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Richard J Traystman

Publications and source records attributed to Richard J Traystman.

At least 19 recordsLinked to original sources
PubMed2006

Recommendations of the National Heart, Lung, and Blood Institute working group on cerebrovascular biology and disease.

The National Heart, Lung, and Blood Institute (NHLBI) convened a conference call working group, consisting of experts in stroke and cerebrovascular biology on January 28, 2005. The purpose of this working group was to develop a prioritized set of recommendations for NHLBI to establish a focused and comprehensive set of research activities in cerebrovascular biology and disease. Three thematic areas of research emerged: (1) molecular and cellular neurobiology of cerebral blood vessels, focusing on genomics and proteomics, neurovascular signaling and cerebrovascular embryogenesis, development and plasticity; (2) resource development, involving the development of new methodological approaches for normal and altered function of the neurovascular unit, collaborative research, and training in cerebrovascular pathobiology; and (3) cerebrovascular diseases and translational approaches, addressing vascular mechanisms of disease, the role of risk factors, importance of biomarkers with the ultimate goal of developing new treatments.

Animals↗
PubMed2006

Differential effect of PARP-2 deletion on brain injury after focal and global cerebral ischemia.

Poly(ADP-ribose) polymerase-2 (PARP-2) is a member of the PARP enzyme family, and, similarly to PARP-1, catalyzes the formation of ADP-ribose polymers in response to DNA damage. While PARP-1 overactivation contributes to ischemic cell death, no information is available regarding the role of PARP-2. In this study, we evaluated the impact of PARP-2 deletion on histopathological outcome from two different experimental models of cerebral ischemia. Male PARP-2-/- mice and wild-type (WT) littermates were subjected to either 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h reperfusion, or underwent 10 mins of KCl-induced cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) and 3-day survival. After MCAO, infarct volume was reduced in PARP-2-/- mice (38%+/-12% of contralateral hemisphere) compared with WT (64%+/-16%). After CA/CPR, PARP-2 deletion significantly increased neuronal cell loss in the hippocampal CA1 field (65%+/-36% ischemic neurons) when compared with WT mice (31%+/-33%), with no effect in either striatum or cortex. We conclude that PARP-2 is a novel executioner of cell death pathways in focal cerebral ischemia, but might be a necessary survival factor after global ischemia to mitigate hippocampal delayed cell death.

Animals↗
PubMed2005

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat.

Glutamine has been shown to influence endothelial-dependent relaxation and nitric oxide production in vitro, possibly by limiting arginine availability, but its effects in vivo have not been well studied. Hyperammonemia is a pathophysiological condition in which glutamine is elevated and contributes to depressed CO(2) reactivity of cerebral arterioles. We tested the hypothesis that acute hyperammonemia decreases pial arteriolar dilation to acetylcholine in vivo and that this decrease could be prevented by inhibiting glutamine synthetase with L-methionine-S-sulfoximine (MSO) or by intravenous infusion of L-arginine. Pial arteriolar diameter responses to topical superfusion of acetylcholine were measured in anesthetized rats before and at 6 h of infusion of either sodium or ammonium acetate. Ammonium acetate infusion increased plasma ammonia concentration from approximately 30 to approximately 600 microM and increased cerebral glutamine concentration fourfold. Arteriolar dilation to acetylcholine was intact after infusion of sodium acetate in groups pretreated with vehicle or with MSO plus methionine, which was coadministered to prevent MSO-induced seizures. In contrast, dilation in response to acetylcholine was completely blocked in hyperammonemic groups pretreated with vehicle or methionine alone. However, MSO plus methionine administration before hyperammonemia, which maintained cerebral glutamine concentration at control values, preserved acetylcholine dilation. Intravenous infusion of L-arginine during the last 2 h of the ammonium acetate infusion partially restored dilation to acetylcholine without reducing cerebral glutamine accumulation. Superfusion of 1 or 2 mM L-glutamine through the cranial window for 1 h in the absence of hyperammonemia attenuated acetylcholine dilation but had no effect on endothelial-independent dilation to nitroprusside. We conclude that 1) hyperammonemia reduces acetylcholine-evoked dilation in cerebral arterioles, 2) this reduction depends on increased glutamine rather than ammonium ions, and 3) increasing arginine partially overcomes the inhibitory effect of glutamine.

Acetylcholine↗
PubMed2005

SOD1 overexpression and female sex exhibit region-specific neuroprotection after global cerebral ischemia due to cardiac arrest.

Cardiac arrest is often associated with poor neurologic outcome since therapeutic options are limited. We tested the hypothesis that overexpression of CuZn superoxide dismutase (SOD+/-) is neuroprotective in a new murine model of cardiac arrest and cardiopulmonary resuscitation (CPR). Second, we investigated if female and male mice sustain similar injury and if sex-specific outcomes are altered by SOD overexpression. Neuronal injury was quantified 3 days after 8 mins of KCl-induced cardiac arrest by calculating the percentage of ischemic neurons for caudoputamen and hippocampal CA1 region. In rostral caudoputamen, less neuronal cell loss was found for SOD+/- mice (31%+/-22%) when compared with wild-type (WT) mice (47%+/-31%, P<0.05). Superoxide dismutase overexpression did not reduce injury in the caudal caudoputamen. No sex-linked protection was evident in either genotype in the caudoputamen. Female WT mice had less CA1 injury than male WT mice (26%+/-31% versus 54%+/-30%, P<0.05), whereas no sex difference was found in SOD+/- mice (female: 42%+/-29%; male: 37%+/-37%). Comparison of hippocampal injury between genotypes revealed no differences for either males or females. In conclusion, SOD1 overexpression and female sex were associated with significant neuroprotection in this murine cardiac arrest model. However, no additive neuroprotection was observed, and these beneficial effects were restricted to specific brain regions.

Animals↗
PubMed2005

Cocaine- and amphetamine-regulated transcript (CART) peptide: a vasoactive role in the cerebral circulation.

Cocaine- and amphetamine-regulated transcript (CART) peptides are known to be involved in the stress response and have been implicated in the regulation of the cardiovascular system. We evaluated the direct vasoactive properties of CART in the cerebral circulation and its potential mechanisms of action. Penetrating cerebral arterioles, isolated from male Sprague-Dawley rats, were cannulated using a concentric micropipette setup, pressurized and perfused. The vascular response to intraluminal and extraluminal CART peptide was characterized. The endothelium dependence of this response was assessed by means of the endothelial light-dye injury model. The nonspecific endothelin receptor antagonist PD-145065, the ET(A)-specific antagonist BQ-123, the ET(B)-specific antagonist BQ-788, and the inhibitor of endothelin-converting enzyme phosphoramidon were used to characterize the involvement of the endothelin pathway in the vascular response to CART peptide. Extraluminal and intraluminal application of CART peptide (0.1 nm to 1 micromol/L) evoked a long-lasting dose-dependent constriction of isolated penetrating cerebral arterioles to approximately 80% of resting myogenic tone. Disruption of the endothelium by the endothelial light/dye injury model resulted in the abolition of this response (P<0.05). Extraluminal administration of PD-145065, BQ-123, and phosphoramidon blocked the constriction response to CART peptide (P<0.01). The ET(B) antagonist, BQ-788, did not alter the constriction response to CART peptide. Cocaine- and amphetamine-regulated transcript peptide is a potent vasoconstrictor in the cerebral circulation. Its direct vasoactive properties are endothelium-dependent and are mediated by ET(A), not ET(B), endothelin receptors.

Animals↗
PubMed2005

Cardiac arrest/cardiopulmonary resuscitation augments cell-mediated immune function and transiently suppresses humoral immune function.

Immune system activation has implications for cerebrovascular health, but little is known about the function of the immune system after a major cerebrovascular event, such as cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Cardiac arrest and cardiopulmonary resuscitation damages the hippocampus, an important component of the hypothalamic-pituitary-adrenal (HPA) axis, and alterations in HPA axis activity can affect immune function. We tested the hypothesis that CA/CPR (approximately 8 mins) would cause HPA axis dysregulation and alter the delayed type hypersensitivity (DTH) response to antigenic challenge. We also assessed the primary and secondary antibody response of mice exposed to CA/CPR. Of the mice exposed to CA/CPR, half had brains protected by hypothermia to isolate the effects of the CA/CPR procedure from the effects of CA/CPR-induced neuronal damage. Cardiac arrest and cardiopulmonary resuscitation-induced neuronal damage resulted in a persistent elevation of blood corticosterone concentration and a concomitant augmentation of the DTH response to antigenic challenge. Furthermore, immune activation before CA/CPR decreased survival after global ischemia. These data highlight the potential impact of neuronal damage on cell-mediated immune function and the role of humoral immune activation in outcome after global ischemia.

Animals↗
PubMed2005

Dose-dependent neuroprotection by 17beta-estradiol after cardiac arrest and cardiopulmonary resuscitation.

OBJECTIVE: Despite recent advances in the treatment of cardiac arrest, neurologic outcome remains poor. 17beta-Estradiol (E2) has been widely shown to reduce damage after experimental brain injury. The present study determined whether E2 also improves neuronal survival after experimental cardiac arrest and cardiopulmonary resuscitation and if any protection is dose-dependent. DESIGN: A randomized trial. SETTING: A research laboratory. SUBJECTS: Male C57Bl/6 mice weighing 20-25 g. INTERVENTIONS: Mice were randomized into one of six groups, receiving treatment with 0.5, 2.5, 12.5, 25, or 50 mug of E2 or vehicle 1.5 mins after return of spontaneous circulation. Ten minutes after induction of cardiac arrest (by KCl injection), cardiopulmonary resuscitation was initiated (with chest compressions, intravenous epinephrine, and ventilation with 100% O2). Additional animals of each E2-treated group were used for plasma estradiol-level analysis. Brains were removed for quantification of injury in the hippocampus and caudoputamen on day 3. MEASUREMENTS AND MAIN RESULTS: The E2 0.5 group had physiologic estrogen levels 60 min after injection (mean +/- se, 28 +/- 5 pg/mL), whereas the E2 50 group still showed supraphysiologic levels 360 min after administration (245 +/- 32 pg/mL). Hippocampal damage was not altered with E2 treatment. Only posttreatment with the lowest E2 dose (E2 0.5) resulted in attenuated neuronal injury in the rostral and caudal caudoputamen (34 +/- 11% and 27 +/- 11%), in comparison with vehicle (68 +/- 5, p < .05; 63 +/- 4%, p < .001). Higher E2 doses did not affect brain injury. CONCLUSIONS: We conclude that E2 has a critical dosing effect on neuronal survival, physiologic levels of E2 are neuroprotective after cardiac arrest/cardiopulmonary resuscitation, and acute exposure is sufficient for brain resuscitation.

Animals↗
PubMed2004

Histopathological and behavioral characterization of a novel model of cardiac arrest and cardiopulmonary resuscitation in mice.

Cardiac arrest is associated with high mortality and poor neurological outcome. We characterized functional and histological outcome in a novel mouse model of cardiac arrest and cardiopulmonary resuscitation (CPR) in order to study neuroprotective mechanisms. Cardiac arrest was induced in male C57Bl/6 and 129SVEV mice by i.v. injection of KCl. After 10 min cardiac standstill, CPR was initiated by administration of epinephrine, ventilation with 100% oxygen and chest compressions. Twenty-four hours before and 3 or 7 days after CPR, mice were subjected to behavioral testing using a passive avoidance task, locomotor activity in an open field, and spontaneous alternation in a T-maze. Hippocampal and caudoputamen injury was quantified 3 or 7 days after CPR. At both time points, caudoputamen injury was worse in 129SVEV mice. Post-ischemic mice of both strains showed a reduced number of correct choices in the T-maze up to 7 days after CPR, and were temporarily impaired in learning the passive avoidance task with a retention deficit on day 3 but not on day 7. Locomotor activity showed strain differences with C57Bl/6 mice being more active, but little ischemia-related effects. A dissociation between functional and histological outcome was found emphasizing the importance of combining both outcome measures for evaluation of neuroprotective strategies.

Animals↗
PubMed2004

Non-classical regulation of estrogen receptor-alpha by ICI182,780.

Estrogen receptor-alpha (ER alpha) regulates transcription through a number of molecular mechanisms. Two mechanisms by which ER alpha acts directly in the nucleus have emerged: (1) in classical ER alpha action, estrogen-bound receptor binds estrogen response elements (ERE) and regulates promoters by recruiting coactivators or corepressors to DNA; (2) non-classical action is not dependent on ER alpha binding to EREs; its mechanism is not as clearly defined as classical action. In many instances, non-classical action is mediated by tethering of ER alpha to other DNA-binding proteins, facilitating recruitment of coregulators to transcription regulatory sequences. In some cell types, non-classical stimulation can be enhanced by antagonists and repressed by agonists of ER alpha. Here, we show that non-classical action of ER alpha in 293 cells occurs in a wide range of enhancers and enhancer binding proteins. ER alpha stimulates AP-1 elements, cyclic AMP response elements (CRE), and serum response elements (SRE) in the presence of the antiestrogen ICI182,780. Further, in the presence of ICI182,780, ER alpha stimulates activation domains of Jun, ATF-2, Elk, and CRE-binding protein (CREB). Non-classical ER alpha regulation described here does not appear to be sensitive to point mutations which affect classical and tethered ER alpha action; moreover, in our experiments, non-classical action is uniquely sensitive to nuclear transport inhibition by leptomycin B. Because ICI182,780 appears to affect multiple and diverse transcriptional systems, our results are likely explained by ER alpha-dependent modulation of common components of the transcriptional machinery and may not be completely explained by tethering of ER alpha to specific transcription factors.

Cell Line↗
PubMed2004

Cardiac arrest/cardiopulmonary resuscitation increases anxiety-like behavior and decreases social interaction.

Advances in medical technology have increased the number of individuals who survive cardiac arrest/cardiopulmonary resuscitation (CPR). This increased incidence of survival has created a population of patients with behavioral and physiologic impairments. We used temperature manipulations to characterize the contribution of central nervous system damage to behavioral deficits elicited by 8 minutes of cardiac arrest/CPR in a mouse model. Once sensorimotor deficits were resolved, we examined anxiety-like behavior with the elevated plus maze and social interaction with an ovariectomized female. We hypothesized that anxiety-like behavior would increase and social interaction would decrease in mice subjected to cardiac arrest/CPR and that these changes would be attributable to central nervous system damage rather than damage to peripheral organs or changes orchestrated by the administration of epinephrine. Mice that were subjected to cardiac arrest/CPR while the peripheral organs, but not the brain, were protected by hypothermia exhibited increased anxiety-like behavior and decreased social interaction, whereas mice with hypothermic brains and peripheral organs during cardiac arrest/CPR did not exhibit behavioral impairments. The present study demonstrates that central nervous system damage from cardiac arrest/CPR results in increased anxiety and decreased social interaction and that these behavioral changes are not attributed to underlying sensorimotor deficits, dynamics of arrest and CPR, or peripheral organ damage.

Animals↗
PubMed2004

Experimental spinal cord ischemia: model characterization and improved outcome with arterial hypertension.

OBJECTIVE: Paraplegia from spinal cord ischemia is a devastating complication of thoracoabdominal aortic aneurysm repair. Perioperative hypoperfusion of the spinal cord is a critical determinant of residual neurologic deficits. We determined if functional and histologic outcome is dependent on systemic blood pressure in a rat model of spinal cord ischemia. DESIGN: Randomized, controlled, prospective study. SETTING: Research laboratory at a university teaching hospital. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Endotracheally intubated adult male Wistar rats (300-450 g) anesthetized with halothane underwent a thoracotomy and placement of a clip across the descending aorta for 27 mins. Mean proximal arterial blood pressure (MPABP) was monitored with a cannula placed in the left common carotid artery. Halothane was adjusted (1.25-1.5%) to maintain MPABP between 70 and 90 mm Hg (n = 20) or 140 and 150 mm Hg (n = 20). Shamoperated rats (n = 10) had a thoracotomy without aortic clamping at an MPABP of 70-90 mm Hg. Following 1, 24, 48, and 72 hrs of recovery from anesthesia, motor function of the hind paws was scored as follows: 0, no evidence of deficit; 1, toes flat under body when walking but with ataxia; 2, knuckle walks; 3, movements in hind limbs but unable to knuckle walk; 4, no movement, drags hind limbs. Body temperature was maintained between 37 and 38 degrees C throughout the experiment. MEASUREMENTS AND MAIN RESULTS: All sham operated rats with MPABP 70-90 mm Hg recovered without neurologic deficits, whereas those that underwent aortic occlusion with MPABP between 70 and 90 mm Hg emerged from anesthesia with grade 3 and 4 deficits and remained in this condition without improvement at 72 hrs. Histopathology at 72 hrs demonstrated moderate to severe neuronal loss with involvement of dorsal, intermediate, and ventral horns. Only eight of 20 rats that underwent aortic occlusion with MPABP between 140 and 150 mm Hg had grade 1 and 2 deficits on emergence but had no neurologic deficit after 1 hr. Most of the surviving neurons in these animals appeared normal histologically, particularly motor neurons around the periphery of the ventral horn. CONCLUSIONS: Systemic blood pressure is a critical determinant of outcome following spinal cord ischemia, and controlled peri-operative blood pressure augmentation may ameliorate neurologic deficits in patients who undergo thoracoabdominal vascular procedures and are at risk for spinal cord hypoperfusion.

Animals↗
PubMed2004

Cardiac arrest with cardiopulmonary resuscitation reduces dendritic spine density in CA1 pyramidal cells and selectively alters acquisition of spatial memory.

The hippocampus is highly sensitive to ischemia and is one of the most extensively damaged regions of brain during cardiac arrest. Damage to hippocampus can subsequently lead to learning and memory deficits. The current study used the Morris water maze to characterize spatial learning and memory deficits elicited by 8 min of cardiac arrest with cardiopulmonary resuscitation (CA/CPR) in mice, which is associated with a 25-50% decrease in CA1 neurons. Mice were trained to navigate the water maze prior to CA/CPR or sham surgery (SHAM). They were retested in the water maze on days 7 and 8 postsurgery; both CA/CPR and SHAM groups were able to perform the task at presurgical levels. However, when the hidden platform was moved to a new location, the SHAM mice were able to adapt more quickly to the change and swam a shorter distance in search of the platform than did CA/CPR mice. Thus, CA/CPR did not affect the ability of mice to retain a previously learned platform location, but it did affect their ability to learn a new platform location. This behavioural impairment was correlated with dendritic spine density in the CA1 region of the hippocampus. Data presented here suggest that morphological changes, such as spine density, that occur in neurons that survive CA/CPR may be associated with cognitive impairments.

Animals↗
PubMed2003

Membrane restraint of estrogen receptor alpha enhances estrogen-dependent nuclear localization and genomic function.

Estrogen receptor (ER) alpha localizes to both the nucleus and the plasma membrane, mediating estrogen-dependent genomic and nongenomic signaling, respectively. In some cells, ERalpha appears to be excluded from the nucleus, and it is unclear whether genomic signaling takes place. The purpose of this study was to determine whether membrane-associated ERalpha is capable of genomic signaling, or whether this pool of receptors strictly serves membrane-mediated signaling. ERalpha fused to the C-terminal cytoplasmic tail of bovine rhodopsin (Rh-ERalpha) activates ER response element-dependent transcription only in the presence of estrogen; the activity is antagonized by the estrogen antagonist ICI 182,780 and by the dominant-negative mutant of ERalpha and is unaffected by inhibitors of MAPKs and Akt signaling, indicating that this was due to direct genomic action. The activity of Rh-ERalpha containing the activating Y537S mutation was also estrogen dependent, suggesting that estrogen gated the entry of Rh-ERalpha into the nucleus. Indeed, cell fractionation studies demonstrated that Rh-ERalpha protein, in contrast to ERalpha that was nuclear at baseline, was excluded from the nucleus in the absence of hormone, and localized to the inner nuclear membrane on incubation with estrogen. These data demonstrate that membrane tethered ERalpha is capable of nuclear function and that its transcriptional activity is regulated by hormone-dependent entry into the inner nuclear membrane. Furthermore, these experiments provide evidence that under certain circumstances, membrane proteins are capable of nuclear function without detectable nucleoplasmic localization.

5' Untranslated Regions↗
PubMed2003

Neurite-localized estrogen receptor-alpha mediates rapid signaling by estrogen.

Classically, estrogen acts on cells by directly activating gene transcription driven by ligand-bound nuclear estrogen receptors (ER). Accumulating evidence demonstrates that estrogen acts on neurons by utilizing diverse molecular mechanisms, including rapid signaling by proteins localized to the plasma membrane. Recent studies showing that ERalpha localizes to axons and dendrites of hippocampal neurons suggest that nonnuclear stores of the receptor may transduce estrogen signaling. Here, we have studied the subcellular localization, dynamic regulation, and function of ERalpha in mouse cortical neurons. Estrogen-stimulated mouse cortical neurons activate both estrogen response element (ERE) stimulated transcription and rapid activation of p44/42 mitogen-activated protein kinases (MAPK). We demonstrate that green fluorescent protein (GFP)-tagged ERalpha localizes to neurites in cultured cortical neurons and that the expression within neurites can be down-regulated by estrogen or up-regulated by antiestrogen administered during synthesis. Neurite ERalpha appears to be directed to neurites directly from its site of translation and not from nuclear stores. By using confocal microscopy, we show that ERalpha within neurites stimulates local activation of p44/42 MAP kinases in response to estrogen. We conclude that hormonal status alters subcellular ERalpha targeting in cortical neurons and that neurite-expressed ERalpha is important in the activation of local MAPK signaling.

Animals↗
PubMed2003

Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI.

In the past decade, it has become possible to use the nuclear (proton, 1H) signal of the hydrogen atoms in water for noninvasive assessment of functional and physiological parameters with magnetic resonance imaging (MRI). Here we show that it is possible to produce pH-sensitive MRI contrast by exploiting the exchange between the hydrogen atoms of water and the amide hydrogen atoms of endogenous mobile cellular proteins and peptides. Although amide proton concentrations are in the millimolar range, we achieved a detection sensitivity of several percent on the water signal (molar concentration). The pH dependence of the signal was calibrated in situ, using phosphorus spectroscopy to determine pH, and proton exchange spectroscopy to measure the amide proton transfer rate. To show the potential of amide proton transfer (APT) contrast for detecting acute stroke, pH effects were noninvasively imaged in ischemic rat brain. This observation opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, as diagnostic tools in clinical imaging.

Animals↗