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)

Previous results from our laboratory have shown that neurogenic inflammation is associated with edema formation after traumatic brain injury (TBI). This neurogenic inflammation was characterized by increased substance P (SP) immunoreactivity and could be attenuated with administration of SP antagonists with a resultant decrease in edema formation. Few studies have examined whether neurogenic inflammation, as identified by increased SP immunoreactivity, occurs after stroke and its potential role in edema formation. The present study examines SP immunoreactivity and edema formation following stroke. Experimental stroke was induced in halothane anaesthetized male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion. Increased SP immunoreactivity at 24 hours relative to the non-infarcted hemisphere was observed in perivascular, neuronal, and glial tissue, and within the penumbra of the infarcted hemisphere. It was not as apparent in the infarct core. This increased SP immunoreactivity was associated with edema formation. We conclude that neurogenic inflammation, as reflected by increased SP immunoreactivity, occurs following experimental stroke, and that this may be associated with edema formation. As such, inhibition of neurogenic inflammation may represent a novel therapeutic target for the treatment of edema following reversible, ischemic stroke.
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PMID:Increased substance P immunoreactivity and edema formation following reversible ischemic stroke. 1667 67

The tachykinin family of vasoactive peptides comprises the neuropeptides substance P, neurokinin A and neurokinin B, and the newly discovered endokinins and hemokinins. Their cardiovascular effects are predominantly mediated by the family of neurokinin receptors. This review summarises the most recent advances in understanding the effects of tachykinins on the vasculature, and summarises their therapeutic potential. Tachykinins stimulate plasma extravasation, particularly acting through neurokinin-1 receptors in an endothelium-dependent manner. They therefore play prominent roles in tissue oedema and inflammation (called neurogenic inflammation). Pro-inflammatory effects of tachykinins are enhanced by their capacity to stimulate inflammatory cell recruitment, and to initiate angiogenesis. Tachykinins also regulate vascular tone and blood flow, although differences between species and between different vascular beds make this a highly complex area of research. They may relax vessels in some scenarios whilst inducing vasoconstriction in other situations, the state of the endothelium appearing to be of key importance. Tachykinins also modulate blood pressure and heart rate, acting both peripherally, and on the central nervous system. Cardiovascular effects of tachykinins and neurokinin receptors may be important therapeutic targets in diverse disorders such as pulmonary oedema, hypertension, pre-eclampsia, complex regional pain syndrome type 2, stroke and chronic inflammatory diseases such as arthritis. Sophisticated modelling of human disease is required to enable neurokinin receptor antagonists to achieve this therapeutic potential.
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PMID:Tachykinins and the cardiovascular system. 1691 31

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

Recent evidence has suggested that neuropeptides, and in particular substance P (SP), may play a critical role in the development of morphological injury and functional deficits following acute insults to the brain. Few studies, however, have examined the role of SP, and more generally, neurogenic inflammation, in the pathophysiology of traumatic brain injury and stroke. Those studies that have been reported suggest that SP is released following injury to the CNS and facilitates the increased permeability of the blood brain barrier, the development of vasogenic edema and the subsequent cell death and functional deficits that are associated with these events. Inhibition of the SP activity, either through inhibition of the neuropeptide release or the use of SP receptor antagonists, have consistently resulted in profound decreases in edema formation and marked improvements in functional outcome. The current review summarizes the role of SP in acute brain injury, focussing on its properties as a neurotransmitter and the potential for SP to adversely affect outcome.
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PMID:Substance P in traumatic brain injury. 1761 72

Each year, 15 million people suffer a stroke, of which 5 million die and 5 million are left permanently disabled. Cerebral swelling is of particular concern following stroke as it accounts for much of the death and disability. However, the mechanisms leading to cerebral swelling are not yet fully understood. Recent studies from our laboratory suggest that neuropeptides, and specifically substance P, may be involved in the injury processes that occur following acute insults to the brain such as stroke and trauma, and may be responsible, in part, for edema formation. Levels of substance P are increased following CNS injury, indicative of neurogenic inflammation, and this is associated with injury to the blood-brain barrier, the development of cerebral edema, cell death and functional deficits. Subsequent studies inhibiting neuropeptide release have consistently shown decreased cerebral edema and improved neurological outcome, while substance P antagonists administered after the insult are efficacious in reducing post-stroke cerebral edema and neurological deficits. The current review summarizes the evidence supporting the benefits of inhibiting neurogenic inflammation to treat ischemic stroke.
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PMID:Inhibition of neurogenic inflammation as a novel treatment for ischemic stroke. 1763 34

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are endogenous lipid mediators produced in the brain by P450 epoxygenases and metabolized through multiple pathways, including soluble epoxide hydrolase (sEH). Epoxyeicosatrienoic acids play important functions in the brain, including regulation of cerebral blood flow and protection from ischaemic brain injury. We previously demonstrated that ischaemic preconditioning induces cytochrome P450 2C11 epoxygenase (CYP2C11) expression in the brain, and that pharmacological inhibition and genetic deletion of sEH increases EETs and protects against stroke-induced brain damage. However, the expression profiles of CYP2C11 and sEH in normal brain remain unknown. In agreement with previous reports in peripheral vessels, we here demonstrate by immunofluorescence double-labelling that within cerebral parenchymal microvessels, sEH-immunoreactivity (IR) is localized to the vascular smooth muscle layer. Unexpectedly, however, analysis of large cerebral conduit arteries such as the middle cerebral artery revealed CYP2C11 and sEH expression in extrinsic perivascular nerves. Double-labelling studies revealed that CYP2C11- and sEH-IR predominantly colocalized with neuronal nitric oxide synthase-IR within perivascular nerve fibres. Significant colocalization for CYP2C11 and sEH was also observed with the parasympathetic markers vasoactive intestinal peptide and choline actetyltransferase, in addition to the sensory fibre markers calcitonin gene-related peptide and substance P. No colocalization was observed for either CYP2C11 or sEH with the sympathetic nerve markers dopamine beta-hydroxylase or neuropeptide Y. The presence of enzymes involved in production and inactivation of EETs within extrinsic parasympathetic and sensory vasodilator fibres suggests a novel role for EETs in the neurogenic control of cerebral arteries.
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PMID:A novel role for P450 eicosanoids in the neurogenic control of cerebral blood flow in the rat. 1763 71

Platelets play an important role in hemostasis, with inappropriate platelet activation being a major contributor to debilitating and often fatal thrombosis by causing myocardial infarction and stroke. Although current antithrombotic treatment is generally well tolerated and effective, many patients still experience cardiovascular problems, which may reflect the existence of alternative underlying regulatory mechanisms in platelets to those targeted by existing drugs. In this study, we define a role for peripherally distributed members of the tachykinin family of peptides, namely substance P and the newly discovered endokinins A and B that are present in platelets, in the activation of platelet function and thrombus formation. We have reported previously that the preferred pharmacologically characterized receptor for these peptides, the NK1 receptor, is present on platelets. Inhibition or deficiency of the NK1 receptor, or SP agonist activity, resulted in substantially reduced thrombus formation in vitro under arterial flow conditions, increased bleeding time in mice, and a decrease in experimentally induced thromboembolism. Inhibition of the NK1 receptor may therefore provide benefit in patients vulnerable to thrombosis and may offer an alternative therapeutic target.
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PMID:Peripheral tachykinins and the neurokinin receptor NK1 are required for platelet thrombus formation. 1789 3

Each year, 15 million people suffer a stroke, of which 5 million die and 5 million are left permanently disabled. Cerebral swelling is of particular concern following stroke as it accounts for much of the death and disability. However, the mechanisms leading to cerebral swelling are not yet fully understood. Recent studies from our laboratory suggest that neuropeptides, and specifically substance P, may be involved in the injury processes that occur following acute insults to the brain such as stroke and trauma, and may be responsible, in part, for edema formation. Levels of substance P are increased following CNS injury, indicative of neurogenic inflammation, and this is associated with injury to the blood-brain barrier, the development of cerebral edema, cell death and functional deficits. Subsequent studies inhibiting neuropeptide release have consistently shown decreased cerebral edema and improved neurological outcome, while substance P antagonists administered after the insult are efficacious in reducing post-stroke cerebral edema and neurological deficits. The current review summarizes the evidence supporting the benefits of inhibiting neurogenic inflammation to treat ischemic stroke.
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PMID:Inhibition of neurogenic inflammation as a novel treatment for ischemic stroke. 1829 37

Clinical studies have demonstrated that cilostazol (CZ), an antiplatelet agent with type 3 phosphodiesterase inhibition, reduces the risk of secondary stroke. To analyze CZ's vascular action, especially in relation to endothelial and perivascular nerve functions, we examined CZ's effects on the responses to endothelial and nerve stimulation in dog cerebral arteries, and on the response to nerve stimulation in dog mesenteric arteries. Low concentrations of CZ (10(-8) and 10(-7) mol/L) failed to relax the cerebral arteries, but a higher concentration (10(-6) mol/L) relaxed them in an endothelium-independent manner. Substance P-induced relaxation was endothelium-dependent in the cerebral arteries, whereas transmural electrical stimulation (TES) and nicotine-induced relaxation were endothelium-independent. This relaxation was abolished by N(G)-nitro-L-arginine, an NO synthase (NOS) inhibitor. A lower concentration (10(-7) mol/L) of CZ enhanced the relaxation caused by nerve-derived NO but did not affect the relaxation caused by endothelium-derived NO in the cerebral arteries; moreover, it did not affect the contractions caused by nerve-derived noradrenaline in the mesenteric arteries under treatment with the NOS inhibitor. It is concluded that CZ may selectively enhance nitrergic nerve function, possibly via the activation of neuronal NOS, in dog cerebral arteries, since it does not affect the function of the noradrenergic nerve or that of endothelial NOS. Therefore, this novel vasodilatory effect of CZ may explain the reduction in the risk of secondary stroke in addition to the antiplatelet action and the direct vasodilatory action on smooth muscle.
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PMID:Cilostazol's effect on the response to perivascular nerve stimulation in isolated dog cerebral and mesenteric arteries. 1895 14

Pneumonia is a common complication with the highest attributable proportion of deaths in patients with stroke. Cilostazol is a potent type III phosphodiesterase inhibitor, approved as an anti-platelet aggregation agent. The present study was designed to determine the protective mechanism of cilostazol against post-stroke pneumonia using a rat chronic cerebral hypoperfusion model. Rats were subjected to bilateral common carotid artery ligation (LBCCA) and divided randomly into the vehicle group (n=72) and cilostazol group (n=72). Rats of each group were sacrificed at baseline and at days 14, 28 and 42 after LBCCA. Cilostazol significantly improved the swallowing reflex by shortening the latency to elicited swallowing and increasing the numbers of swallows (P<0.05) at 14 days of hypoperfusion. It also decreased the numbers of bacterial colonies grown in cultures from homogenized lungs. Cilostazol markedly upregulated cyclic AMP responsive element binding protein (CREB) phosphorylation, increased tyrosine hydroxylase (TH) expression in the substantial nigra, and maintained dopamine (84.7+/-2.3 vs. 79.2+/-4.1% control; P=0.0512) and substance P levels (86.6+/-7.9 vs. 73.9+/-6.5% control; P<0.05) in the striatum, compared with the vehicle group. Our results indicate that cilostazol improves the swallowing reflex by enhancing the expression of TH through the CREB phosphorylation signaling pathway, and suggest that cilostazol could be useful in preventing pneumonia in the chronic stage of stroke.
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PMID:Activation of tyrosine hydroxylase prevents pneumonia in a rat chronic cerebral hypoperfusion model. 1903 75


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