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)

Ischemic lesions of the cerebral cortex occur frequently in humans as a result of stroke. One major consequence of the death of cortical neurons is the loss of excitatory cortical projections to subcortical regions. Little is known, however, about the transsynaptic effect of such lesions on neurotransmitter expression in subcortical structures. We have examined the effects of ischemic cortical lesions on the peptidergic neurotransmitters enkephalin and tachykinins in the striatum, a brain region massively innervated by glutamatergic cortical inputs. The levels of enkephalin and tachykinin mRNAs increased in the striatum of adult rats after thermocoagulation of pial vessels. The effects were more pronounced in the striatal region most heavily innervated by the lesioned cortex but were also observed in other striatal regions and on the contralateral side. Increased gene expression was accompanied by increased immunoreactivity for the two peptides. Elevated levels of enkephalin mRNA were observed up to 3 months after surgery in the ipsilateral striatum. Whereas results of previous studies of acute cortical ablations suggested that excitatory corticostriatal neurons were necessary to maintain normal peptide levels in striatal efferent neurons, the present data indicate that lesions of the same corticostriatal neurons secondary to local ischemia result in a paradoxical transsynaptic activation of neuropeptide synthesis in subcortical structures. This effect may play a role in the functional consequences of cortical strokes and progressive cortical atrophy in humans and may have critical bearing for their treatment and prognosis.
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PMID:Paradoxical increase in striatal neuropeptide gene expression following ischemic lesions of the cerebral cortex. 140 26

Neuronal degeneration that occurs in both ischemia and degenerative neurologic illnesses may involve excitotoxic mechanisms. In the present study, we examined whether cortical lesions with agonists acting at subtypes of glutamate receptors result in selective patterns of neuronal death. Injections of quinolinic acid, NMDA, homocysteic acid, kainic acid (KA), and alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) were made at 2 sites in the dorsolateral frontoparietal cortex in rats. After 1 week, the cerebral cortex was either dissected for neurochemical studies, or animals were perfused for histologic evaluation. Concentrations of somatostatin (SS), neuropeptide Y (NPY), substance P (SP), cholecystokinin (CCK), and vasoactive intestinal polypeptide (VIP) were measured by radioimmunoassay, while amino acids and catecholamines were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. NMDA agonists (quinolinic acid, homocysteic acid, and NMDA itself) resulted in dose-dependent reductions in glutamate and GABA, while SS, NPY, SP, CCK, and VIP were either unchanged or significantly increased in concentration. KA and AMPA at doses that resulted in comparable GABA depletions caused significant reductions in SS concentrations. Markers of cortical afferents were spared. All excitotoxins resulted in dose-dependent marked increases in uric acid concentrations. Histologic examination verified that lesions with NMDA agonists produced relative sparing of NADPH-diaphorase, SS, VIP, and CCK neurons. These results show that NMDA excitotoxin lesions result in a pattern of selective neuronal damage in the cerebral cortex that is similar to that which occurs in both ischemia and Huntington's disease.
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PMID:Neurochemical characterization of excitotoxin lesions in the cerebral cortex. 167 Jul 82

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

In the present study we investigated the relative vulnerability of neuronal subsets in the striatum to ischemia that was induced by bilateral transient ligation of the common carotid arteries in gerbils. After 4 days of survival, brains were evaluated using histochemical methods (NADPH-diaphorase and silver degeneration procedures) and neurochemical methods with radioimmunoassays for somatostatin-, neuropeptide Y-, and substance P-like immunoreactivity and measurements of amino acids using high-pressure liquid chromatography with electrochemical detection. NADPH-diaphorase-positive neurons were strikingly preserved in the ischemic dorsolateral portion of the striatum, in which there was severe neuronal loss. There was no significant depletion of NADPH-diaphorase-positive neurons in the striatum or cerebral cortex. Concentrations of neuropeptide Y-like and somatostatin-like immunoreactivity were unchanged despite a significant 25% depletion of substance P-like immunoreactivity and gamma-aminobutyric acid. Ischemic brain damage may be mediated by a neurotoxic effect of glutamate acting at the N-methyl-D-aspartate (NMDA) receptor. Previous studies of NMDA excitotoxin lesions in rat striatum have shown a sparing of neurons containing NADPH-diaphorase, somatostatin, and neuropeptide Y. The similar sparing of these neurons following ischemic lesions in gerbil striatum provides further evidence that NMDA receptor activation may play a role in ischemic injury.
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PMID:Selective sparing of NADPH-diaphorase-somatostatin-neuropeptide Y neurons in ischemic gerbil striatum. 197 76

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

The effects of the vasoactive perivascular neuropeptides calcitonin gene-related peptide (CGRP), neurokinin A (NKA), neuropeptide Y (NPY), and vasoactive intestinal polypeptide (VIP) on proliferation of cultured human umbilical vein endothelial cells (HUVECs) were investigated. CGRP was shown to increase both cell number and DNA synthesis, whereas NKA, NPY, and VIP were ineffective. 125I-labeled CGRP was shown to bind to HUVECs and this binding was displaced by addition of unlabeled CGRP, suggesting the existence of specific CGRP receptors. The effect of CGRP on formation of adenosine 3',5'-cyclic monophosphate (cAMP) and inositol phosphates (InsP), two intracellular messengers known to be involved in regulation of cell proliferation, was investigated. CGRP stimulated cAMP formation but was without effect on the formation of InsP. Proliferation, as well as cAMP formation, was also stimulated by cholera toxin. Basic fibroblast growth factor stimulated growth without affecting cAMP or InsP formation, whereas thrombin, which increased InsP formation, did not stimulate proliferation. We thus suggest that CGRP may act as a local factor stimulating proliferation of endothelial cells; that the mechanism of action is associated with cAMP formation; and that this effect of CGRP may be important for formation of new vessels during physiological and pathophysiological events such as ischemia, inflammation, and wound healing.
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PMID:Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. 215 44

Local chemical factors, such as H+, K+, Ca2+, adenosine, and osmolarity, affect cerebral resistance vessels. Their participation in the regulation of cerebral blood flow is suggested by changes in their concentration in the interstitial space during increased neuronal activity, strong hypoxia, and transient of incomplete ischemia. Such changes are not observed during autoregulation. Possible interactions between several factors must be considered when estimating their role. Autonomic nerves innervating cerebral vessels include: sympathetic nerves releasing the constrictor transmitter noradrenaline; parasympathetic nerves (liberating the dilator transmitter acetylcholine) and other dilator fibers (containing either serotonin, substance P, or vasoactive intestinal polypeptide). Participation of these systems in the adjustment of cerebral blood flow is still a matter of discussion, except for the protective effect of sympathetic nerves on the upper limit of autoregulation and on the blood--brain barrier. Humoral compounds, generated and released within the brain, which can affect cerebral blood flow include: histamine, bradykinin, and prostaglandins. Histamine, bradykinin, prostaglandin E2, and prostacyclin dilate cerebral arteries in situ, while prostaglandin F2 alpha reduces cerebral blood flow. Histamine and bradykinin alter the permeability of the blood--brain barrier and might be involved in pathological events, such as edema.
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PMID:Local chemical, neural, and humoral regulation of cerebrovascular resistance vessels. 240 98

We have noted, recently, that early after experimental intestinal ischemia, endotoxemia or whole-body trauma in rats, that the endothelial cells (EC) lining splanchnic precapillary microvessels (i.e., arterioles and metarterioles) appear to be contorted, often exhibit swelling and appear to have lost a great deal of their normal wetable surfaces as evidenced by sticking of white blood cells and platelets. Using identical circulatory shock and trauma models, we now report that irrespective of the ischemic or traumatic etiology, neither of four vasodilators, e.g., acetylcholine, bradykinin, substance P or histamine, were able to elicit much in the way of vasodilatation of metarterioles (10-12 microns in size) early after induction of intestinal ischemia, endotoxemia or whole-body trauma. Irrespective of the mechanism(s), if our results are seen in other organ regions as well, the end result would be a severe reduction in lumen sizes of the microscopic resistance and capacitance vessels in the lung ("shock lung"), kidneys, liver, etc., resulting in multiple organ failure.
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PMID:Failure of microscopic metarterioles to elicit vasodilator responses to acetylcholine, bradykinin, histamine and substance P after ischemic shock, endotoxemia and trauma: possible role of endothelial cells. 242 37

Antagonists of the putative peptide neurotransmitter substance P have been found to produce pronounced cardiovascular effects when administered into the spinal subarachnoid space. These previous studies have not, however, provided any direct evidence that these effects result from interaction with substance P receptors. The present study was designed to characterize the modification of cardiovascular function resulting from administration of these compounds, and evaluate their effects on the integrity of spinal cord function. Intrathecal administration of two substance P antagonists produced a depressor response accompanied by a reduction of hindquarter vascular resistance. Following administration of a substance P antagonist, the integrated cardiovascular responses to electrical stimulation of the renal afferent nerves and ventrolateral medulla were markedly attenuated. Intrathecal administration to conscious rats of three substance P antagonists led to a variety of sensory and motor dysfunctions, including loss of spontaneous motor function, responsiveness to mechanical and thermal stimuli, and bladder function. No such effects were produced by administration of substance P, luteinizing hormone releasing hormone (LHRH), or LHRH antagonist. These effects from administration of a substance P antagonist were associated with a dose-dependent necrosis of spinal cord tissue. The necrosis may be secondary to ischemia since pretreatment with the vasodilator adenosine significantly delayed or blocked the sensory and motor dysfunctions. This conclusion was supported by the demonstration that cerebrovascular smooth muscle (pial vessels) was constricted by a SP antagonist. Taken together, these data suggest that substance P antagonists appear to non-specifically block transmission in the spinal cord, by mechanisms which may involve reduction of blood flow to the spinal cord.
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PMID:Autonomic, sensory, and motor dysfunction following intrathecal administration of three substance P antagonists. 245 43

The responses of long and short half-lived proteins to ischemia were measured in rat brain during 6 days of recovery from 30 min of transient forebrain ischemia produced by four-vessel occlusion. At the end of the ischemic interval, the neocortical activities of four vulnerable enzymes [ornithine (ODC) and S-adenosylmethionine (SAMDC) decarboxylases, and RNA polymerases I and II] were unchanged, but within 30 min of reperfusion, their activities dropped by 25-50%. The loss of substance P in the striatum and substantia nigra was slower, reaching about 50% by 12 h. On the other hand, the activities of 5 long half-lived enzymes did not change in the neocortex at 5 and 15 h of reperfusion and regional protein concentrations were essentially unaffected over 6 days survival. The rate and extent of normalization of the amounts or activities of the vulnerable proteins varied. RNA polymerase II and ODC activities were restored within 4 h, and ODC showed a biphasic increase in activity, with peaks at 10 h and 2-3 days. RNA polymerase I and SAMDC activities were restored by 18 h and 5 days, respectively, whereas substance P concentrations did not completely recover, even at 6-15 days. The greater the regional reduction of blood flow during ischemia, the larger the net change (gain or loss) of SAMDC or ODC activity and the longer the time required to normalize the activities of these enzymes. The average rate of proteolysis, assessed by measuring the rate of clearance of 14C from protein prelabeled with [14C]bicarbonate, was abnormal during the first 2 days of reperfusion. Postischemic changes in both protein synthesis and degradation could affect the amounts of some of the proteins responsive to transient ischemia.
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PMID:Temporal profiles of proteins responsive to transient ischemia. 257 82


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