Biomedical subjects

L C Pettigrew

Publications and source records attributed to L C Pettigrew.

At least 37 records · Page 2Linked to original sources

PubMed1996

Metyrapone, an inhibitor of glucocorticoid production, reduces brain injury induced by focal and global ischemia and seizures.

Increasing evidence indicates that glucocorticoids (GCs), produced in response to physical/emotional stressors, can exacerbate brain damage resulting from cerebral ischemia and severe seizure activity. However, much of the supporting evidence has come from studies employing nonphysiological paradigms in which adrenalectomized rats were compared with those exposed to constant GC concentrations in the upper physiological range. Cerebral ischemia and seizures can induce considerable GC secretion. We now present data from experiments using metyrapone (an 11-beta-hydroxylase inhibitor of GC production), which demonstrate that the GC stress-response worsens subsequent brain damage induced by ischemia and seizures in rats. Three different paradigms of brain injury were employed: middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia; four-vessel occlusion (4VO) model of transient global forebrain ischemia; and kainic acid (KA)-induced (seizure-mediated) excitotoxic damage to hippocampal CA3 and CA1 neurons. Metyrapone (200 mg/kg body wt) was administered systemically in a single i.p. bolus 30 min prior to each insult. In the MCAO model, metyrapone treatment significantly reduced infarct volume and also preserved cells within the infarct. In the 4VO model, neuronal loss in region CA1 of the hippocampus was significantly reduced in rats administered metyrapone. Seizure-induced damage to hippocampal pyramidal neurons (assessed by cell counts and immunochemical analyses of cytoskeletal alterations) was significantly reduced in rats administered metyrapone. Measurement of plasma levels of corticosterone (the species-typical GC of rats) after each insult showed that metyrapone significantly suppressed the injury-induced rise in levels of circulating corticosterone. These findings indicate that endogenous corticosterone contributes to the basal level of brain injury resulting from cerebral ischemia and excitotoxic seizure activity and suggest that drugs that suppress glucocorticoid production may be effective in reducing brain damage in stroke and epilepsy patients.

Animals↗

PubMed1996

Microtubular proteolysis in focal cerebral ischemia.

Calpain, a neutral protease activated by calcium, may promote microtubular proteolysis in ischemic brain. We tested this hypothesis in an animal model of focal cerebral ischemia without reperfusion. The earliest sign of tissue injury was observed after no more than 15 min of ischemia, with coiling of apical dendrites immunolabeled to show microtubule-associated protein 2 (MAP2). After 6 h of ischemia, MAP2 immunoreactivity was markedly diminished in the infarct zone. Quantitative Western analysis demonstrated that MAP2 was almost unmeasurable after 24 h of ischemia. An increase in calpain activity, shown by an antibody recognizing calpain-cleaved spectrin fragments, paralleled the loss of MAP2 immunostaining. Double-labeled immunofluorescent studies showed that intraneuronal calpain activity preceded evidence of MAP2 proteolysis. Perikaryal immunolabeling of tau protein became increasingly prominent between 1 and 6 h in neurons located within the transition zone between ischemic and unaffected tissue. Western blot experiments confirmed that dephosphorylation of tau protein occurred during 24 h of ischemia, but was not associated with significant loss of tau antigen. We conclude that focal cerebral ischemia is associated with early microtubular proteolysis caused by calpain.

Animals↗

PubMed1995

Delayed elevation of platelet activating factor in ischemic hippocampus.

We used in vivo microdialysis to define the chronological relationship between release of thromboxane and platelet activating factor (PAF) into the extracellular space of ischemic hippocampus. The thromboxane level peaked after 20 min of postischemic reperfusion, followed by a delayed PAF response 120 min later. We conclude that cerebral ischemia causes delayed elevation of PAF in the extracellular space, long after the immediate synthesis and release of thromboxane metabolites.

Analysis of Variance↗

PubMed1995

Frontal lobe phosphorus metabolism and neuropsychological function in aging and in Alzheimer's disease.

31P Magnetic resonance spectroscopy of the frontal lobe was performed in 17 patients with Alzheimer's disease (AD), 8 elderly controls (EC), and 17 young controls (YC). The phosphocreatine/inorganic phosphate (PCr/Pi) ratio in AD (2.32 +/- 0.26 SD) was significantly lower than in EC (2.65 +/- 0.41). In AD patients, a correlation was observed between the PCr/Pi ratio and the dementia rating scale (r = -0.50, p = 0.04). A significant positive correlation between PCr/Pi ratio and age was observed in both AD (r = 0.67, p = 0.003) and YC (r = 0.63, p = 0.006) groups, however, suggesting caution in interpretation of this ratio in AD. We did not find differences between AD, EC, or YC in any other spectroscopic measure. A significant sex difference in the phosphomonoester/phosphodiester ratio (PME/PDE) ratio was observed in AD brain. Females had a lower PME/PDE ratio than males.

Adult↗

PubMed1995

Cranial arteriopathy in familial Vogt-Koyanagi-Harada syndrome.

A 59-year-old woman with Vogt-Koyanagi-Harada (VKH) syndrome presented with transient ischemic attacks. Magnetic resonance angiography showed multiple areas of stenosis affecting the intracranial portions of both internal carotid arteries. Conventional angiography confirmed these abnormalities and also demonstrated tapering stenosis of the extracranial segment of the left internal carotid artery. This patient and her similarly affected daughter represent the first reported association between cranial arteriopathy and intergenerational passage of VKH syndrome.

Carotid Artery, Internal↗

PubMed1995

Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial.

BACKGROUND AND PURPOSE: CGS 19755 is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist that limits neuronal damage in animal stroke models. The objectives of this multicenter (7 centers), randomized, double-blind, placebo-controlled, ascending-dose phase IIa study were to evaluate the safety and tolerability of CGS 19755 and obtain pharmacokinetic and preliminary data on its efficacious dose range in patients treated within 12 hours of hemispheric ischemic stroke. METHODS: At each dose level, 6 patients were randomized to one or two intravenous bolus doses of CGS 19755, and 2 patients were randomized to placebo. An unblinded safety and monitoring committee-evaluated results at each dose before ascending to the next level. All patients at the first level (1 mg/kg) received two doses separated by 12 hours. The first 2 patients at 2 mg/kg received two doses, but adverse experiences occurred in both; subsequent patient groups received single doses of 2.0, 1.75, or 1.5 mg/kg. RESULTS: Adverse experiences (agitation, hallucinations, confusion, paranoia, and delirium) occurred in all 6 patients treated with 2 mg/kg, and in 3 of 5 at 1.75 mg/kg. Similar but milder adverse experiences were noted in 4 of 7 patients at 1.5 mg/kg and 1 of 6 patients at 1.0 mg/kg. Adverse experiences began between 20 minutes and 22 hours (mean, 8 hours) after treatment and lasted 2 to 60 hours (mean, 24 hours). Mortality was 1 of 8 in patients receiving placebo and 3 of 24 in treated patients. In treated survivors, median and mean percent improvement in National Institutes of Health Stroke Scale scores from baseline to terminal visit (mean, 86 days) was comparable at all doses, and 95% of treated patients had Barthel Index scores of > or = 70 at the terminal visit. CONCLUSIONS: We conclude that a single intravenous dose of 1.5 mg/kg CGS 19755 is safe and tolerable in patients with acute ischemic stroke. An efficacy trial is indicated.

Acute Disease↗

PubMed1994

Alterations in tau immunostaining in the rat hippocampus following transient cerebral ischemia.

Previous studies in gerbils have shown that cytoskeletal disruption and a loss of the dendritic microtubule-associated protein, MAP2, may occur after short periods of transient global ischemia. tau, a predominantly axonal microtubule-associated protein, has not been examined following ischemia. We compared neuronal damage with alterations in MAP2, tau, and 72-kD heat shock protein (HSP72) immunostaining at various reperfusion times following 20 min of ischemia in the rat four-vessel occlusion model. tau accumulated in neuronal cell bodies throughout the hippocampal formation 30 min to 2 h after the ischemic insult. Perikaryal tau immunostaining was transient in most regions, but persisted in polymorphic hilar neurons. This was accompanied by a loss of immunostaining in the target of many hilar neurons, the inner molecular layer of the dentate gyrus. The same neuronal populations that exhibited increased tau immunostaining of perikarya later displayed an induction of HSP72 immunoreactivity. In contrast, loss of MAP2 immunostaining was not consistently observed before neuronal death and did not correspond to HSP72 induction. The altered tau immunostaining is not the direct result of excitotoxic insult, as intrahippocampal injection of kainic acid did not cause the somal accumulation of tau, but did cause disruption of MAP2 immunostaining. Taken together, the results suggest that the somal accumulation of tau is an early, sensitive, and selective marker of ischemic insult.

Animals↗

PubMed1994

Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury.

The beta-amyloid precursor protein (beta APP) is the source of the amyloid beta-peptide that accumulates in the brain in Alzheimer's disease. A major processing pathway for beta APP involves an enzymatic cleavage within the amyloid beta-peptide sequence that liberates secreted forms of beta APP (APPss) into the extracellular milieu. We now report that postischemic administration of these APPss intracerebroventricularly protects neurons in the CA1 region of rat hippocampus against ischemic injury. Treatment with APPs695 or APPs751 resulted in increased neuronal survival, and the surviving cells were functional as demonstrated by their ability to synthesize protein. These data provide direct evidence for a neuroprotective action of APPss in vivo.

Amyloid beta-Protein Precursor↗

PubMed1994

A simplified high-performance liquid chromatographic method for direct determination of warfarin enantiomers and their protein binding in stroke patients.

A simplified method for direct determination of warfarin enantiomers by high-pressure liquid chromatography with fluorescence detection has been developed. This method involves solid phase extraction of warfarin in plasma, precolumn derivatization to form diastereoisomeric esters, and post-column reaction to discriminate each enantiomer separately. Ultrafiltration was employed in the separation of unbound warfarin enantiomers. Twelve plasma samples from six stroke patients taking warfarin regularly were analyzed. The average concentration of total warfarin was 0.47 +/- 0.17 mg/L for the S-isomer and 0.69 +/- 0.18 mg/L for the R-isomer. The average protein binding was 99.67 +/- 0.33% for S-warfarin and 99.44 +/- 0.33% for R-warfarin. This methodology provides a quick and reliable technique for determining enantiomeric protein binding of warfarin in clinical settings.

Aged↗

PubMed1993

Thromboxane receptor antagonism and synthase inhibition in cerebral ischemia.

Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that may suppress regional cerebral blood flow (rCBF) during postischemic hypoperfusion. This study was undertaken to determine if rCBF could be elevated by postischemic treatment with a TXA2 receptor antagonist, SQ29,548, given alone or in combination with 1-benzylimidazole (1-BI), a thromboxane synthase inhibitor. Wistar rats were subjected to 30 min of reversible forebrain ischemia and treated with SQ29,548 or an SQ29,548/1-BI combination during 60 min of reperfusion. Cerebral TXB2, the stable metabolite of TXA2, was 1.33 +/- 0.91 ng mg brain protein-1 in animals treated with SQ29,548 and exposed to ischemia, compared to 1.15 +/- 0.32 in ischemic controls (p = NS). Administration of SQ29,548/20 mg kg-1 1-BI reduced cerebral TXB2 to 0.20 +/- 0.25 (p < or = 0.01). Regional CBF was depressed significantly in ischemic controls compared to sham-ischemic animals (p < or = 0.01 in all regions except for p < or = 0.05 in diencephalon) and was not altered by treatment with SQ29,548. Rats given the SQ29,548/1-BI combination showed an overall increase in rCBF that did not reach statistical significance when compared to ischemic controls. However, rCBF in hippocampus and diencephalon of animals given the drug combination was significantly greater than in rats treated with SQ29,548 alone (p < or = 0.05).

Animals↗

PubMed1992

Correction of ischaemic brain acidosis with SQ29,548/1-benzylimidazole.

Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that is synthesized and released during reperfusion of ischaemic brain. We administered a TXA2 receptor antagonist, SQ29,548, and a thromboxane A synthase inhibitor, 1-benzylimidazole (1-BI), to rats subjected to 30 min of reversible forebrain ischaemia. Cerebral thromboxane B2 (TXB2), the stable metabolite of TXA2, measured after 60 min of reperfusion was 0.37 +/- 0.08 ng/mg brain protein in animals treated with SQ29,548/1-BI compared with 1.20 +/- 0.16 in ischaemic controls (p < 0.05). Cerebral pH determined by 31P magnetic resonance spectroscopy was higher in treated animals, 7.06 +/- 0.04, than in ischaemic controls, 6.5 +/- 0.01, after 20 min of reperfusion (p < or = 0.01). The significant elevation of cerebral pH in treated animals persisted at 30 (7.17 +/- 0.05 vs. 6.5 +/- 0.01; p < or = 0.01), 35 (7.17 +/- 0.05 vs. 6.44 +/- 0.04; p < or = 0.01), and 40 min of reperfusion (7.06 +/- 0.06 vs. 6.37 +/- 0.01; p < or = 0.05). We conclude that SQ29,548/1-BI reduces thromboxane levels and promotes resolution of tissue acidosis in ischaemic brain. The combination of a TXA2 receptor antagonist with a thromboxane A synthase inhibitor deserves further study as a potential treatment for acute cerebral infarction.

Acidosis↗

PubMed1990

Growth regulatory activities of endothelial extracellular matrix: mediation by transforming growth factor-beta.

The potential of transforming growth factor-beta (TGF-beta) to modulate the growth of endothelial cells via alterations in the cell's extracellular matrix (ECM) was examined. Rat brain endothelial cells were cultured in the presence or absence of TGF-beta, and subsequently ECM was prepared from the cell cultures by hypotonic lysis of the cells. Untreated endothelial cells were then cultured on the various matrices. Cells grown on TGF-beta-treated ECM showed a significant decrease in cell number (41 +/- 6% mean growth inhibition at 6 days, P less than 0.005 by paired T-test) compared with cells grown on untreated ECM. The growth inhibitory activity of the ECM was depleted by 9 days of culture, and resumption of exponential cell growth was observed. A similar phenomenon was observed if anti-TGF-beta neutralizing antibodies were incubated with the ECM. When the TGF-beta-treated matrix was exposed to a brief dithiothreitol treatment in order to inactivate residual TGF-beta, an approximately equal degree of growth inhibition was observed initially, but the reversal of inhibition occurred at an earlier time point than that with unreduced TGF-beta-treated matrix. Analyses of the composition of matrices synthesized in the presence or absence of TGF-beta revealed about a twofold increase in the accumulation of various radioactive metabolic precursors in the TGF-beta-treated matrices. However, no qualitative alterations in the matrix or cellular-associated proteins or glycoproteins were observed, as analyzed by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. An increase in cell-associated heparan sulfate, however, was observed in TGF-beta-treated cells. The results suggest that certain growth regulatory effects of TGF-beta may be mediated, at least in part, by alterations in the ECM.

Animals↗

PubMed1990

Transplantation of adrenal medullary tissue to caudate nucleus using stereotactic techniques.

Stereotactic techniques were used to transplant adrenal medullary tissue to the head of the right caudate nucleus in 12 patients with Parkinson's disease. No significant lasting complications were seen. All patients had an initial improvement. 11 of the 12 patients remain improved over their preoperative condition after 6-18 months, 3 with good results and 9 with only modest improvement. At 6 months, the mean Schwab and England score had improved from 59.2 +/- 18.8 preoperatively to 75.8 +/- 15.1 (p less than or equal to 0.01) and the mean Hoehn and Yahr scale had improved from 3.42 +/- 0.90 to 2.92 +/- 0.63 (p less than or equal to 0.01).

Adrenal Medulla↗

PubMed1990

Baclofen does not protect against cerebral ischemia in rats.

Presynaptic release of glutamate into the extracellular compartment and activation of receptor-operated calcium channels may contribute to ischemic neuronal damage. We evaluated the effect of baclofen, a selective inhibitor of presynaptic glutamate release, on mortality, working memory, and light microscopic hippocampal and cortical damage in the four-vessel occlusion model of cerebral ischemia using 64 male Wistar rats. Baclofen (10 mg/kg i.p.) given 1 hour before and 30-60 minutes after 20 minutes of global ischemia did not lessen mortality, prevent ischemic cellular damage, or significantly improve working memory compared with no treatment. We conclude that preischemic and postischemic administration of baclofen does not protect neurons from ischemic injury.

Animals↗

PubMed1990

Pilot study of nicardipine for acute ischemic stroke.

The author performed a pilot study of nicardipine (NC), a Ca(+)+ channel blocker, to study its dosing, toxicity, and possible efficacy for hemispheric cerebral infarction within 12 hours (mean 6.9 hr) of onset to determine the advisability of proceeding with a multi-centered controlled trial. NC was administered IV (3 to 7 mg/hr) X 72 hours by titrating dose to mean arterial blood pressure (MABP not less than 10% of baseline), then orally X 30 days. Forty-three patients have been entered; mean age 63 (range 34-89), 25 male and 18 female. Only 3 had CT evidence of infarct on entry. Results have shown improvement in a 100-point (pt) graded exam (40 pts at entry, 68 pts at 3 months). Of 20 patients completing 3 months' evaluation, 17 improved and none worsened. Sixteen out of 20 were at home and 8 had minimal or no impairment. Mean Barthel's index was 72. Mean maximal serum NC level was 75 ng/mL. MABP decreased from 103 (entry) to 83 (72 hours). A larger controlled study is warranted to determine the efficacy of NC for acute cerebral infarct.

Acute Disease↗

PubMed1989

Effect of thromboxane synthase inhibition on eicosanoid levels and blood flow in ischemic rat brain.

Reperfusion of ischemic brain is associated with production of thromboxane A2 (TXA2), a proaggregatory vasoconstrictor. We used an animal model of transient forebrain ischemia to study the effects of 1-benzylimidazole (1-BI), a selective inhibitor of thromboxane synthase, upon cerebral eicosanoid levels and cerebral blood flow. Male Wistar rats were subjected to 30 minutes of four-vessel occlusion. The mean +/- SEM brain level of TXB2, the stable metabolite of TXA2, determined after 60 minutes of reperfusion was 101 +/- 20 pg/mg brain protein in five ischemic control rats. Infusion of 10 micrograms/g 1-BI reduced mean +/- SEM cerebral TXB2 concentration to 11 +/- 3 pg/mg brain protein in five rats (p less than or equal to 0.002). Mean +/- SEM hemispheric cerebral blood flow measured in four ischemic control rats after 60 minutes of reperfusion was 42 +/- 9 ml/100 g brain/min compared with 104 +/- 13 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.001). Mean +/- SEM hippocampal blood flow in four ischemic control rats after 60 minutes of reperfusion was 51 +/- 14 ml/100 g brain/min compared with 125 +/- 25 ml/100 g brain/min in three 1-BI-treated rats (p less than or equal to 0.04). We conclude that selective inhibition of thromboxane synthase may alleviate ischemic brain damage by reducing cerebral TXA2 concentrations and elevating cerebral blood flow.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

Prediction of carotid stenosis progression by lipid and hematologic measurements.

We followed 19 men and 19 women with asymptomatic carotid stenosis up to 30 months to determine whether hematologic or lipid abnormalities could identify those individuals developing progressing carotid atherosclerosis (defined as an increase in mean percent stenosis greater than or equal to 19% or an increase in a single region of greater than or equal to 23%) on B-mode carotid ultrasonography performed at 2- to 6-month intervals. Our patients demonstrated increased beta-thromboglobulin, platelet factor 4, and fibrinogen compared with age-matched controls. Eight patients developed progression of carotid stenosis, and this group had higher baseline low-density lipoprotein (LDL) and fibrinogen than the 30 nonprogressing patients. Multiple regression analyses of age, sex, smoking, coronary artery disease, peripheral vascular disease, diabetes, hypertension, and baseline high-density lipoprotein (HDL), HDL2, HDL3, LDL, beta-thromboglobulin, platelet factor 4, and fibrinogen identified coronary artery disease and elevated LDL and fibrinogen as the only independent variables significantly associated with the progressing group. We conclude that, in patients with carotid atherosclerosis, a combination of coronary artery disease and elevated LDL and fibrinogen will predict with 88% accuracy whether the patient will have progressing carotid stenosis.

Aged↗

PubMed1988

Regional depletion of adenosine triphosphate, phosphocreatine, and glucose in ischemic hippocampus.

The selective vulnerability of pyramidal neurons in the CA1 hippocampal region in ischemic rat brain may be preceded by regional alterations of energy metabolism during early reperfusion. We measured ATP, phosphocreatine (PCr), and glucose in paramedian and lateral CA1 and in an area showing little postischemic cell loss, CA2. ATP levels in paramedian CA1 were depressed immediately after 30 min of ischemia (P less than or equal to 0.02) and remained abnormal after 2 hr of reperfusion (P less than or equal to 0.05). PCr was reduced substantially in both subdivisions of CA1 immediately after ischemia (P less than or equal to 0.04) but returned to normal levels after 2 hr. Glucose levels were depressed in paramedian CA1 and CA2 after ischemia (P less than or equal to 0.02) but corrected with reperfusion. We determined approximately P, the sum of ATP and PCr, in separate experiments investigating regional differences in consumption of high-energy phosphate metabolites during complete ischemia. The approximately P levels of rats subjected to 30 min of reversible ischemia followed by 2 hr of reperfusion showed a different pattern of regional differences from those seen in sham-ischemic animals (P less than or equal to 0.01), indicating a persistent depression of metabolic rate in CA1 during reperfusion. We conclude that regional depletion of high-energy phosphates and alteration of metabolic rate may contribute to the selective vulnerability of the CA1 region during brain ischemia.

Adenosine Triphosphate↗