with a neuroprotective role for PACAP in late response to injury, i.e., even when administered 1 hr or more after MCAO. Putative injury effector transcripts regulated by PACAP include beta-actin, midline 2, and metallothionein 1. Potential neuroprotective transcripts include several demonstrated to be PACAP-regulated in other contexts. Prominent among these were transcripts encoding the PACAP-regulated gene Ier3, and the neuropeptides enkephalin, substance P (tachykinin 1), and neurotensin.
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PMID:Neuroprotection by endogenous and exogenous PACAP following stroke. 1702 94

Focal cerebral ischemia leads to delayed neurodegeneration in remote brain regions. The substantia nigra (SN) does not normally show primary neuronal death after ischemic events affecting the striatum, but can exhibit delayed neuronal loss after the ischemic injury through mechanisms that are unknown. No data are available in mice showing acute post-stroke inflammation and remote injury in the SN. Substance P (SP), a mediator of neurogenic inflammation, is a key element of the striato-nigral circuitry, but alterations of SP in the SN have not been studied after acute striatal injury. Inflammation, a key contributor to neuronal death, is found in the SN after striatal ischemia, but it is unknown whether it precedes or occurs concomitantly with neuronal death. We hypothesised that focal striatal ischemia induces changes in SP levels in the SN and that inflammation precedes neuronal death in the SN. Using the middle cerebral artery occlusion model, we found a significant loss of SP in the ipsilateral SN 24h after striatal ischemia in mice. In the same area where SP loss occurs, significant glial and vascular activation, but no neuronal death, were observed. In contrast, a marked neuronal loss was observed within six days in the area of SP loss and inflammation. Our data suggest that focal loss of SP and early inflammatory changes in the SN precede remote neuronal injury after striatal ischemic damage. These observations may have important implications for motor impairment in stroke patients and indicate that striatal ischemia might facilitate Parkinson's disease development.
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PMID:Loss of substance P and inflammation precede delayed neurodegeneration in the substantia nigra after cerebral ischemia. 2323 1

Stroke is a leading cause of death, disability and dementia worldwide. Despite extensive pre-clinical investigation, few therapeutic treatment options are available to patients, meaning that death, severe disability and the requirement for long-term rehabilitation are common outcomes. Cell loss and tissue injury following stroke occurs through a number of diverse secondary injury pathways, whose delayed nature provides an opportunity for pharmacological intervention. Amongst these secondary injury factors, increased blood-brain barrier permeability and cerebral oedema are well-documented complications of cerebral ischaemia, whose severity has been shown to be associated with final outcome. Whilst the mechanisms of increased blood-brain barrier permeability and cerebral oedema are largely unknown, recent evidence suggests that the neuropeptide substance P (SP) plays a central role. The aim of this review is to examine the role of SP in ischaemic stroke and report on the potential utility of NK1 tachykinin receptor antagonists as therapeutic agents.
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PMID:The role of substance p in ischaemic brain injury. 2496 10

Substance P (SP), a member of tachykinin family, is involved in the inflammation of the central nervous system and in the appearance of cerebral edema. Higher serum levels of SP have been found in 18 patients with cerebral ischemia compared with healthy controls. The aim of our multi-center study was to analyze the possible association between serum levels of SP and mortality in ischemic stroke patients. We included patients with malignant middle cerebral artery infarction (MMCAI) and a Glasgow Coma Scale (GCS) lower than 9. Non-surviving patients at 30 days (n = 31) had higher serum concentrations of SP levels at diagnosis of severe MMCAI than survivors (n = 30) (p < 0.001). We found in multiple regression an association between serum concentrations of SP higher than 362 pg/mL and mortality at 30 days (Odds Ratio = 5.33; 95% confidence interval = 1.541-18.470; p = 0.008) after controlling for age and GCS. Thus, the major novel finding of our study was the association between serum levels of SP and mortality in patients suffering from severe acute ischemic stroke.
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PMID:Serum Levels of Substance P and Mortality in Patients with a Severe Acute Ischemic Stroke. 2733 72


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