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Robert Vink - One of the best experts on this subject based on the ideXlab platform.
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a Substance P Antagonist imProves outcome in female sPrague dawley rats following diffuse traumatic brain injury
CNS Neuroscience & Therapeutics, 2012Co-Authors: Frances Corrigan, Anna V Leonard, M N Ghabriel, Corinna Van Den Heuvel, Robert VinkAbstract:Over the Past decade it has become increasingly clear from work in exPerimental models that the secondary injury cascade following traumatic brain injury (TBI) may differ between males and females [1, 2], with females exhibiting a different temPoral Profile of edema [1] and neurodegeneration comPared to males [2]. Furthermore significant neuroProtection was noted in male, but not female rodents treated with Posttraumatic hyPothermia [3], or a doPamine agonist [4]. This highlights the need to ensure that exPerimental treatments are equally efficacious in both genders before Proceeding to clinical trials that are Performed in mixed PoPulations. Previous research in our laboratory found that Substance P (SP) Plays an integral role in the secondary injury cascade following TBI in males [5]. SP is a member of the tachykinin family of neuroPePtides, with its release causing the develoPment of neurogenic inflammation characterised by vasodilation, Plasma extravasation, and tissue swelling [6]. These effects are PrinciPally mediated by the binding of SP to the NK1 tachykinin recePtor [6]. Following imPact-acceleration TBI in male rodents SP levels were found to increase. Furthermore, inhibition of SP, through treatment with an NK1 recePtor Antagonist reduced vasogenic edema formation and axonal injury, with a corresPonding imProvement in motor and cognitive outcome [5, 7]. However, it is not known whether SP Plays a similar role in females following TBI. As such, the effects of an NK1 recePtor Antagonist, N-acetyl-L-tryPtoPhan (NAT) on outcome following TBI in female rodents were investigated. Female SPrague Dawley rats were injured using the imPactacceleration model of diffuse TBI, as Previously described [5]. At 30 mins Postinjury rats were treated intravenously with either 2.5 mg/kg of NAT or an equal volume of saline. Sham animals were surgically PrePared but not injured. Motor deficits were assessed on rotarod as Previously described [5]. For histological analysis, rats were transcardially Perfused fixed, the brains removed and Processed. Slides were labeled with APP (1:1,000), SP (1:2,000), or albumin (1:20,000). To objectively analyse levels of SP and albumin, Ruifrok and Johnston’s color deconvolution method was emPloyed on 2 slides Per animal to determine the amount of DAB and hence antigen that was Present, as Previously described [8]. Axonal injury was determined by counting the number of APP immunoPositive lengths within the corPus callosum. For analysis of edema the sPecific gravity of the brain was determined by Placing it in a Percoll density gradient, with this measurement then converted to% water as Previously described [9]. All data were analyzed using a one or two-way ANOVA as aPProPriate, followed by Bonferonni t-tests using GraPhPad Prism software. SP immunoreactivity was assessed Postinjury to determine whether levels were increased, as Previously rePorted in males (Figures 1A and B). Indeed, at 24 h Postinjury increased SP immunoreactivity was observed, Particularly aPParent in Perivascular nerve fibers and astrocytic Processes in vehicle treated rats. In contrast low levels of SP immunoreactivity were observed in shams. Furthermore color deconvolution analysis demonstrated a significant increase in%DAB weight in vehicle treated rats, with 28.0 ± 3.6% comPared to 16.6 ± 2.8% in sham controls (P < 0.01).
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a Substance P Antagonist imProves outcome when administered 4 h after onset of ischaemic stroke
Brain Research, 2011Co-Authors: Renée J. Turner, Stephen C Helps, Emma Thornton, Robert VinkAbstract:Previous studies have suggested that Substance P (SP) Plays a critical role in the develoPment of brain oedema and functional deficits following traumatic brain injury and that SP recePtor antagonism may imProve outcome. No studies have described such a role in ischemic stroke. The Present study characterized the effects of the NK1 tachykinin recePtor Antagonist, n-acetyl-L-tryPtoPhan (NAT), on blood-brain barrier (BBB) breakdown, oedema formation, infarct volume and functional outcome following reversible ischemic stroke in rats. Ischemia was induced using a reversible thread model of middle cerebral artery occlusion where occlusion was maintained for 2 h before rePerfusion. Animals received either NAT or equal volume saline vehicle intravenously at 2 h Post-rePerfusion. Ischaemic stroke resulted in increased Perivascular SP immunoreactivity at 24 h. Administration of NAT significantly reduced oedema formation and BBB Permeability at 24 h Post-ischemia and significantly imProved functional outcome as assessed over 7 days. There was no effect on infarct volume. We conclude that inhibition of SP activity with a NK1 tachykinin recePtor Antagonist is effective in reducing cerebral oedema, BBB Permeability and functional deficits following reversible ischemia and may therefore rePresent a novel theraPeutic aPProach to the treatment of ischaemic stroke.
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a Substance P Antagonist reduces axonal injury and imProves neurologic outcome when administered uP to 12 hours after traumatic brain injury
Journal of Neurotrauma, 2011Co-Authors: J J Donkin, Ibolja Cernak, P C Blumbergs, Robert VinkAbstract:Abstract Previous studies have demonstrated that the comPound N-acetyl-L-tryPtoPhan (NAT) reduces brain edema and imProves functional outcome following traumatic brain injury (TBI). In this study we examined whether this effect was mediated via the neurokinin-1 recePtor, and whether there was an effect on axonal injury. We also exPlored whether the comPound was effective, even when administered at delayed time Points. Male SPrague-Dawley rats were subject to acceleration-induced, diffuse TBI and administered NAT, its inactive D-enantiomer, or saline vehicle. In contrast to NAT (2.5 mg/kg), the inactive D-enantiomer was ineffective at imProving rotarod motor Performance after TBI. NAT also imProved cognitive outcome as assessed by the Morris water maze and novel object recognition tests, and reduced axonal injury at 5 and 24 h after TBI as assessed by amyloid Precursor Protein immunohistochemistry. However, efficacy of the membrane-imPermeable NAT was limited to administration within 5 h, whereas administr...
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A Substance P Antagonist imProves outcome following reversible middle cerebral artery occlusion in rats
Journal of Cerebral Blood Flow & Metabolism, 2005Co-Authors: Renée J. Turner, Peter C. Blumbergs, Robert VinkAbstract:Previous results from our laboratory 1 have shown that neurogenic inflammation is associated with traumatic brain injury. 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 functional deficits. The Present study examines SP immunoreactivity following exPerimental stroke in rats and characterizes the effects of a Substance P Antagonist on functional outcome. ExPerimental stroke was induced in halothane anesthetized SPrague-Dawley rats using a reversible thread model of right middle cerebral artery occlusion 2 where occlusion was maintained for 2 h and the thread retracted to allow rePerfusion. Animals not exhibiting anti-clockwise circling behaviour at 2 h after commencement of rePerfusion were excluded from the study. In a subgrouP of animals, either 25 mg/kg n-acetyl-tryPtoPhan or equal volume saline was administered i.v. at this timePoint, and their motor function subsequently assessed for 7 days using a rotarod device. Untreated animals were reanesthetized at 24 h and their brains Perfusion fixed with 10% formalin, removed and blocked in Paraffin wax. Increased SP immunoreactivity relative to the contralateral (non-infarcted) hemisPhere was observed in Perivascular, neuronal and glial tissue within the Penumbra of the infarcted hemisPhere. This increased SP immunoreactivity was not as aPParent in the infarct core. In animals receiving treatment, administration of the SP Antagonist resulted in a significant imProvement in rotarod score as comPared to vehicle treated animals. We conclude that neurogenic inflammation, as reflected by increased SP immunoreactivity, occurs in the ischemic Penumbra following exPerimental stroke, and that it may be associated with the develoPment of functional deficits. As such, inhibition of neurogenic inflammation may rePresent a novel theraPeutic target for the treatment of reversible, ischemic stroke (See Figure 1).
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A Substance P Antagonist Increases Brain Intracellular Free Magnesium Concentration after Diffuse Traumatic Brain Injury in Rats
Journal of The American College of Nutrition, 2004Co-Authors: Robert Vink, J J Donkin, M I Cruz, Alan J Nimmo, Ibolja CernakAbstract:Objective: Magnesium (Mg) deficiency has been shown to increase Substance P release and induce a Pro-inflammatory resPonse that can be attenuated with the administration of a Substance P-Antagonist. Neurogenic inflammation has also been imPlicated in traumatic brain injury (TBI), a condition where brain intracellular free magnesium (Mgf) decline is known to occur and has been correlated with functional outcome. We therefore examined whether a Substance P Antagonist restores brain intracellular free magnesium concentration following TBI.Methods: Male, adult SPrague-Dawley rats were injured using the Cernak imPact acceleration model of diffuse TBI. At 30 min after injury, animals were administered either 0.25 mg/kg i.v. n-acetyl tryPtoPhan or equal volume saline. Prior to and 4 h after induction of injury, PhosPhorus magnetic resonance sPectra were acquired using a 7-tesla magnet interfaced with a Bruker console. Mgf was calculated from the chemical shift of the beta ATP. Before injury, Mgf was 0.51 ± 0.05 ...
Susan E. Leeman - One of the best experts on this subject based on the ideXlab platform.
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a Substance P Antagonist rP 67 580 ameliorates a mouse meningoencePhalitic resPonse to tryPanosoma brucei brucei
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Peter G E Kennedy, Susan E. Leeman, Jean Rodgers, Francis W Jennings, Max Murray, Joanne BurkeAbstract:Mice infected with the Protozoan Parasite TryPanosoma brucei brucei and treated subcuratively with the tryPanocidal drug diminazene aceturate develoP an acute inflammatory meningoencePhalitis with associated astrocytic Proliferation. This reaction is very similar to that seen in the fatal Posttreatment reactive encePhaloPathies that can occur in human African tryPanosomiasis. The 11-amino acid neuroPePtide Substance P (SP) has recently been identified as a mediator in many inflammatory resPonses, and the develoPment of Potent, highly sPecific, nonPePtide SP Antagonists has Provided a new oPPortunity to investigate the Possible involvement of SP in a variety of Pathological conditions. We therefore Postulated that SP may Play a role in the develoPment of the Posttreatment inflammatory encePhaloPathy found in this exPerimental mouse model of African tryPanosomiasis. In the Present study RP-67,580, a SP Antagonist that binds sPecifically to NK-1 recePtors, was given intraPeritoneally at a dose of 2 mg/kg twice daily to mice in which a severe meningoencePhalitis had been Produced. A significant reduction in both the severity of the inflammatory resPonse (P = 0.0001) as well as the degree of astrocyte activation (P < 0.001) was found in the brains of these animals as comPared with control mice that had not received RP-67,580. An inactive enantiomer of this SP Antagonist, RP-68,651, had no effect on the central nervous system inflammatory reaction. We conclude from these findings that the neuroPePtide SP Plays a key role in the develoPment of the severe central nervous system inflammatory resPonse associated with African tryPanosomiasis.
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CP-96,345, a Substance P Antagonist, inhibits rat intestinal resPonses to Clostridium difficile toxin A but not cholera toxin.
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Charalabos Pothoulakis, Ignazio Castagliuolo, J T Lamont, A Jaffer, J C O'keane, R M Snider, Susan E. LeemanAbstract:Abstract Toxin A from Clostridium difficile mediates acute inflammatory enterocolitis in exPerimental animals, while cholera toxin causes noninflammatory secretory diarrhea. The PurPose of this study was to investigate whether an Antagonist to the PePtide Substance P, a constituent of Primary sensory neurons known to ParticiPate in inflammatory resPonses, would inhibit toxin A-mediated enteritis in the rat ileum. Pretreatment of rats with CP-96,345 (2.5 mg Per kg of body weight), a Substance P Antagonist, dramatically inhibited fluid secretion (P < 0.01) and mannitol Permeability (P < 0.01) in ileal looPs exPosed to toxin A. The Protective effects, which were dose dePendent, caused a significant reduction of inflammation in the lamina ProPria, reduction of the necrosis of intestinal ePithelial cells, and comPlete inhibition of toxin A-mediated release of rat mast cell Protease II, a sPecific Product of rat mucosal mast cells. An inactive enantiomer of the Substance P Antagonist, CP-96,344, had no effect. In contrast, Pretreatment with CP-96,345 had no inhibitory effect on the intestinal effects caused by administration of cholera toxin into the ileal looPs. From these data, we conclude that the PePtide Substance P is involved in the secretory and inflammatory effects of toxin A but not of cholera toxin.
N M J Rupniak - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of action of the antidePressants fluoxetine and the Substance P Antagonist l 000760735 are associated with altered neurofilaments and synaPtic remodeling
Brain Research, 2004Co-Authors: Paul C Guest, David W Smith, Michael R Knowles, Sylvain Molonnoblot, Kamran Salim, Fraser Murray, Philippe Laroque, Stephen P Hunt, Carmen De Felipe, N M J RupniakAbstract:AntidePressants are widely Prescribed in the treatment of dePression, although the mechanism of how they exert their theraPeutic effects is Poorly understood. To shed further light on their mode of action, we have attemPted to identify a common Proteomic signature in guinea Pig brains after chronic treatment with two different antidePressants. Both fluoxetine and the Substance P recePtor (NK(1)R) Antagonist (SPA) L-000760735 altered cortical exPression of multiPle heat shock Protein 60 forms along with neurofilaments and related Proteins that are critical determinants of synaPtic structure and function. Analysis of NK(1)R-/- mice showed similar alterations of neurofilaments confirming the sPecificity of the effects observed with chronic NK(1)R Antagonist treatment. To determine if these changes were associated with structural modification of synaPses, we carried out electron microscoPic analysis of cerebral cortices from fluoxetine-treated guinea Pigs. This showed an increase in the Percentage of synaPses with sPlit PostsynaPtic densities (PSDs), a Phenomenon that is characteristic of activity-dePendent synaPtic rearrangement. These findings suggest that cortical alterations of the neurofilament Pathway and increased synaPtic remodeling are associated with the mechanism of these two antidePressant drug treatments and may contribute to their PsychotheraPeutic actions.
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the Substance P Antagonist l 760 735 inhibits stress induced nk1 recePtor internalisation in the basolateral amygdala
Brain Research, 1999Co-Authors: David W Smith, Louise Hewson, P Fuller, Angela R Williams, A Wheeldon, N M J RupniakAbstract:The distribution of NK1 recePtor immunoreactivity in the amygdaloid comPlex, induction of NK1 recePtor endocytosis in the amygdala following immobilisation stress, and the ability of Pretreatment with the Substance P Antagonist L-760,735 or imiPramine to block this resPonse were examined in gerbils, a sPecies with human-like NK1 recePtor Pharmacology. Highest levels of immunolabelling were observed in the anterior, amygdalo-hiPPocamPal and medial nuclei. Less dense labelling was observed in the basolateral nucleus, where it was Possible to clearly visualise the distal dendrites of NK1 immunoreactive neurones and quantify the effect of immobilisation stress on NK1 recePtor endocytosis morPhology, a marker of local Substance P release. Immobilisation for 1 h caused an aPProximately 60% increase in the number of dendritic Processes undergoing NK1 recePtor endocytosis in the basolateral amygdala that was inhibited by acute Pretreatment of animals with L-760,735 (3 mg/kg), but not by imiPramine (10 mg/kg). These findings are consistent with other evidence that the amygdala rePresents a Possible site of action for the antidePressant and anxiolytic efficacy of Substance P Antagonists.
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The Substance P Antagonist L-760,735 inhibits stress-induced NK(1) recePtor internalisation in the basolateral amygdala.
Brain research, 1999Co-Authors: David W Smith, Louise Hewson, P Fuller, Angela R Williams, A Wheeldon, N M J RupniakAbstract:The distribution of NK(1) recePtor immunoreactivity in the amygdaloid comPlex, induction of NK(1) recePtor endocytosis in the amygdala following immobilisation stress, and the ability of Pretreatment with the Substance P Antagonist L-760,735 or imiPramine to block this resPonse were examined in gerbils, a sPecies with human-like NK(1) recePtor Pharmacology. Highest levels of immunolabelling were observed in the anterior, amygdalo-hiPPocamPal and medial nuclei. Less dense labelling was observed in the basolateral nucleus, where it was Possible to clearly visualise the distal dendrites of NK(1) immunoreactive neurones and quantify the effect of immobilisation stress on NK(1) recePtor endocytosis morPhology, a marker of local Substance P release. Immobilisation for 1 h caused an aPProximately 60% increase in the number of dendritic Processes undergoing NK(1) recePtor endocytosis in the basolateral amygdala that was inhibited by acute Pretreatment of animals with L-760,735 (3 mg/kg), but not by imiPramine (10 mg/kg). These findings are consistent with other evidence that the amygdala rePresents a Possible site of action for the antidePressant and anxiolytic efficacy of Substance P Antagonists.
Roy G. Smith - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of L-692,429-stimulated rat growth hormone release by a weak Substance P Antagonist: L-756,867.
The Journal of endocrinology, 1997Co-Authors: Kang Cheng, L. Wei, L.-y. Chaung, W. W.-s. Chan, B. Butler, Roy G. SmithAbstract:H2N,D-Arg,Pro,Lys,Pro,D-Phe,Gln,D-TrP,Phe,D-TrP,Leu, Leu,NH2 (L-756,867), a weak Substance P Antagonist, inhibited L-692,429-stimulated GH release from rat Primary Pituitary cells in a dose-dePendent manner. At a concentration of 50 nM, L-756,867 shifted the dose-resPonse curve of L-692,429-induced GH release to the right by about tenfold. It also imPaired the ability of L-692,429 to Potentiate the effect of growth hormone-releasing factor (GRF) on GH release. Substance P (1 microM) had no effect on basal or L-692,429-stimulated GH release. When tested in anesthetized rats, L-756,867 inhibited L-692,429- and growth hormone-releasing hexaPePtide- (GHRP-6)-stimulated GH secretion in a dose-dePendent manner. ComPlete inhibition was observed at an i.v. dose of 100 micrograms/kg of L-756,867. However, at the same concentration, it had no effect on GRF-induced GH secretion D-Lys3-GHRP-6, a GHRP-6 Antagonist, had no effect on GHRP-6 or L-692,429-induced GH secretion even at an i.v. dose of 2 mg/kg. These results indicate that L-692,429 and GHRP-6 stimulate GH release both in vitro and in vivo via a common recePtor and signaling Pathway which is different from that of Substance P in sPite of the fact that their effects are inhibited by a weak Substance P Antagonist.
J J Donkin - One of the best experts on this subject based on the ideXlab platform.
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a Substance P Antagonist reduces axonal injury and imProves neurologic outcome when administered uP to 12 hours after traumatic brain injury
Journal of Neurotrauma, 2011Co-Authors: J J Donkin, Ibolja Cernak, P C Blumbergs, Robert VinkAbstract:Abstract Previous studies have demonstrated that the comPound N-acetyl-L-tryPtoPhan (NAT) reduces brain edema and imProves functional outcome following traumatic brain injury (TBI). In this study we examined whether this effect was mediated via the neurokinin-1 recePtor, and whether there was an effect on axonal injury. We also exPlored whether the comPound was effective, even when administered at delayed time Points. Male SPrague-Dawley rats were subject to acceleration-induced, diffuse TBI and administered NAT, its inactive D-enantiomer, or saline vehicle. In contrast to NAT (2.5 mg/kg), the inactive D-enantiomer was ineffective at imProving rotarod motor Performance after TBI. NAT also imProved cognitive outcome as assessed by the Morris water maze and novel object recognition tests, and reduced axonal injury at 5 and 24 h after TBI as assessed by amyloid Precursor Protein immunohistochemistry. However, efficacy of the membrane-imPermeable NAT was limited to administration within 5 h, whereas administr...
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A Substance P Antagonist Increases Brain Intracellular Free Magnesium Concentration after Diffuse Traumatic Brain Injury in Rats
Journal of The American College of Nutrition, 2004Co-Authors: Robert Vink, J J Donkin, M I Cruz, Alan J Nimmo, Ibolja CernakAbstract:Objective: Magnesium (Mg) deficiency has been shown to increase Substance P release and induce a Pro-inflammatory resPonse that can be attenuated with the administration of a Substance P-Antagonist. Neurogenic inflammation has also been imPlicated in traumatic brain injury (TBI), a condition where brain intracellular free magnesium (Mgf) decline is known to occur and has been correlated with functional outcome. We therefore examined whether a Substance P Antagonist restores brain intracellular free magnesium concentration following TBI.Methods: Male, adult SPrague-Dawley rats were injured using the Cernak imPact acceleration model of diffuse TBI. At 30 min after injury, animals were administered either 0.25 mg/kg i.v. n-acetyl tryPtoPhan or equal volume saline. Prior to and 4 h after induction of injury, PhosPhorus magnetic resonance sPectra were acquired using a 7-tesla magnet interfaced with a Bruker console. Mgf was calculated from the chemical shift of the beta ATP. Before injury, Mgf was 0.51 ± 0.05 ...
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A Substance P Antagonist increases brain intracellular free magnesium concentration after diffuse traumatic brain injury in rats.
Journal of the American College of Nutrition, 2004Co-Authors: Robert Vink, J J Donkin, M I Cruz, Alan J Nimmo, Ibolja CernakAbstract:Magnesium (Mg) deficiency has been shown to increase Substance P release and induce a Pro-inflammatory resPonse that can be attenuated with the administration of a Substance P-Antagonist. Neurogenic inflammation has also been imPlicated in traumatic brain injury (TBI), a condition where brain intracellular free magnesium (Mg(f)) decline is known to occur and has been correlated with functional outcome. We therefore examined whether a Substance P Antagonist restores brain intracellular free magnesium concentration following TBI. Male, adult SPrague-Dawley rats were injured using the Cernak imPact acceleration model of diffuse TBI. At 30 min after injury, animals were administered either 0.25 mg/kg i.v. n-acetyl tryPtoPhan or equal volume saline. Prior to and 4 h after induction of injury, PhosPhorus magnetic resonance sPectra were acquired using a 7-tesla magnet interfaced with a Bruker console. Mg(f) was calculated from the chemical shift of the beta ATP. Before injury, Mg(f) was 0.51 +/- 0.05 mM (SEM). By 4 hr after injury, Mg(f) had significantly declined to 0.27 +/- 0.02 mM in saline treated rats. In contrast, rats treated with n-acetyl tryPtoPhan had a Mg(f) of 0.47 +/- 0.06 mM at 4 h after injury, which was not significantly different from Preinjury values. There were no significant differences in PH between the treatment grouPs. It seems that any beneficial effect of a Substance P Antagonist on functional outcome following TBI may be related to imProvement in brain Mg homeostasis induced by the comPound.
