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Tracy K Mcintosh - One of the best experts on this subject based on the ideXlab platform.
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the sodium channel blocker and glutamate release inhibitor bw1003c87 and magnesium attenuate regional cerebral edema following Experimental Brain Injury in the rat
Journal of Neurochemistry, 2002Co-Authors: Koichi Okiyama, Douglas H Smith, Thomas A Gennarelli, Roger P Simon, Michael Leach, Tracy K McintoshAbstract:Excitatory amino acid (EAA) neurotransmitters may play a role in the pathophysiology of traumatic Injury to the CNS. Although NMDA receptor antagonists have been reported to have therapeutic efficacy in animal models of Brain Injury, these compounds may have unacceptable toxicity for clinical use. One alternative approach is to inhibit the release of EAAs following traumatic Injury. The present study examined the effects of administration of a novel sodium channel blocker and EAA release inhibitor, BW1003C87, or the NMDA receptor-associated ion channel blocker magnesium chloride on cerebral edema formation following Experimental Brain Injury in the rat. Animals (n = 33) were subjected to fluid percussion Brain Injury of moderate severity (2.3 atm) over the left parietal cortex. Fifteen minutes after Injury, the animals received a constant infusion of BW1003C87 (10 mg/kg, i.v.), magnesium chloride (300 mumol/kg, i.v.), or saline over 15 min (2.75 ml/kg/15 min). In all animals, regional tissue water content in Brain was assessed at 48 h after Injury, using the wet weight/dry weight technique. In saline-treated control animals, fluid percussion Brain Injury produced significant regional Brain edema in injured left parietal cortex (p < 0.001), the cortical area adjacent to the site of maximal Injury (p < 0.001), left hippocampus (p < 0.001), and left thalamus (p = 0.02) at 48 h after Brain Injury. Administration of BW1003C87 15 min postInjury significantly reduced focal Brain edema in the cortical area adjacent to the site of maximal Injury (p < 0.02) and left hippocampus (p < 0.01), whereas magnesium chloride attenuated edema in left hippocampus (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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REGIONAL LEVELS OF LACTATE AND NOREPINEPHRINE AFTER Experimental Brain Injury
Journal of neurochemistry, 2002Co-Authors: M. Renuka Prasad, Tracy K Mcintosh, Robert J. Dempsey, C. Ramaiah, Susan B. Hipkens, David M. YurekAbstract:The recently developed controlled cortical impact model of Brain Injury in rats may be an excellent tool by which to attempt to understand the neurochemical mechanisms mediating the pathophysiology of traumatic Brain Injury. In this study, rats were subjected to lateral controlled cortical impact Brain Injury of low grade severity; their Brains were frozen in situ at various times after Injury to measure regional levels of lactate, high energy phosphates, and norepinephrine. Tissue lactate concentration in the Injury site left cortex was increased in injured animals by sixfold at 30 min and twofold at 2.5 h and 24 h after Injury (p < 0.05). At all postInjury times, lactate concentration was also increased in injured animals by about twofold in the cortex and hippocampus adjacent to the Injury site (p < 0.05). No significant changes occurred in the levels of ATP and phosphocreatine in most of the Brain regions of injured animals. However, in the primary site of Injury (left cortex), phosphocreatine concentration was decreased by 40% in injured animals at 30 min after Injury (p < 0.05). The norepinephrine concentration was decreased in the Injury site left cortex of injured animals by 38% at 30 min, 29% at 2.5 h, and 30% at 24 h after Injury (p < 0.05). The level of norepinephrine was also reduced by approximately 20% in the cortex adjacent to the Injury site in injured animals. The present results suggest that controlled cortical impact Brain Injury produces disorder in the neuronal oxidative and norepinephrine metabolism.
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Alterations in regional Brain catecholamine concentrations after Experimental Brain Injury in the rat.
Journal of neurochemistry, 2002Co-Authors: Tracy K Mcintosh, Thomas A GennarelliAbstract:: Although activation of Brain catecholaminergic systems has been implicated in the cerebrovascular and metabolic changes during subarachnoid hemorrhage, cerebral ischemia, cortical ablation, and cortical freeze lesions, little is known of the response of regional Brain catecholamine systems to traumatic Brain Injury. The present study was designed to characterize the temporal changes in concentrations of norepinephrine (NE), dopamine (DA), and epinephrine (E) in discrete Brain regions following Experimental fluid-percussion traumatic Brain Injury in rats. Anesthetized rats were subjected to fluid-percussion Brain Injury of moderate severity (2.2–2.3 atm) and killed at 1 h, 6 h, 24 h, 1 week, and 2 weeks postInjury (n = 6 per timepoint). Control animals (surgery and anesthesia without Injury) were killed at identical timepoints (n = 6 per timepoint). Tissue concentrations of NE, DA, and E were evaluated using HPLC. Following Brain Injury, an acute decrease was observed in DA concentrations in the injured cortex (p < 0.05) at 1 h postInjury, which persisted up to 2 weeks postInjury. Striatal concentrations of DA were significantly increased (p < 0.05) only at 6 h postInjury. Hypothalamic concentrations of DA and NE increased significantly beginning at 1 h postInjury (p < 0.05 and p < 0.05, respectively) and persisted up to 24 h for DA (p < 0.05) and 1 week (p < 0.05) for NE. These data suggest that acute alterations occur in regional concentrations of Brain catecholamines following Brain trauma, which may persist for prolonged periods postInjury.
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Temporal patterns of poly(ADP-ribose) polymerase activation in the cortex following Experimental Brain Injury in the rat.
Journal of neurochemistry, 2002Co-Authors: Michelle C. Laplaca, Ramesh Raghupathi, Ajay Verma, Andrew A. Pieper, Kathryn E. Saatman, Solomon H. Snyder, Tracy K McintoshAbstract:Abstract: The activation of poly(ADP-ribose) polymerase, a DNA base excision repair enzyme, is indicative of DNA damage. This enzyme also undergoes site-specific proteolysis during apoptosis. Because both DNA fragmentation and apoptosis are known to occur following Experimental Brain Injury, we investigated the effect of lateral fluid percussion Brain Injury on poly(ADP-ribose) polymerase activity and cleavage. Male Sprague-Dawley rats (n = 52) were anesthetized, subjected to fluid percussion Brain Injury of moderate severity (2.5-2.8 atm), and killed at 30 min, 2 h, 6 h, 24 h, 3 days, or 7 days postInjury. Genomic DNA from injured cortex at 24 h, but not at 30 min, was both fragmented and able to stimulate exogenous poly(ADP-ribose) polymerase. Endogenous poly(ADP-ribose) polymerase activity, however, was enhanced in the injured cortex at 30 min but subsequently returned to baseline levels. Slight fragmentation of poly(ADP-ribose) polymerase was detected in the injured cortex in the first 3 days following Injury, but significant cleavage was detected at 7 days postInjury. Taken together, these data suggest that poly(ADP-ribose) polymerase-mediated DNA repair is initiated in the acute posttraumatic period but that subsequent poly(ADP-ribose) polymerase activation does not occur, possibly owing to delayed apoptosis-associated proteolysis, which may impair the repair of damaged DNA.
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Acute Cytoskeletal Alterations and Cell Death Induced by Experimental Brain Injury Are Attenuated by Magnesium Treatment and Exacerbated by Magnesium Deficiency
Journal of neuropathology and experimental neurology, 2001Co-Authors: Kathryn E. Saatman, Florence M. Bareyre, M. Sean Grady, Tracy K McintoshAbstract:Traumatic Brain Injury results in a profound decline in intracellular magnesium ion levels that may jeopardize critical cellular functions. We examined the consequences of preInjury magnesium deficiency and post-traumatic magnesium treatment on Injury-induced cytoskeletal damage and cell death at 24 h after Injury. Adult male rats were fed either a normal (n = 24) or magnesium-deficient diet (n = 16) for 2 wk prior to anesthesia and lateral fluid percussion Brain Injury (n = 31) or sham Injury (n = 9). Normally fed animals were then randomized to receive magnesium chloride (125 micromol, i.v., n = 10) or vehicle solution (n = 11) at 10 min postInjury. Magnesium treatment reduced cortical cell loss (p < 0.05), cortical alterations in microtubule-associated protein-2 (MAP-2) (p < 0.05), and both cortical and hippocampal calpain-mediated spectrin breakdown (p < 0.05 for each region) when compared to vehicle treatment. Conversely, magnesium deficiency prior to Brain Injury led to a greater area of cortical cell loss (p < 0.05 compared to vehicle treatment). Moreover, Brain Injury to magnesium-deficient rats resulted in cytoskeletal alterations within the cortex and hippocampus that were not observed in vehicle- or magnesium-treated animals. These data suggest that cortical cell death and cytoskeletal disruptions in cortical and hippocampal neurons may be sensitive to magnesium status after Experimental Brain Injury, and may be mediated in part through modulation of calpains.
Sarah E. Stabenfeldt - One of the best experts on this subject based on the ideXlab platform.
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Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury
Tissue engineering. Part A, 2020Co-Authors: Vimala N. Bharadwaj, Trent Anderson, Jonathan Lifshitz, Vikram D. Kodibagkar, Connor Copeland, Ethan Mathew, Jason M. Newbern, Sarah E. StabenfeldtAbstract:The development of effective therapeutics for Brain disorders is challenging, in particular, the blood-Brain barrier (BBB) severely limits access of the therapeutics into the Brain parenchyma. Trau...
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Sex-dependent macromolecule and nanoparticle delivery in Experimental Brain Injury
2019Co-Authors: Vimala N. Bharadwaj, Trent Anderson, Jonathan Lifshitz, Vikram D. Kodibagkar, Connor Copeland, Ethan Mathew, Jason M. Newbern, Sarah E. StabenfeldtAbstract:Development of effective therapeutics for Brain disorders is challenging, in particular, the blood-Brain barrier (BBB) severely limits access of the therapeutics into the Brain parenchyma. Traumatic Brain Injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NP) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24 h post-focal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared to male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 d after focal Injury in both female and male mice. The delineation of Injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics.
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Blood-Brainbarrier disruption dictates nanoparticle accumulation following Experimental Brain Injury.
Nanomedicine : nanotechnology biology and medicine, 2018Co-Authors: Vimala N. Bharadwaj, Rachel K. Rowe, Jordan L. Harrison, Trent Anderson, Jonathan Lifshitz, P. David Adelson, Vikram D. Kodibagkar, Sarah E. StabenfeldtAbstract:Abstract Clinically, traumatic Brain Injury (TBI) results in complex heterogeneous pathology that cannot be recapitulated in single pre-clinical animal model. Therefore, we focused on evaluating utility of nanoparticle (NP)-based therapeutics following three diffuse-TBI models: mildclosed-head Injury (mCHI), repetitive-mCHI and midline-fluid percussion Injury (FPI). We hypothesized that NP accumulation after diffuse TBI correlates directly with blood–Brainbarrier permeability. Mice received PEGylated-NP cocktail (20-500 nm) (intravenously) after single- or repetitive-(1 impact/day, 5 consecutive days) CHI (immediately) and midline-FPI (1 h, 3 h and 6 h). NPs circulated for 1 h before perfusion/Brain extraction. NP accumulation was analyzed using fluorescent microscopy in Brain regions vulnerable to neuropathology. Minimal/no NP accumulation after mCHI/RmCHI was observed. In contrast, midlineFPI resulted in significant peak accumulation of up to 500 nm NP at 3 h post-Injury compared to sham, 1 h, and 6 h groups in the cortex. Therefore, our study provides the groundwork for feasibility of NP-delivery based on NPinjection time and NPsize after mCHI/RmCHI and midline-FPI.
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temporal assessment of nanoparticle accumulation after Experimental Brain Injury effect of particle size
Scientific Reports, 2016Co-Authors: Vimala N. Bharadwaj, Jonathan Lifshitz, Vikram D. Kodibagkar, David P Adelson, Sarah E. StabenfeldtAbstract:Nanoparticle (NP) based therapeutic and theranostic agents have been developed for various diseases, yet application to neural disease/Injury is restricted by the blood-Brain-barrier (BBB). Traumatic Brain Injury (TBI) results in a host of pathological alterations, including transient breakdown of the BBB, thus opening a window for NP delivery to the injured Brain tissue. This study focused on investigating the spatiotemporal accumulation of different sized NPs after TBI. Specifically, animal cohorts sustaining a controlled cortical impact Injury received an intravenous injection of PEGylated NP cocktail (20, 40, 100, and 500 nm, each with a unique fluorophore) immediately (0 h), 2 h, 5 h, 12 h, or 23 h after Injury. NPs were allowed to circulate for 1 h before perfusion and Brain harvest. Confocal microscopy demonstrated peak NP accumulation within the Injury penumbra 1 h post-Injury. An inverse relationship was found between NP size and their continued accumulation within the penumbra. NP accumulation preferentially occurred in the primary motor and somatosensory areas of the Injury penumbra as compared to the parietal association and visual area. Thus, we characterized the accumulation of particles up to 500 nm at different times acutely after Injury, indicating the potential of NP-based TBI theranostics in the acute period after Injury.
H S Dhillon - One of the best experts on this subject based on the ideXlab platform.
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Enhanced Phosphodiestric Breakdown of Phosphatidylinositol Bisphosphate After Experimental Brain Injury
Journal of neurochemistry, 2002Co-Authors: M. Renuka Prasad, H S Dhillon, Robert J. Dempsey, Timothy J. Carbary, Stephen W. ScheffAbstract:Regional levels of lactate and inositol 1,4,5-trisphosphate (IP3), a cellular second messenger of the excitatory neurotransmitter system, were measured after lateral fluid percussion (FP) Brain Injury in rats. At 5 min postInjury, tissue lactate concentrations were significantly elevated in the cortices and hippocampi of both the ipsilateral and contralateral hemispheres. By 20 min postInjury, lactate concentrations were elevated only in the cortices and hippocampus of the ipsilateral hemisphere. Whereas the IP3 concentrations were elevated in the hippocampi of the ipsilateral and contralateral hemisphere and in the cortex of ipsilateral hemisphere at 5 min postInjury, no elevation in these sites was found at 20 min postInjury. Histologic analysis revealed neuronal damage in the cortex and CA3 regions of hippocampus ipsilateral to the Injury at 24 h postInjury. The present results suggest activation of the phosphoinositide signal transduction pathway at the onset of Injury and of a possible requirement of early persistent metabolic dysfunction (> 20 min) such as the lactate accumulation in the delayed neuronal damage.
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Effects of chronic ethanol administration on expression of BDNF and trkB mRNAs in rat hippocampus after Experimental Brain Injury.
Brain research. Molecular brain research, 2000Co-Authors: L Zhang, H S Dhillon, S Barron, R R Hicks1, R M Prasad, Kim B. SeroogyAbstract:Previous evidence indicates that both chronic alcohol treatment and traumatic Brain Injury modulate expression of certain neurotrophins and neurotrophin receptors in cortical tissue. However, the combined effects of chronic alcohol and Brain trauma on expression of neurotrophins and their receptors have not been investigated. In the present study, we examined the effects of 6 weeks of chronic ethanol administration on lateral fluid percussion (FP) Brain Injury-induced alterations in expression of mRNAs for the neurotrophin Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, trkB, in rat hippocampus. In both the control- (pair-fed isocaloric sucrose) diet and the chronic ethanol-diet groups, unilateral FP Brain Injury induced a bilateral increase in levels of both BDNF and trkB mRNAs in the dentate gyrus granule cell layer, and of BDNF mRNA in hippocampal region CA3. However, no significant differences in expression were found between the control-diet and ethanol-diet groups, in either the sham-injured or FP-injured animals. These findings suggest that 6 weeks of chronic ethanol administration does not alter the plasticity of hippocampal BDNF/trkB expression in response to Experimental Brain Injury.
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Regional activities of phospholipase C after Experimental Brain Injury in the rat.
Neurochemical research, 1999Co-Authors: H S Dhillon, Heidi M. Carman, Renuka M. PrasadAbstract:Regional activities of phosphoinositide-specific phospholipase C (PLC) were measured after lateral fluid percussion (FP) Brain Injury in rats. The activity of PLC on phosphatidylinositol 4,5-bisphosphate (PIP2) in the rat cortex required calcium, and at 45 μM concentration it increased PLC activity by about ten-fold. The activity of PLC was significantly increased in the cytosol fraction in the injured (left) cortex (IC) at 5 min, 30 min and 120 min after Brain Injury. However, in the same site, increases were observed in the membrane fraction only at 5 min after Brain Injury. In both the contralateral (right) cortex (CC) and ipsilateral hippocampus (IH), the activity of PLC was increased in the cytosol only at 5 min after Brain Injury. These results suggest that increased activity of PLC may contribute to increases in levels of cellular diacylglycerol and inositol trisphosphate in the IC (the greatest site of Injury), and to a smaller extent in the IH and CC, after lateral FP Brain Injury. It is likely that this increased PLC activity is caused by alteration in either the levels or activities of one or more of its isozymes (PLCβ, PLCγ, and PLCδ) after FP Brain Injury.
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Alterations in Brain protein kinase C after Experimental Brain Injury.
Brain research, 1996Co-Authors: B. Padmaperuma, H S Dhillon, R Mark, M P Mattson, M R PrasadAbstract:Regional activities and levels of protein kinase C were measured after lateral fluid percussion Brain Injury in rats. At 5 min and 20 min after Injury, neither cofactor-dependent nor -independent PKC activities in the cytosol and membrane fractions changed in the injured and contralateral cortices or in the ipsilateral hippocampus. Western blot analysis revealed decreases in the levels of cytosolic PKC alpha and PKC beta in the injured cortex after Brain Injury. In the same site, a significant increase in the levels of membrane PKC alpha and PKC beta was observed after Injury. Although the level of PKC alpha did not change and that of PKC beta decreased in the cytosol of the ipsilateral hippocampus, these levels did not increase in the membrane fraction after Injury. The levels of PKC gamma were generally unchanged in the cytosol and the membrane, except for its decrease in the cytosol of the hippocampus. There were no changes in the levels of any PKC isoform in either the cytosol or the membrane of the contralateral cortex after Injury. The present results suggest a translocation of PKC alpha and PKC beta from the cytosol to the membrane in the injured cortex after Brain Injury. The observation that such a translocation occurs only in the Brain regions that undergo substantial neuronal loss suggests that membrane PKC may play a role in neuronal damage after Brain Injury.
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Regional generation of leukotriene C4 after Experimental Brain Injury in anesthetized rats.
Journal of neurotrauma, 1996Co-Authors: H S Dhillon, John M. DoseAbstract:ABSTRACT Regional concentrations of leukotriene C4 and extravasation of Evans blue were measured after lateral fluid-percussion Brain Injury in rats. Tissue levels of LTC4 were elevated in the inju...
Douglas H Smith - One of the best experts on this subject based on the ideXlab platform.
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the sodium channel blocker and glutamate release inhibitor bw1003c87 and magnesium attenuate regional cerebral edema following Experimental Brain Injury in the rat
Journal of Neurochemistry, 2002Co-Authors: Koichi Okiyama, Douglas H Smith, Thomas A Gennarelli, Roger P Simon, Michael Leach, Tracy K McintoshAbstract:Excitatory amino acid (EAA) neurotransmitters may play a role in the pathophysiology of traumatic Injury to the CNS. Although NMDA receptor antagonists have been reported to have therapeutic efficacy in animal models of Brain Injury, these compounds may have unacceptable toxicity for clinical use. One alternative approach is to inhibit the release of EAAs following traumatic Injury. The present study examined the effects of administration of a novel sodium channel blocker and EAA release inhibitor, BW1003C87, or the NMDA receptor-associated ion channel blocker magnesium chloride on cerebral edema formation following Experimental Brain Injury in the rat. Animals (n = 33) were subjected to fluid percussion Brain Injury of moderate severity (2.3 atm) over the left parietal cortex. Fifteen minutes after Injury, the animals received a constant infusion of BW1003C87 (10 mg/kg, i.v.), magnesium chloride (300 mumol/kg, i.v.), or saline over 15 min (2.75 ml/kg/15 min). In all animals, regional tissue water content in Brain was assessed at 48 h after Injury, using the wet weight/dry weight technique. In saline-treated control animals, fluid percussion Brain Injury produced significant regional Brain edema in injured left parietal cortex (p < 0.001), the cortical area adjacent to the site of maximal Injury (p < 0.001), left hippocampus (p < 0.001), and left thalamus (p = 0.02) at 48 h after Brain Injury. Administration of BW1003C87 15 min postInjury significantly reduced focal Brain edema in the cortical area adjacent to the site of maximal Injury (p < 0.02) and left hippocampus (p < 0.01), whereas magnesium chloride attenuated edema in left hippocampus (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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enduring cognitive neurobehavioral and histopathological changes persist for up to one year following severe Experimental Brain Injury in rats
Neuroscience, 1998Co-Authors: Jean E.s. Pierce, Douglas H Smith, John Q. Trojanowski, Tracy K McintoshAbstract:Clinical studies have demonstrated that patients sustain prolonged behavioral deficits following traumatic Brain Injury, in some cases culminating in the cognitive and histopathological hallmarks of Alzheimer's disease. However, few studies have examined the long-term consequences of Experimental traumatic Brain Injury. In the present study, anesthetized male Sprague-Dawley rats (n = 185) were subjected to severe lateral fluid-percussion Brain Injury (n = 115) or sham Injury (n = 70) and evaluated up to one year post-Injury for cognitive and neurological deficits and histopathological changes. Compared with sham-injured controls, Brain-injured animals showed a spatial learning impairment that persisted up to one year post-Injury. In addition, deficits in specific neurologic motor function tasks also persisted up to one year post-Injury. Immunohistochemistry using multiple antibodies to the amyloid precursor protein and/or amyloid precursor protein-like proteins revealed novel axonal degeneration in the striatum, corpus callosum and injured cortex up to one year post-Injury and in the thalamus up to six months post-Injury. Histologic evaluation of injured Brains demonstrated a progressive expansion of the cortical cavity, enlargement of the lateral ventricles, deformation of the hippocampus, and thalamic calcifications. Taken together, these findings indicate that Experimental traumatic Brain Injury can cause long-term cognitive and neurologic motor dysfunction accompanied by continuing neurodegeneration.
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Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after Experimental Brain Injury in the rat
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1996Co-Authors: Jean E.s. Pierce, Douglas H Smith, John Q. Trojanowski, David I. Graham, Tracy K McintoshAbstract:Recent reports suggest a relationship between traumatic Brain Injury and the precocious development of neurodegenerative cascades, including diffuse deposits of beta-amyloid peptides (A beta) in the injured Brain. Because the lateral fluid-percussion (FP) model of Experimental Brain Injury produces clinically relevant neuropathological sequelae in the rat Brain, we used this model together with a series of antibodies specific for amyloid precursor proteins (APPs), APP-like proteins (APLPs), or A beta to identify acute neurodegenerative changes after Brain trauma. Male Sprague-Dawley rats were anesthetized and subjected to lateral FP Brain Injury of moderate to high severity. At 1 hr, 2 hr, 48 hr, 1 week, or 2 weeks after Injury, animals were killed and their Brains were removed for immunohistochemical analysis. APP/APLP immunoreactivity increased in specific Brain regions as early as 1 hr after Injury and persisted for at least 2 weeks. Axons in the thalamus and subcortical white matter showed the greatest APP/APLP accumulation. Injured cortex, striatum, cingulum, and hippocampus also demonstrated significant axonal accumulations of APP/APLP. Accumulation of APP/APLPs occurred primarily ipsilateral to the Injury, although bilateral changes were observed in some Brain regions. No deposition of A beta was observed in any Brain region at any time point examined. These results demonstrate a pattern of widespread axonal pathology after lateral FP Brain Injury in the rat, characterized by intra-axonal accumulations of APP/APLP immunoreactivity in the absence of plaque- like deposits of A beta in the traumatized Brain.
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Characterization of Alterations in the Distribution of Amyloid Precursor Proteins and P-Amyloid Peptide after Experimental Brain Injury in the Rat
1996Co-Authors: Jean E.s. Pierce, John Q. Trojanowski, David I. Graham, Douglas H SmithAbstract:Recent reports suggest a relationship between traumatic Brain Injury and the precocious development of neurodegenerative cascades, including diffuse deposits of p-amyloid peptides (Ap) in the injured Brain. Because the lateral fluid-percussion (FP) model of Experimental Brain Injury produces clinically relevant neuropathological sequelae in the rat Brain, we used this model together with a series of antibodies specific for amyloid precursor proteins (APPs), APP-like proteins (APLPs), or A8 to identify acute neurodegenerative changes after Brain trauma. Male Sprague-Dawley rats were anesthetized and subjected to lateral FP Brain Injury of moderate to high severity. At 1 hr, 2 hr, 48 hr, 1 week, or 2 weeks after Injury, animals were killed and their Brains were removed for immunohistochemical analysis. APP/ APLP immunoreactivity increased in specific Brain regions as early as 1 hr after Injury and persisted for at least 2 weeks. Axons in the thalamus and subcortical white matter showed the greatest APP/APLP accumulation. Injured cortex, striatum, cingulum, and hippocampus also demonstrated significant axonal accumulations of APP/APLP. Accumulation of APP/APLPs occurred primarily ipsilateral to the Injury, although bilateral changes were observed in some Brain regions. No deposition of A8 was observed in any Brain region at any time point examined. These results demonstrate a pattern of widespread axonal pathology after lateral FP Brain Injury in the rat, characterized by intra-axonal accumulations of APP/APLP immunoreactivity in the absence of plaque-like deposits of A/3 in the traumatized Brain.
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Cellular responses to Experimental Brain Injury.
Brain pathology (Zurich Switzerland), 1995Co-Authors: Ramesh Raghupathi, Tracy K. Mclntosh, Douglas H SmithAbstract:Little is known regarding the molecular (genomic) events associated with the pathophysiology of traumatic Brain Injury (TBI). This review focusses on the Experimental efforts to date elucidating the acute alterations in expression of immediate early genes (IEGs), heat shock proteins (HSPs) and cytokines following Experimental Brain Injury. The immediate early genes, c-fos, c-jun and junB were observed to be bilaterally induced in the cortex and hippocampus as early as 5 min following lateral fluid-percussion (FP) Brain Injury in the rat. While levels of c-fos and junB mRNA returned to control levels by 2h, c-jun mRNA remained elevated up to 6h post-Injury. Increased levels of mRNA for the inducible heat-shock protein (hsp72) were observed up to 12h following Injury and were restricted to the cortex ipsilateral to the impact site. Mild induction of the glucose-regulated proteins (grp78 and grp94), which share sequence homology with hsp72, was apparent in the ipsilateral cortex. The cytokines IL-1 beta and TNF alpha were induced at 1h following FP Brain Injury and remained elevated up to 6h post-Injury. These data, while indicative of the complex genomic response to TBI, are also suggestive of the trauma-induced activation of multiple signal transduction pathways.
Niu Guangming - One of the best experts on this subject based on the ideXlab platform.
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Effect of TRH on CBF after the Experimental Brain Injury
Journa of Henan Medical University, 2001Co-Authors: Niu GuangmingAbstract:Aim: To discuss the effect of TRH on the cerebral blood flow during the early phase after the Experimental Brain Injury. Methods :Rabbits heads were hit with free falling object,the hitting energy being 800×80 g·cm.A total of 22 rabbits were randomized into 2 groups:TRH group,10 animals in which,TRH was injected intravenousg 0.5 h after Injury, and every 0.5 h it was repeated at the dosage of 1.0 mg/(ml·kg), until 4 h after the Injury;control group,12 animals weretreated the same way as described above but nor mal saline was used instead. V d, PI, ICP and the water content of Brain constitution were measured with TCD, ICP monitor. Results :①Within 3 h after the Injury, the Vd value of TRH group was markedly higher than that of the control group( P 0.01).②After TRH was applied in the TRH group the increasing rate of ICP decreased, and 1.5 h after the Injury the ICP was much lower than that of the control group. This was still the case 2.5 h after the medication till to the end( P 0.01). ③The water content of Brain tissue was much lower than that of the control group( P 0.01). Conclusion :TRH can increase the velocity of CBF, improve Brain blood flow, lower ICP and reduce Brain edema as well, thus partially reverse the secondary damage due to Brain ischemia.
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Effect of TRH on free radical reaction in the Experimental Brain Injury of rabbits
Journa of Henan Medical University, 2001Co-Authors: Niu GuangmingAbstract:Aim: To investigate the effect of TRH on free radical reactions in Brain tissues after acute Experimental Brain Injury. Methods: The acute Experimental rabbit Brain Injury model was established by direct hit with free falling objects.Thirty rabbits were randomly divided into 3 groups.Group A,the treatment group in which TRH was injected through veins to each rabbit.Group B,the control group in which the equal quantity of normal saline was injected as above.Group C was the sham control group.Rabbits in group A and B were killed 4 h after the Injury.The contents of LPO,water and activity of SOD in Brain tissues were measured. Results: The contents of LPO and water in Brain tissue of group A were lower and the activity of SOD was higher than those of group B( P 0.05).After the Injury ICP rose rapidly and continuously with extending of Injury in group A and B,but after TRH was given to group A ,the rising speed of ICP slowed down significantly( P 0.05). Conclusion: It is suggested that the effects of TRH on Brain Injury are suppression of free radical reaction and decreasing the content of water in Brain tissues.
