Biomedical subjects

P D Hurn

Publications and source records attributed to P D Hurn.

At least 19 recordsLinked to original sources

PubMed2006

Mechanism of progesterone neuroprotection of rat cerebellar Purkinje cells following oxygen-glucose deprivation.

The survival of rat Purkinje cell (PCs) cerebellar cultures was used to test the hypothesis that progesterone is protective against oxygen-glucose deprivation through potentiation of GABA(A) receptor activity. Electrophysiological recordings confirm that PCs develop robust excitatory and inhibitory synapses in culture. Exposure of cultured PCs to increasing concentrations of progesterone during oxygen-glucose deprivation revealed a concentration-dependent protection by progesterone, with significant protection observed at physiological concentrations, as low as 10 nm. The concurrent application of the GABA(A) receptor antagonist picrotoxin (100 microm) completely abolished the neuroprotection afforded by progesterone, indicating that progesterone is neuroprotective through activation of GABA(A) receptors. Progesterone potentiates GABA(A) receptor activity indirectly through its metabolites, such as allopregnanolone (ALLO). Therefore, ALLO was applied to PC cultures and was observed to produce significant protection at all concentrations tested, from 10 to 1000 nm. Finally, the inhibition of progesterone metabolism with finasteride abolished the protection afforded by progesterone without having any effect on the neuroprotection caused by ALLO. These data indicate that progesterone protects cerebellar PCs at physiological concentrations through a GABA-active metabolite.

Animals↗

PubMed2004

Cytochrome P450 in neurological disease.

Advances in a multitude of disciplines support an emerging role for cytochrome P450 enzymes and their metabolic substrates and end-products in the pathogenesis and treatment of central nervous system disorders, including acute cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such as Alzheimer's and Parkinson's disease, as well as epilepsy, multiple sclerosis and psychiatric disorders, including anxiety and depression. The neural tissue contains its own unique set of P450 genes that are regulated in a manner that is distinct from their molecular regulation in peripheral tissue. Furthermore, brain P450s catalyze the formation of important brain signaling molecules, such as neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics and environmental neurotoxins. These unique characteristics allow this family of proteins and their metabolites to perform such vital functions in brain as neurotrophic support, neuroprotection, control of cerebral blood flow, temperature control, neuropeptide release, maintenance of brain cholesterol homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter levels and other functions important in brain physiology, development and disease.

Anesthetics↗

PubMed2002

Physiological and pathological caspase cleavage of the neuronal RasGEF GRASP-1 as detected using a cleavage site-specific antibody.

Caspases are proteases involved in various physiological and pathological processes in the nervous system, including development and pathogenesis. GRASP-1 is a recently identified neuronal substrate of caspase-3-subfamily caspases. It is a Ras-guanine nucleotide exchange factor (RasGEF) that interacts with the glutamate receptor interacting protein (GRIP). This alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor/GRIP protein complex has been proposed to be involved in AMPA receptor synaptic targeting. The caspase-3 cleavage of GRASP-1 separates the N-terminal RasGEF catalytic domain from the C-terminal GRIP-interacting region, potentially disrupting regulation of the RasGEF activity by GRIP. To examine the regulation and regional distribution of the caspase-3 cleavage of GRASP-1 in vivo, we generated a cleavage site-specific antibody, termed CGP, against the cleaved N-terminal fragment of GRASP-1. Using this antibody, we have examined the caspase cleavage of GRASP-1 during postnatal development and following ischemia in mice. We found that caspase cleavage of GRASP-1 occurs in specific brain regions in a time-dependent manner during development and ischemia. This data provides an important account of the brain areas that might require caspase-3 activity in postnatal development and ischemic damage, which has not been documented. It also demonstrates that the CGP antibody is a powerful tool for studying neuronal activity of the caspase-3-subfamily caspases in vivo.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Selective estrogen receptor modulators: tissue actions and potential for CNS protection.

Significant physiologic changes occur during menopause. Evidence exists to suggest that estrogen may be neuroprotective under specific conditions. However, there are limitations in the neuroprotection afforded by standard hormone therapy. Accordingly, alternative agents with selected estrogenic effects may hold even greater promise rather than conventional hormone replacement therapy for the prevention and treatment of CNS injury. Recently, a variety of selective estrogen receptor modulators (SERMs) have been developed to retain the favorable and minimize the adverse side effects of estrogens. This review focuses on the CNS and known neuroprotective effects of two specific SERMs, raloxifene and arzoxifene. Recent studies hint that raloxifene and arzoxifene are neuroprotective and may preserve some elements of cognitive function. However, the mechanism of action is not well described and it is unclear if the beneficial effects of SERMs rely on activation of estrogen receptors.

Animals↗

PubMed2001

Female gender exacerbates respiratory depression in leptin-deficient obesity.

Obese females are less predisposed to sleep-disordered breathing and have higher serum leptin levels than males of comparable body weight. Because leptin is a powerful respiratory stimulant, especially during sleep, we hypothesized that the elevated leptin level is necessary to maintain normal ventilatory control in obese females. We examined ventilatory control during sleep and wakefulness in male and female leptin-deficient obese C57BL/6J-Lep(ob) mice, wild-type C57BL/6J mice with dietary-induced obesity and high serum leptin levels, and normal weight wild-type C57BL/6J mice. Both male and female C57BL/6J-Lep(ob) mice had depressed hypercapnic ventilatory response (HCVR) in comparison with wild-type animals. In comparison with male C57BL/6J-Lep(ob) mice, female C57BL/6J-Lep(ob) mice had reduced HCVR and respiratory drive (a ratio of tidal volume to inspiratory time) both during non-rapid eye movement (NREM) sleep and wakefulness. In contrast, the HCVR did not differ between sexes in wild-type mice during NREM sleep and wakefulness, but was lower in females during REM sleep. Thus, leptin deficiency in female obesity is even more detrimental to hypercapnic ventilatory control during wakefulness and NREM sleep than in obese, leptin-deficient males.

Animals↗

PubMed2001

Estrogen and Bcl-2: gene induction and effect of transgene in experimental stroke.

Female rodents producing endogenous estrogens are protected from stroke damage in comparison with male counterparts. This natural protection is lost after ovariectomy or reproductive senescence. The aim of this study is to determine whether estrogen reduces early neuronal injury and cell loss after ischemia by increasing the expression of Bcl-2. Male, intact female, ovariectomized, and estrogen-repleted ovariectomized rats were subjected to middle cerebral artery occlusion, and 22 hr later the level and localization of Bcl-2 mRNA and protein were determined. The levels of post-ischemic bcl-2 mRNA and protein were increased exclusively in neurons within the peri-infarct region. Intact females and estrogen-treated castrates demonstrated increased bcl-2 mRNA and protein expression compared with males and estrogen-deficient females, accompanied by a decrease in infarct size. To test the hypothesis that the neuroprotective mechanism of estrogen functions via Bcl-2, we compared ischemic outcome in male, female, and ovariectomized wild-type mice and mice overexpressing Bcl-2 exclusively in neurons. Wild-type female mice sustained smaller infarcts compared with males. Bcl-2 overexpression reduced infarct size in males, but provided no added protection in the female. Moreover, ovariectomy exacerbated infarction in wild-type females, but had no effect in Bcl-2 overexpressors. These data indicate that overexpression of Bcl-2 simulates the protection against ischemic injury conferred by endogenous female sex steroids. We concluded that estrogen rescues neurons after focal cerebral ischemia by increasing the level of Bcl-2 in peri-infarct regions and that estrogen-induced bcl-2 gene expression is an important downstream component of neuronal protection in female stroke.

Animals↗

PubMed2001

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression.

The relationship between stressful life events and the onset of disease is well documented. However, the role of psychological stress as a risk factor for life-threatening cerebrovascular insults such as stroke remains unspecified, but could explain individual variation in stroke outcome. To discover the mechanisms through which psychological stress may alter stroke outcome, we modeled the effects of chronic social intimidation and stress on ischemia-induced bcl-2 expression and early neuronal cell loss resulting from cerebral artery occlusion in mice (C57BL/6). The bcl-2 protooncogene promotes cell survival and protects against apoptosis and cellular necrosis in numerous neurodegenerative disorders, including stroke. In our study, male mice were chronically exposed to aggressive social stimuli before induction of a controlled, mild ischemic insult. Stressed mice expressed approximately 70% less bcl-2 mRNA than unstressed mice after ischemia. In addition, social stress greatly exacerbated infarct in wild-type mice but not in transgenic mice that constitutively express increased neuronal bcl-2. Despite similar postischemic concentrations of corticosterone, the major stress hormone in mice, high corticosterone concentrations were significantly correlated with larger infarcts in wild-type mice but not bcl-2 transgenic mice. Thus, enhanced bcl-2 expression offsets the potentially deleterious consequences of high postischemic plasma corticosterone concentrations. Taken together, these data demonstrate that stressful prestroke social milieu strongly compromises an endogenous molecular mechanism of neuroprotection in injured brain and offer a new behavioral target for stroke therapy.

Animals↗

PubMed2001

Deleterious effect of beta-estradiol in a rat model of transient forebrain ischemia.

Estrogen has demonstrated great potential as a therapeutic agent in focal ischemic brain injury, as exogenous beta-estradiol has proven beneficial in a variety of focal stroke models. In contrast, the relatively few studies of estrogen's efficacy in transient forebrain ischemia have produced inconsistent results. The present study was therefore designed to clarify estrogen's neuroprotective potential in selective hippocampal neuronal injury resulting from four-vessel occlusion in the rat. Female Wistar rats (normal, ovariectomized, or ovariectomized and estradiol-treated) received 5 or 10 min of ischemia. No differences in hippocampal cell loss were found amongst the groups with 10 min of ischemia. Amongst the groups with 5 min of ischemia, the mildest injury was found in the ovariectomized animals, which lost only 32% of their CA1 pyramidal cells. In comparison, mean cell losses were 54% and 49%, respectively, in intact females and in ovariectomized animals with estradiol replacement. Linear regression analysis demonstrated a highly significant relationship between cell loss and plasma estradiol levels. The mechanism by which exogenous and endogenous estrogen exacerbated the injury is unclear, as estrogen has many neuroprotective effects. On the other hand, many other reported effects of estrogen in hippocampal area CA1 might confer increased sensitivity to ischemia, either by modulating the excitatory effects of glutamate or by modifying the inhibitory effects of GABA. Determining how to modulate the various competing effects of estrogen is of both theoretical and practical importance, as it is now clear that one cannot assume that estrogen administration will always improve outcome in cerebral ischemia.

Animals↗

PubMed2001

Rapid three-dimensional diffusion MRI facilitates the study of acute stroke in mice.

MRI studies using mouse brain models of ischemia are becoming a valuable tool for understanding the mechanism of stroke, since transgenic models are now available. However, the small size of the mouse brain and the surgical complexity of creating ischemia in mice make it technically challenging to obtain high-quality MRI data. Therefore, there are few reports of MRI studies in murine cerebral ischemia. In this project a newly developed rapid 3D diffusion-weighted imaging (DWI) technique was applied to study experimental stroke in a mouse model of reversible middle cerebral artery occlusion (MCAO). Ischemic volumes were successfully delineated using this 3D whole-brain imaging technique with high spatial (0.34 x 0.5 x 1.0 mm(3) before zero-filling) and temporal (7 min) resolution. The 3D observation revealed the characteristic evolution of stroke after transient MCAO. There was a temporarily high diffusion constant in the cortex during early reperfusion, followed by a secondary energy failure in the cortex and caudate-putamen at 6 and 21 h of reperfusion. Magn Reson Med 46:183-188, 2001.

Animals↗

PubMed2001

Cognitive and behavioral assessment in experimental stroke research: will it prove useful?

Stroke in humans is associated with deficits in sensorimotor and cognitive function. Consequently, many stroke researchers recently have expanded their techniques to assess cognitive and behavioral correlates of histologically-determined stroke damage in animal models. Although the incorporation of functional outcome assessment represents an important step forward in stroke research, reports of middle cerebral artery occlusion (MCAO) induced behavioral deficits often conflict, and a significant correlation between post-stroke histology and behavior has been reported in few stroke studies. Discrepancies in behavioral outcomes among studies may be due to several factors, such as method of MCAO, duration of occlusion, strain, the timing and method of the behavioral testing and the laboratory environment. Furthermore, proper experimental and control groups, necessary to rule out potential confounding factors during cognitive testing, often are not incorporated. The goal of this review is: (1) to provide a description of the techniques most commonly employed to assess functional outcome after (MCAO) in rodents and (2) to identify potential confounding factors that may interfere with a clear interpretation of the behavioral data.

Animals↗

PubMed2001

Experimental stroke in the female diabetic, db/db, mouse.

Diabetic hyperglycemia increases brain damage after cerebral ischemia in animals and humans, although the underlying mechanisms remain unclear. Gender-linked differences in ischemic tolerance have been described but have not been studied in the context of diabetes. In the current study, we used a model of unilateral common carotid artery ligation, combined with systemic hypoxia, to study the effects of diabetes and gender on hypoxic-ischemic (HI) brain damage in the genetic model of Type II diabetes, the db/db, mouse. Male and female, control and db/db, mice were subjected to right common carotid artery ligation followed by varying periods of hypoxia (8% oxygen/92% nitrogen) to assess mortality, infarct volume, and tissue damage by light microscopic techniques. End-ischemic regional cerebral blood flow (CBF) was determined using [14C] iodoantipyrine autoradiography. Glycolytic and high energy phosphate compounds were measured in blood and brain by enzymatic and fluorometric techniques. Gender and diabetes had significant effects on mortality from HI and extent of brain damage in the survivors. Female mice were more resistant than their male counterparts, such that the severity (mortality and infarction size) in the male diabetics > female diabetics - male controls > female controls. Endischemic CBF and depletion of cerebral high energy reserves were comparable among all groups. Surprisingly, female diabetic mice were more hyperglycemic and demonstrated a greater prolonged lactacidosis than the males; however, they were more resistant to damage. The results suggest a unique pathophysiology of hypoxia-ischemia in the female diabetic brain.

Animals↗

PubMed2001

Estrogen restores postischemic pial microvascular dilation.

Estrogen protects the brain from experimental cerebral ischemia, likely through both vascular and neuronal cellular mechanisms. The purpose of this study was to determine whether chronic estrogen treatment in males and repletion in ovariectomized (Ovx) females reverses abnormalities in pial arteriolar reactivity during reperfusion from global forebrain ischemia (4-vessel occlusion, 15 min) and whether the site of protection is vascular endothelium. Male and Ovx female rats were implanted with either placebo or a 25-microg 17 beta-estradiol pellet 10 days before ischemia. With the use of intravital microscopy, pial vessel dilation to ACh (10 microM) and S-nitroso-N-acetyl-penicillamine (SNAP; 1 microM) and vasoconstriction to serotonin (10 microM) was examined in situ at 30--60 min of reperfusion. Postischemic changes in vessel diameter were compared with preischemic values for each agent. Postischemic response to both ACh and SNAP was lost in males and Ovx females, but not in estrogen pellet-implanted males and estrogen-implanted Ovx females, suggesting that estrogen protects both endothelial and smooth muscle-mediated vasodilation. Ischemia blunted vessel constriction to serotonin regardless of treatment. These data demonstrate that estrogen acts as a vasoprotective agent within the cerebral circulation and can improve microvascular function under conditions of an acutely evolving ischemic pathology.

Acetylcholine↗

PubMed2001

Anticonvulsant lamotrigine administered on reperfusion fails to improve experimental stroke outcomes.

BACKGROUND AND PURPOSE: Recent results suggest that selective inhibitors of presynaptic neuronal ion channels can diminish glutamate release during cerebral ischemia and modulate excitotoxic cell death. The aim of the present study was to evaluate lamotrigine (LTG), an antiepileptic that inhibits presynaptic sodium and voltage-sensitive calcium channels, as a potential stroke resuscitation agent in the rat. Three dosages of LTG were examined for effect on infarction volume and sensorimotor behavioral recovery after middle cerebral artery (MCA) occlusion. METHODS: Halothane-anesthetized male Wistar rats were subjected to 2 hours of MCA occlusion by the intraluminal occlusion technique. Physiological variables were controlled, and ipsilateral cortical perfusion was monitored by laser Doppler flowmetry throughout ischemia. At onset of reperfusion, rats received intravenous LTG 5, 10, or 20 mg/kg or PBS (n=9 to 11 per group) during 15 minutes. Behavioral assessment was completed at 3 and 7 days after stroke, and the brain was harvested for histology (triphenyltetrazolium chloride staining). RESULTS: Values are mean+/-SE. Cortical infarction volumes were unchanged in LTG-treated animals: 14+/-6% of contralateral cortex at 5 mg/kg LTG, 17+/-7% at 10 mg/kg, and 30+/-6% at 20 mg/kg, versus saline-treated cohorts (12+/-3%; P:=0.19; n=9). Caudate-putamen infarction injury was also unchanged (37+/-11% of contralateral caudate-putamen at 5 mg/kg LTG, 44+/-8% at 10 mg/kg, and 65+/-9% at 20 mg/kg versus saline (38+/-11%; P:=0.18). Total infarction was not different among groups (P:=0.15). Consistent with histology, behavioral outcomes were unimproved by treatment. CONCLUSIONS: Histological damage and behavioral recovery at 7 days after MCA occlusion was not altered by LTG treatment over the dosage range used in the present study.

Animals↗

PubMed2001

Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke.

BACKGROUND AND PURPOSE: Estrogen is a known neuroprotective and vasoprotective agent in experimental cerebral ischemia. Preischemic steroid treatment protects animals of both sexes from focal cerebral ischemia. This study determined whether intravenous estrogen acts as a vasodilator when administered on reperfusion and whether the resulting increase in cerebral blood flow (CBF) provides tissue protection from middle cerebral artery occlusion. METHODS: Adult male Wistar rats were treated with reversible middle cerebral artery occlusion (2 hours), then infused with intravenous estrogen (Premarin; 1 mg/kg) or vehicle during the first minutes of reperfusion (n=15 per group). Cortical laser-Doppler flowmetry was used to assess adequacy of occlusion. Ischemic lesion volume was determined at 22 hours after occlusion by 2,3,5-triphenyltetrazolium chloride staining and image analysis. Cortical and striatal CBF was measured by (14)[C]iodoantipyrine autoradiography at 10 (n=10) or 90 (n=11) minutes of reperfusion. RESULTS: As expected, supraphysiological plasma estrogen levels were achieved during reperfusion (estrogen, 198+/-45 pg/mL; vehicle, 6+/-5; P:=0.001). Physiological variables were controlled and not different between groups. Total hemispheric infarction was reduced in estrogen-treated rats (estrogen, 49+/-4% of ipsilateral structure; vehicle, 33+/-5%; P:=0.02), which was most pronounced in striatum (estrogen, 40+/-6% of ipsilateral striatum; vehicle, 60+/-3%; P:=0.01). CBF recovery was strikingly increased by estrogen infusion at 10 minutes in frontal (estrogen, 102+/-12 mL/100 g per minute; vehicle, 45+/-15; P:=0.01) and parietal cortex (estrogen, 74+/-15 mL/100 g per minute; vehicle, 22+/-13; P:=0.028) and throughout striatum (estrogen, 87+/-13 mL/100 g per minute; vehicle, 25+/-20; P:=0.02). Hemispheric volume with low CBF recovery (eg, <20 mL/100 g per minute) was smaller in estrogen-treated animals (estrogen, 73+/-18 mm(3); vehicle, 257+/-46; P:=0.002). However, differences in CBF recovery could not be appreciated between groups by 90 minutes of reperfusion. CONCLUSIONS: Acute estrogen therapy during reperfusion improves tissue outcome from experimental stroke. The steroid rapidly promotes CBF recovery and reduces hemispheric no-reflow zones. This beneficial effect appears only during early reperfusion and likely complements other known mechanisms by which estrogen salvages brain from focal necrosis.

Animals↗

PubMed2001

Neuroprotective effect of sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production.

BACKGROUND AND PURPOSE: The potent final sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) provides neuroprotection in experimental stroke. We tested the hypothesis that PPBP attenuates striatal tissue damage after middle cerebral artery occlusion (MCAO) by a mechanism involving reduction of ischemia-evoked nitric oxide (NO) production. Furthermore, we determined whether the agent fails to protect ischemic brain when neuronal nitric oxide synthase (nNOS) is genetically deleted or pharmacologically inhibited (selective nNOS inhibitor, 7-nitroindazole [7-NI]). METHODS: Halothane-anesthetized adult male Wistar rats were subjected to 2 hours of MCAO by the intraluminal filament occlusion technique. All physiological variables were controlled during the ischemic insult. In vivo striatal NO production was estimated via microdialysis by quantification of local, labeled citrulline recovery after labeled arginine infusion. In a second series of experiments, nNOS null mutants (nNOSKOs) and the genetically matched wild-type (WT) strain were treated with 90 minutes of MCAO. Brains were harvested at 22 hours of reperfusion for measurement of infarction volume by triphenyltetrazolium chloride histology. RESULTS: PPBP attenuated infarction volume at 22 hours of reperfusion in cerebral cortex and striatum and markedly attenuated NO production in ischemic and nonischemic striatum during occlusion and early reperfusion. Treatment with 7-NI mimicked the effects of PPBP. In WT mice, infarction volume was robustly decreased by both PPBP and 7-NI, but the efficacy of PPBP was not altered by pharmacological nNOS inhibition in combined therapy. In contrast, PPBP did not decrease infarction volume in nNOSKO mice. CONCLUSIONS: These data suggest that the mechanism of neuroprotection of PPBP in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of PPBP are lost when nNOS is not present or is inhibited; therefore, PPBP likely acts upstream from NO generation and its subsequent neurotoxicity.

Animals↗

PubMed2001

Anesthetic choice of halothane versus propofol: impact on experimental perioperative stroke.

BACKGROUND AND PURPOSE: It is not known whether preischemic exposure to anesthetic agents affects the amount of damage from transient focal ischemia that occurs after cessation of the anesthetic. We compared the effect of prior exposure to halothane or propofol on infarction size after transient middle cerebral artery occlusion (MCAO) induced in the awakening animal to test the hypothesis that anesthetic type and exposure duration would independently affect the amount of brain injury. METHODS: Male Wistar rats (weight, 200 to 300 g) were anesthetized briefly with halothane for placement of hemodynamic instrumentation. Twenty-four hours later, rats were treated with either a short (approximately 1 hour) or long (8 hours) duration of inhaled halothane (1% to 2%) or intravenous propofol (10 mg/kg bolus, 30 mg/kg per hour infusion). Each cohort (n=8 per group) was then subjected to 2-hour MCAO by the intraluminal suture technique. All anesthesia was discontinued once MCAO was achieved. Infarct volume was measured at 22 hours of reperfusion. In a second cohort, regional cerebral blood flow (CBF) was measured ([(14)C]iodoantipyrine autoradiography) at end-occlusion in short-duration halothane (n=5) or short-duration propofol (n=5) anesthesia groups and in corresponding surgical shams (n=3 each). RESULTS: Pericranial temperature, PaO(2), PaCO(2), and blood pressure were controlled and not different among groups before or during occlusion. MCAO resulted in a similar immediate reduction in laser-Doppler flow signal after discontinuation of anesthesia in the awakening animals. Infarct volume was smaller in rats exposed to short-duration halothane in cortex (87.5+/-16.6 mm(3)) (mean+/-SEM) and caudoputamen (38.3+/-13.7 mm(3)) compared with rats exposed to short-duration propofol (cortex, 177.5+/-16.9 mm(3); caudoputamen, 47.8+/-2.9 mm(3)). Infarct volume was not different in long-duration halothane versus long-duration propofol treatment. Absolute cortical or caudoputamen intraischemic CBF was not different between short-duration halothane or short-duration propofol treatment. CONCLUSIONS: These data demonstrate that short-duration halothane exposure before MCAO in the awakening animal attenuates infarction volume compared with propofol. This protection by halothane is not mediated through preservation of intraischemic CBF. Longer durations of halothane exposure may activate secondary injury pathways, which negate the protective effects of short-term halothane preischemic treatment.

Administration, Inhalation↗

PubMed2001

The effect of brief halothane anesthesia during daily gavage on complications and body weight in rats.

We examined retrospectively the effects of brief halothane anesthesia during daily gavage administration of vehicle on gavage-related complications and body weight in ovariectomized female Wistar rats. The number of gavage-related deaths or animals requiring euthanasia due to gavage problems was dramatically reduced, but the occurrence of incomplete vehicle retention during gavage was increased appreciably in halothane-anesthetized animals. Halothane-anesthetized rats maintained daily body weight for a longer period than did awake animals. Our observations suggest that the use of brief inhalational anesthesia reduces gavage-associated death and euthanasia due to esophageal trauma and minimizes stress-related weight loss.

Anesthesia↗

PubMed2000

Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse.

Recent findings in animals emphasize that experimental ischemic brain damage can be strikingly reduced by estrogen: however, the neuroprotective mechanisms are not well understood. It was hypothesized that estrogen signaling via cognate estrogen receptors (ERs) within the vasculature is an important aspect of cerebral ischemic protection in the female brain, in part by amplifying intraischemic cerebral blood flow (CBF). In the present study, the hypothesis that chronic treatment with the pure ER antagonist ICI182,780 (ICI) would increase ischemic brain damage by a blood flow-mediated mechanism was investigated. Adult C57B1/6J mice were pretreated with either subcutaneous ICI (100 microg/day) or oil/ethanol vehicle for 1 week before 2 hours of middle cerebral artery occlusion (MCAO) and 22 hours of reperfusion. End-ischemic regional CBF was evaluated in additional cohorts using [14C]iodoantipyrine autoradiography. Infarction volume as measured by cresyl violet histology was greater in the striatum of ICI-treated females (70 +/- 3% of contralateral striatum vs. 40 +/- 12% in vehicle-treated females). Cortical injury was not enhanced relative to control animals (39 +/- 6% of contralateral cortex in ICI group vs. 27 +/- 8% in vehicle-treated group). Physiologic variables and ischemic reduction of the ipsilateral cortical laser-Doppler flow signal were similar between groups. Further, ICI treatment did not alter end-ischemic cortical or striatal CBF. The deleterious effect of ICI was limited to females, as there were no differences in stroke damage or CBF between male treatment groups. These data suggest that estrogen inhibits ischemic brain injury in striatum of the female by receptor-mediated mechanisms that are not linked to preservation of intraischemic CBF.

Animals↗