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David S Warner

Publications and source records attributed to David S Warner.

At least 19 recordsLinked to original sources
PubMed2007

Isoflurane provides long-term protection against focal cerebral ischemia in the rat.

BACKGROUND: Long-term neuroprotection by isoflurane has been questioned. The authors examined factors in experimental models potentially critical to definition of enduring isoflurane neuroprotection. METHODS: Rats were prepared for temporary middle cerebral artery occlusion (MCAO). Pericranial normothermia was maintained. Neurologic deficits (range, 0-48; 0=no deficit) and cerebral infarct volumes were measured. In experiment 1, rats underwent 50 or 80 min MCAO while awake or anesthetized with 1.8% isoflurane. Blood pressure was controlled with phenylephrine. Outcome was evaluated 2 weeks later. In experiment 2, rats underwent 50 min MCAO while awake or anesthetized with isoflurane, with outcome evaluated 8 weeks later. In experiment 3, rats underwent 50 min MCAO while awake or anesthetized with isoflurane and 2 weeks recovery. Effects of phenylephrine and the mitochondrial adenosine triphosphate-sensitive K channel antagonist 5-hydroxydecanoate were studied. In experiment 4, isoflurane-anesthetized rats underwent 50 min MCAO with permanent or temporary common carotid artery occlusion, with outcome evaluated 2 weeks later. RESULTS: In experiment 1, isoflurane reduced neurologic deficit (median+/-interquartile range; awake vs. isoflurane: 11+/-12 vs. 8+/-6 for 80 min and 13+/-4 vs. 3+/-9 for 50 min; P=0.0006) and infarct size (160+/-97 vs. 84+/-62 mm for 80 min and 169+/-78 vs. 68+/-61 mm for 50 min; P<0.0001). In experiment 2, isoflurane protection persisted at 8 weeks after ischemia. In experiment 3, there was no effect of phenylephrine or 5-hydroxydecanoate. In experiment 4, permanent common carotid ligation increased infarct size threefold versus temporary occlusion. CONCLUSIONS: Isoflurane repeatedly improved long-term neurologic and histologic outcome from focal ischemia independent of ischemia duration, perfusion pressure, or pretreatment with 5-hydroxydecanoate.

Anesthetics, Inhalation↗
PubMed2006

Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage.

OBJECT: The efficacy of nimodipine was examined in a murine model of subarachnoid hemorrhage (SAH). End points included the diameter of the lumen of the middle cerebral artery (MCA) and behavioral outcome. An apolipoprotein E (apoE)-mimetic peptide, acetyl-AS-Aib-LRKL-Aib-KRLL-amide, previously shown to have promise in this model was tested both alone and in combination with nimodipine. The effects of carboxyamidotriazole (CAI), a non-voltage-gated calcium channel blocker, were explored using the same animal paradigm. METHODS: Experimental SAH was induced in male C57B1/6J mice. For 3 days postoperatively, behavioral analyses were performed. In the first experiment, the mice were treated with vehicle or with low- or high-dose CAI for 3 days. In the second experiment, the mice were treated with vehicle, high- and low-dose nimodipine, and/or the apoE-mimetic peptide. On postoperative Day 3 each mouse was killed and perfused. Following this, the right MCA was removed and its lumen measured. Mice that received nimodipine demonstrated significant behavioral improvements when compared with vehicle-treated mice, but there was no clear dose-dependent effect on MCA diameter. Administration of the apoE-mimetic peptide was associated with improved functional performance and a significant reduction in vasospasm. Mice that received high-dose CAI performed worse on functional tests, despite a significant increase in the diameters of their MCA lumina. CONCLUSIONS: These results demonstrate a dissociation between vasospasm and neurological outcomes that is consistent with findings of previous clinical trials.

Animals↗
PubMed2006

Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform.

We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.

Aging↗
PubMed2006

Effects of a manganese (III) porphyrin catalytic antioxidant in a mouse closed head injury model.

Closed head injury induces cerebral oxidative stress. The efficacy of a Mn (III) porphyrin catalytic antioxidant was assessed in a mouse closed head injury model. Mice were subjected to closed head injury and treated 15 min later with an i.v. bolus of vehicle or 3 mg/kg MnTE-2-PyP5+. Aconitase activity, Fluoro-Jade staining, glial fibrillary acidic protein immunoreactivity, and rotarod falling latencies were measured. Closed head injury altered all variables. MnTE-2-PyP5+ had no effect on any variable with the exception of attenuation of aconitase inactivation at 2 h post-closed head injury. In a second experiment, mice received 3 mg/kg or 6 mg/kg MnTE-2-PyP5+ or vehicle i.v. 15 min post-closed head injury. Rotarod and Morris water maze latencies were measured. Closed head injury altered performance in both tests. No statistically significant effect of MnTE-2-PyP5+ was observed. We conclude that single dose MnTE-2-PyP5+ does not alter outcome in this mouse closed head injury model.

Aconitate Hydratase↗
PubMed2006

A comparison of hyperbaric oxygen versus hypoxic cerebral preconditioning in neonatal rats.

The potency of hyperbaric preconditioning (HBO-PC) is uncertain compared to well-validated ischemic or hypoxic models and no studies have directly compared HBO-PC to hypoxic preconditioning (HPC). We subjected rat pups to unilateral carotid cauterization followed by 90 min (min) of hypoxia using 8% O(2). Three HBO-PC regimes (maximum 2.5 atmospheres for 150 min) were compared to HPC (150 min of 8% O(2)) for changes in mortality and brain weight. Preconditioning-induced oxidative stress was assessed using aconitase activity and manganese superoxide dismutase (MnSOD) transcript levels. Initial brain weight data revealed a large coefficient of variation and compelled an examination of the temperature sensitivity of the model that revealed a narrow optimal range of 35 to 37 degrees C of variability in brain injury and mortality. With rigorous temperature control, high dose HBO-PC and HPC showed comparable anatomic (mean hemispheric weight decrease: control 42%, HPC 25% (P=0.01), HBO-PC 26% (P=0.01) and mortality protection (control 14.7%, HPC 5.9% HBO-PC 5.7%, P=0.001). High dose HBO-PC, but not HPC, suppressed aconitase activity by 65% at 24 h after the preconditioning stimulus (P=0.001). In contrast, MnSOD mRNA increased 2.5-fold at 24 h after HPC (P=0.007) but not after high dose HBO-PC. Thus, when temperature variability is eliminated, HBO-PC and HPC elicit similar preconditioning efficacy in neonatal brain but invoke different defenses against oxidative stress.

Animals↗
PubMed2006

Selective gamma-aminobutyric acid type A receptor antagonism reverses isoflurane ischemic neuroprotection.

BACKGROUND: Isoflurane provides protection against severe forebrain ischemia in the rat. The authors hypothesized that this is attributable to interaction with the gamma-aminobutyric acid type A (GABAA) receptor resulting in altered time to onset of ischemic hippocampal depolarization. METHODS: Organotypic hippocampal slices were subjected to oxygen-glucose deprivation in the presence of isoflurane and combinations of GABAA (bicuculline) and GABAB (phaclofen) receptor antagonists. Cell death was measured. Rats were subjected to severe forebrain ischemia while anesthetized with fentanyl-nitrous oxide or 1.4% isoflurane. In the isoflurane group, rats also received intravenous bicuculline (0, 1, or 2 mg/kg). Neurologic and histologic outcomes and time to depolarization were assessed. RESULTS: In slices, 2% isoflurane caused near-complete protection against oxygen-glucose deprivation. This was unaffected by coadministration of phaclofen but largely reversed by bicuculline. The GABAA agonist muscimol was also protective, having an effect equivalent to 1% isoflurane. In rats, isoflurane (0 mg bicuculline) improved neurologic and histologic outcome versus fentanyl-nitrous oxide (CA1 percentage of alive neurons: fentanyl-nitrous oxide, 15 +/- 7; isoflurane, 61 +/- 24). The isoflurane effect was reversed in a dose-dependent manner by bicuculline (CA1 percentage alive: 1 mg/kg, 44 +/- 22; 2 mg/kg, 21 +/- 15). Time to depolarization was delayed with isoflurane versus fentanyl-nitrous oxide (137 vs. 80 s) but was not affected by bicuculline (149 s). In contrast, postischemic time to repolarization was more rapid with fentanyl-nitrous oxide or isoflurane plus bicuculline versus isoflurane alone. CONCLUSIONS: These studies are consistent with the hypothesis that the GABAA receptor serves as a major site of action for isoflurane neuroprotection both in vitro and in vivo. However, the mechanism by which this interaction confers in vivo protection cannot be attributed to effects on the duration of ischemic depolarization.

Animals↗
PubMed2006

NMDA-induced apoptosis in mixed neuronal/glial cortical cell cultures: the effects of isoflurane and dizocilpine.

In animal models of severe ischemia, it has not been uniformly observed that anesthetics are protective. However, anesthetics have not been evaluated in the presence of a mild excitotoxic insult. We hypothesized that in the presence of a mild excitotoxic insult, 3 microm N-methyl-D-aspartate (NMDA), isoflurane may prevent apoptotic cell death. Primary mixed neuronal/glial cultures were prepared from fetal rat brains. Mature cultures were exposed to dissolved isoflurane [0 mM, 0.4 mM (1.8 minimum alveolar concentration) or 1.6 mM (7 minimum alveolar concentration)] or dizocilpine (10 microM), and NMDA (0 or 3 microM) at 37 degrees C for 30 minutes. Apoptosis was assessed using terminal-deoxy-nucleotidyl end-nick labeling oligonucleosomal DNA fragmentation enzyme-linked immunosorbent assay, and caspases-3 and -9 activation assays. NMDA (3 muM) induced apoptosis in mixed neuronal/glial cell cultures. Apoptosis induced by 3 microm NMDA was caspase-3 but not caspase-9 mediated. In the presence of a mild excitotoxic insult, this investigation showed an attenuation of apoptotic cell death by dizocilpine, but not isoflurane.

Anesthetics, Inhalation↗
PubMed2006

The effect of age on sciatic nerve block duration.

The physiologic changes that occur with advancing age and their effect on the duration of peripheral nerve blocks have yet to be defined. We prospectively studied the duration of sciatic nerve block using mepivacaine in younger and older patients. Eighty ASA physical status I-III patients, aged 18-35 (n = 40) or 55-80 (n = 40) yr, having outpatient knee arthroscopy with a femoral block and a standardized sciatic nerve block were enrolled; 37 in each group completed the study. All patients received a Labat sciatic nerve block using 20 mL of 1.0% mepivacaine with 0.1 mEq/mL sodium bicarbonate and 1:400,000 (2.5 microg/mL) epinephrine and a femoral nerve block. The duration of sensory block (sensation of pinprick, temperature, and vibration), motor block (plantar and dorsi flexion), and complete sensory and motor block in the sciatic nerve distribution of the operative extremity were measured. The time for complete return of both sensory and motor function was longer in the older group, 329 +/- 47 min compared with 306 +/- 46 min (mean +/- sd) in the younger group (P = 0.04). The difference was small under the conditions of this study and would not be perceived clinically. Age also increased the time to return of vibratory sensation (younger = 292 +/- 58 min, older = 257 +/- 50 min; P = 0.007). The other measurements did not differ between groups. We conclude that age may affect peripheral nerve blocks and that more investigation is needed to determine the pharmacologic, physiologic, and chronologic factors behind these findings.

Adolescent↗
PubMed2006

Induction of hypothermia after intraoperative hypoxic brain insult.

Hypoxic brain injury can be a devastating complication of anesthesia. Fortunately, it has become increasingly rare. Here we report a case of suspected intraoperative hypoxic brain injury treated with moderate hypothermia. Anesthesiologists should be aware of the option of using this therapy and how to employ it in the setting of suspected hypoxic brain injury.

Female↗
PubMed2006

A novel apoE-derived therapeutic reduces vasospasm and improves outcome in a murine model of subarachnoid hemorrhage.

INTRODUCTION: Recent clinical observations demonstrate that the APOE4 genotype increases the development of delayed ischemic deficit and worsens prognosis following aneurysmal subarachnoid hemorrhage (SAH). In the current study, we use targeted replacement mice expressing only human apoE3 or apoE4 to model the isoform-specific effects of apoE following SAH. We then test the hypothesis that an apoE-derived therapeutic peptide reduces vasospasm and improves functional recovery after SAH. METHODS: Experimental SAH was induced in APOE3- and APOE4-targeted replacement mice. For 3 days following injury, daily functional assessments were made. Mice were then sacrificed and the cerebral vasculature visualized to quantify vasospasm. In a separate experiment, C57Bl/6 mice were treated with intravenous injection of vehicle, low-dose, or high-dose apoE-mimetic peptide every 12 hours for 3 days post-SAH. Functional endpoints were assessed on a daily basis, followed by measurement of middle cerebral artery diameter. RESULTS: Mice expressing the apoE4 isoform had greater functional deficit, mortality, cerebral edema, and vasospasm as compared with their apoE3 counterparts. Mice treated with the apoE-mimetic peptide had decreased mortality, functional deficits, and histological evidence of vasospasm as compared with vehicle-treated animals. CONCLUSION: Consistent with the clinical literature, the apoE4 isoform is associated with an increased incidence of vasospasm and poor functional recovery after experimental SAH. An apoE-derived peptide represents a novel therapeutic approach for the treatment of SAH.

Animals↗
PubMed2006

Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage.

OBJECTIVES: Prophylactic treatment with antiepileptic drugs is common practice following subarachnoid hemorrhage (SAH) and traumatic brain injury. However, commonly used antiepileptic drugs have multiple drug interactions, require frequent monitoring of serum levels, and are associated with adverse effects that may prompt discontinuation. In the current study, we test the hypothesis that levetiracetam, an anticonvulsant with favorable interaction and adverse event profiles, is neuroprotective in clinically relevant models of SAH and closed head injury (CHI). METHODS: A single intravenous dose of vehicle, low-dose (18 mg/kg), or high-dose (54 mg/kg) levetiracetam was administered intravenously followed CHI. Functional assessments were performed on a daily basis, and histological assessments performed at 24 hours. In a separate series of experiments, mice were randomized to receive intravenous administration of vehicle, low-dose, or high-dose levetiracetam every 12 hours for 3 days following SAH. Functional endpoints were assessed daily, followed by measurement of MCA luminal diameter on day 3. RESULTS: A single dose of levetiracetam improved functional and histological outcomes after CHI. This effect appeared specific for levetiracetam and was not associated with fosphenytoin treatment. Treatment with levetiracetam also improved functional outcomes and reduced vasospasm following SAH. CONCLUSION: Levetiracetam is neuroprotective in clinically relevant animal models of SAH and CHI. Levetiracetam may be a therapeutic alternative to phenytoin following acute brain injury in the clinical setting when seizure prophylaxis is indicated.

Animals↗
PubMed2005

Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial.

BACKGROUND AND PURPOSE: Cerebral vasospasm remains a major source of morbidity after aneurysmal subarachnoid hemorrhage (SAH). We demonstrate that simvastatin reduces serum markers of brain injury and attenuates vasospasm after SAH. METHODS: Patients with angiographically documented aneurysmal SAH were randomized within 48 hours of symptom onset to receive either simvastatin (80 mg daily; n=19) or placebo (n=20) for 14 days. Plasma alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase were recorded weekly to evaluate laboratory evidence of hepatitis or myositis. Serum markers of brain injury were recorded daily. The primary end point of vasospasm was defined as clinical impression (delayed ischemic deficit not associated with rebleed, infection, or hydrocephalus) in the presence of > or =1 confirmatory radiographic test (angiography or transcranial Doppler demonstrating mean V(MCA) >160 m/sec). RESULTS: There were no significant differences in laboratory-defined transaminitis or myositis between groups. No patients developed clinical symptoms of myopathy or hepatitis. Plasma von Willebrand factor and S100beta were decreased 3 to 10 days after SAH (P<0.05) in patients receiving simvastatin versus placebo. Highest mean middle cerebral artery transcranial Doppler velocities were significantly lower in the simvastatin-treated group (103+/-41 versus 149+/-47; P<0.01). In addition, vasospasm was significantly reduced (P<0.05) in the simvastatin-treated group (5 of 19) compared with those who received placebo (12 of 20). CONCLUSIONS: The use of simvastatin as prophylaxis against delayed cerebral ischemia after aneurysmal SAH is a safe and well-tolerated intervention. Its use attenuates serum markers associated with brain injury and decreases the incidence of radiographic vasospasm and delayed ischemic deficit.

Adult↗
PubMed2005

Intrathecal administration of a novel apoE-derived therapeutic peptide improves outcome following perinatal hypoxic-ischemic injury.

Perinatal hypoxic-ischemic brain injury remains a significant clinical problem for which there remains no adequate therapeutic intervention. Apolipoprotein E (apoE) is a 299 amino acid protein that has been demonstrated to modify functional recovery following acute ischemic and traumatic brain injury. The aim of the current study was to evaluate whether administration of an apoE-derived peptide could reduce CNS injury in a rodent model of perinatal hypoxia and ischemia. We found that intrathecal delivery of an apoE-mimetic peptide caused a significant reduction in post-ischemic brain necrosis, as reflected by decreased reduction in ipsilateral brain weight 7 days following hypoxic-ischemic injury. These results suggest that administration of an apoE-derived therapeutic peptide represents a novel therapeutic strategy in the clinical setting of perinatal hypoxic-ischemic injury.

Animals↗
PubMed2005

A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury.

Although apolipoprotein E4 (APOE4) was initially identified as a susceptibility gene for the development of Alzheimer's disease, the presence of the APOE4 allele is also associated with poor outcome after acute brain injury. One mechanism by which apoE may influence neurological outcome is by downregulating the neuroinflammatory response. Because it does not readily cross the blood-brain barrier, the apoE holoprotein has limited therapeutic potential. We demonstrate that a single intravenous injection of a small peptide derived from the apoE receptor binding region crosses the blood-brain barrier and significantly improves histological and functional outcomes after traumatic brain injury (TBI). The development of an apoE-based intervention represents a novel therapeutic strategy in the management of acute brain injury.

Animals↗
PubMed2005

Analysis of the brain bioavailability of peripherally administered magnesium sulfate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia.

OBJECTIVE: Based on preclinical investigations, magnesium sulfate (MgSO4) has gained interest as a neuroprotective agent. However, the ability of peripherally administered MgSO4 to penetrate the blood-brain barrier is limited in normal brain. The current study measured the passage of intravenously administered Mg into cerebrospinal fluid in patients with brain injury requiring ventricular drainage. DESIGN: A prospective evaluation of the cerebrospinal fluid total and ionized magnesium concentration, [Mg], during sustained hypermagnesemia was performed. SETTING: Neurosciences intensive care unit at a major teaching institution. PATIENTS: Thirty patients with acute brain injury secondary to subarachnoid hemorrhage, traumatic brain injury, primary intracerebral hemorrhage, subdural hematoma, brain tumor, central nervous system infection, or ischemic stroke were studied. INTERVENTIONS: Patients underwent 24 hrs of induced hypermagnesemia during which total and ionized cerebrospinal fluid [Mg] was measured. Serum [Mg] was adjusted to 2.1-2.5 mmol/L. Cerebrospinal fluid [Mg] was measured at baseline, at 12 and 24 hrs after onset of infusion, and at 12 hrs following infusion termination. MEASUREMENTS AND MAIN RESULTS: At baseline, total (1.25 +/- 0.14 mmol/L) and ionized (0.80 +/- 0.10 mmol/L) cerebrospinal fluid [Mg] was greater than serum total (0.92 +/- 0.18 mmol/L) and ionized (0.63 +/- 0.07 mmol/L) [Mg] (p < .05). Total (1.43 +/- 0.13 mmol/L) and ionized (0.89 +/- 0.12 mmol/L) cerebrospinal fluid [Mg] was maximally increased by 15% and 11% relative to baseline, respectively, during induced hypermagnesemia (p < .05). CONCLUSIONS: Hypermagnesemia produced only marginal increases in total and ionized cerebrospinal fluid [Mg]. Regulation of cerebrospinal fluid [Mg] is largely maintained following acute brain injury and limits the brain bioavailability of MgSO4.

Adolescent↗
PubMed2005

A retrospective analysis of a remifentanil/propofol general anesthetic for craniotomy before awake functional brain mapping.

UNLABELLED: We performed this study to summarize drug dosing, physiologic responses, and anesthetic complications from an IV general anesthetic technique for patients undergoing craniotomy for awake functional brain mapping. Review of 98 procedures revealed "most rapid" IV infusion rates for remifentanil 0.05, 0.05-0.09 microg x kg(-1) x min(-1) and propofol 115, 100-150 microg x kg(-1) x min(-1). The infusions lasted for 78, 58-98 min. Intraoperative emergence from general anesthesia was 9 (6-13) min after discontinuing IV infusions to allow for brain mapping and was independent of infusion duration and duration of craniotomy before mapping. Spontaneous ventilation was generally satisfactory during drug infusion, as evidenced by Sao(2) = 95% (92%-98%) and Paco(2) = 50 (47-55) mm Hg. However, we recorded at least one 30-s epoch of apnea in 69 of 96 patients. Maximum systolic arterial blood pressure was 150 (139-175) mm Hg and minimal systolic arterial blood pressure was 100 (70-150) mm Hg during drug infusion. Three patients experienced intraoperative seizures. Two patients did not tolerate the awake state and required reinduction of general anesthesia. No patients required endotracheal intubation or discontinuation of surgery. This general anesthetic technique is effective for craniotomy with awake functional brain mapping and offers an alternative to continuous wakefulness or other IV sedation techniques. IMPLICATIONS: An IV general anesthetic technique using remifentanil and propofol is an effective method allowing for reliable emergence for intraoperative awake functional brain mapping during craniotomy.

Adolescent↗