Biomedical subjects

G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 55 records · Page 3Linked to original sources

PubMed1994

Lyophilized liposome encapsulated hemoglobin: evaluation of hemodynamic, biochemical, and hematologic responses.

OBJECTIVE: To characterize the hemodynamic, biochemical, and hematologic responses to the administration of the oxygen-carrying fluid lyophilized liposome-encapsulated hemoglobin in the conscious, normovolemic rat. DESIGN: Prospective, randomized trial. SETTING: Animal laboratory, Jefferson Medical College. SUBJECTS: Eighty-four male Sprague-Dawley rats. INTERVENTIONS: Catheters were introduced into the right atrium (through the jugular vein) and both femoral arteries of test animals, and a thermistor was placed in the ascending aorta through the left common carotid artery for infusion of lyophilized liposome-encapsulated hemoglobin, blood collection, and blood pressure (BP) and cardiac output determinations. MEASUREMENTS AND MAIN RESULTS: Lyophilized liposome-encapsulated hemoglobin (n = 8) infusion (1 mL/min iv) at 1 or 6 mL/kg (10% of estimated blood volume) had no detectable effect on BP, cardiac output, total peripheral resistance, and heart rate during the 5-hr observation period. The infusion also had no effect on hematocrit, leukocyte count, and serum tumor necrosis factor-alpha concentrations. Survival at 7 days was 100% (n = 20). Lyophilized liposome-encapsulated hemoglobin caused transient (2-hr) thrombocytopenia (-24 +/- 9% vs. a Ringer's lactate control group, p < .01), and marginally increased serum thromboxane B2 concentrations (14.6 +/- 6 pg/100 microL, p < .01). CONCLUSIONS: These data suggest that lyophilized liposome-encapsulated hemoglobin can be safely administered to conscious rats, supporting the development of this substance as a potential blood substitute.

6-Ketoprostaglandin F1 alpha↗

PubMed1993

Platelet-activating factor inhibits excitatory transmission in rat neostriatum.

Platelet-activating factor (PAF) and its receptor have been found in mammalian brain but its neuronal action is unclear. Using brain slice and whole-cell patch-clamp techniques, it was found that PAF dose-dependently inhibited excitatory postsynaptic current in neostriatal neurons but not the current induced by exogenously applied glutamate. These effects were also observed with the synthetic agonist 2-methylcarbamyl-PAF and were blocked by BN50739, a competitive antagonist at PAF receptors. It is concluded that PAF acts presynaptically to inhibit the release of glutamate at excitatory synapses in the neostriatum.

2-Amino-5-phosphonovalerate↗

PubMed1993

Respiratory mu-opioid and benzodiazepine interactions in the unrestrained rat.

Interactions of mu-opioid receptors with the benzodiazepine system were studied by examining the modulatory effects of flumazenil (a benzodiazepine antagonist) and alprazolam (a benzodiazepine agonist) on the respiratory effects of the opioid peptide dermorphin. Dermorphin, 1-30 nmol administered i.c.v., to conscious, unrestrained rats decreased ventilation rate (VR) and minute volume (MV) dose-dependently. The ventilatory depression was antagonized by naloxone and by the benzodiazepine antagonist flumazenil. The benzodiazepine alprazolam potentiated the respiratory inhibition of a small (1 nmol) dose of dermorphin but antagonized that of a higher dose (3 nmol). The results suggest that the benzodiazepine/GABA receptor complex modulates respiratory depression induced by central mu-receptor stimulation in the rat.

Alprazolam↗

PubMed1993

Distribution of spin-trapping compounds in rat blood and brain: in vivo microdialysis determination.

Microdialysis was utilized to determine blood and brain distribution of spin-trapping nitrone compounds in the rat following intraperitoneal administration. In vivo quantitation by high-pressure liquid chromatography (HPLC) analysis, in vitro calibration of microdialysis probes, optimum perfusion rate, and the relationship of microdialysis sample recovery to tissue levels were evaluated in detail. The microdialysis sampling and HPLC analysis provided on-line, within-animal pharmacokinetic time-course determinations. At equimolar concentrations, 150 mg/kg alpha-phenyl-N-tert-butyl nitrone (PBN) or 165 mg/kg alpha-4-pyridyl-N-oxide N-tert-butyl nitrone (POBN) reached a similar, steady-state venous blood concentration of 224 +/- 21 microM and 210 +/- 10 microM, respectively. The POBN steady-state brain concentration was 149 +/- 9 microM, a significantly (p < .05) lower concentration than in the blood. In contrast, the brain concentration of PBN was 331 +/- 25 microM, significantly (p < .05) higher than its concentration in the blood. The increased brain distribution/penetration of PBN was attributed to its greater lipophilicity as measured by its octanol/water partition coefficient. All microdialysis results were validated by direct measurement of blood and brain levels at steady-state using conventional extraction procedures and assays. Also, the amount of tissue/cell bound versus unbound nitrones was determined by comparing the microdialysis "dialyzable" fraction with the total amount from whole tissue extracts. These data demonstrate that on-line determinations of nitrone spin-trap brain penetration/levels can be carried out accurately using in vivo microdialysis. The implication of these results for potential use of the microdialysis technique for detection of free radical products in in vivo animal models is discussed.

Animals↗

PubMed1993

Serum tumor necrosis factor-alpha profile in trauma patients.

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in several late consequences of trauma such as sepsis, multiple organ failure, and ischemia-reperfusion injury. However, no data are available to indicate whether TNF-alpha is involved in the initial pathophysiologic response to trauma. To address this issue, serum TNF-alpha was determined (by ELISA) longitudinally (first blood sample on admission) in 100 randomly selected trauma patients admitted to the emergency department and trauma division at Jefferson Medical Center, Philadelphia. The TNF-alpha levels were detectable at one or more time points in 35 patients. Mean values tended to be elevated (50.3 +/- 11.5 pg/mL) during the first 5 days, but this trend did not differ statistically from that in healthy controls (n = 12) and did not correlate with the severity of injury (Injury Severity Score and Glasgow Coma Scale score). The TNF-alpha response was not dependent on the mechanism and site of injury, the presence of shock (systolic blood pressure < 90 mm Hg), and the need for emergent surgery. Also, serum TNF-alpha levels were not significantly elevated in patients who subsequently developed multiple organ failure (n = 4), septic shock (n = 5), or both (n = 3). Taken together, these data do not support a role for circulating TNF-alpha in the initial acute inflammatory response to trauma.

Adult↗

PubMed1993

ARDS-like lung injury produced by endotoxin in platelet-activating factor-primed rats.

We recently reported that the combined administration of lipopolysaccharide (LPS) and platelet-activating factor (PAF) in rats, at doses that are completely devoid of any effect when given alone, caused lung injury characterized by neutrophil adhesion to lung capillaries and postcapillary venules, neutrophil accumulation in the lung parenchyma, platelet-fibrin deposits in postcapillary venules, and pulmonary edema. A marked increase in lung myeloperoxidase activity and an elevation of serum tumor necrosis factor-alpha and thromboxane B2, along with leukopenia and thrombocytopenia, were also noticed. The present study aimed to examine whether repeated LPS-PAF stimulus can cause progressive lung injury reminiscent of adult respiratory distress syndrome (ARDS). A second LPS-PAF challenge, 4 h (n = 11) after the original challenge, induced mortality (69% at 24 h, P < 0.01) and some of the pathological changes seen in clinical ARDS, including severe pulmonary edema, alveolar proteinaceous exudates, monocytic infiltration, and a further increase in lung myeloperoxidase activity (700%, P < 0.01). Repeated LPS-PAF dosing also resulted in sustained increased serum tumor necrosis factor-alpha levels (1,610 +/- 470 pg/ml, P < 0.01) and further exacerbation of the leukopenia (-68 +/- 6%, P < 0.01) and thrombocytopenia (-65 +/- 8%, P < 0.01). These data suggest that repeated LPS-PAF actions are sufficient to elicit pathophysiology of ARDS-like lung injury.

Animals↗

PubMed1993

Increased release of tumor necrosis factor-alpha into the cerebrospinal fluid and peripheral circulation of aged rats.

BACKGROUND AND PURPOSE: We earlier reported that risk factors for stroke prepare brain stem tissue for a modified Shwartzman reaction, including the development of ischemia and hemorrhage and the production of tumor necrosis factor-alpha, after a provocative dose of lipopolysaccharide. In the present study, we sought to determine whether blood and central nervous system cells of rats with the stroke risk factor of advanced age produce more proinflammatory and prothrombotic mediators than do those of young rats of the same strain. METHODS: Levels of tumor necrosis factor-alpha and platelet activating factor in the cerebrospinal fluid and tumor necrosis factor-alpha in the serum of 2-year-old and 16-week-old Sprague-Dawley rats were monitored before and after challenge with lipopolysaccharide. RESULTS: No consistent tumor necrosis factor-alpha activity was found in the cerebrospinal fluid or blood of control animals. Intravenous administration of lipopolysaccharide (1.8 mg/kg) increased serum tumor necrosis factor-alpha levels but had no effect on tumor necrosis factor-alpha in the cerebrospinal fluid. Serum tumor necrosis factor-alpha increased much more in aged rats than in young rats. When lipopolysaccharide was injected intracerebroventricularly, tumor necrosis factor-alpha activity in cerebrospinal fluid increased significantly more in old rats than in young rats. Baseline levels of platelet activating factor in cerebrospinal fluid were significantly higher in old rats than in young rats, and the levels increased to a greater degree in aged rats on stimulation. CONCLUSIONS: Rats with the stroke risk factor of advanced age respond to lipopolysaccharide with a more exuberant production of tumor necrosis factor-alpha and platelet activating factor than young rats of the same strain. These findings are consistent with our working hypothesis that perivascular cells are capable of exaggerated signaling of endothelium through cytokines such as tumor necrosis factor-alpha in animals with stroke risk factors. The effect of such signaling might be to prepare the endothelium of the local vascular segment for thrombosis or hemorrhage in accord with the local Shwartzman reaction paradigm.

Aging↗

PubMed1993

Extracellular catecholamine levels in rat hippocampus after a selective alpha-2 adrenoceptor antagonist or a selective dopamine uptake inhibitor: evidence for dopamine release from local dopaminergic nerve terminals.

The effect of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1-H-3-benzazepine (SKF 86466), a selective nonimidazoline alpha-2 adrenoceptor antagonist, on hippocampal release of norepinephrine and dopamine in conscious rats was investigated by in vivo microdialysis and high-pressure liquid chromatography. Additionally, extracellular concentrations of hippocampal dopamine (DA) and norepinephrine (NE), during infusion of selective monoamine uptake inhibitors, were determined in freely moving rats. The basal concentration of NE in the dialysate was 4.9 +/- 0.3 pg/20 microliters. Intravenous administration of 5 or 10 mg/kg of SKF 86466 was associated with a transient increase (30 min) of 2-fold (12 +/- 1 pg/20 microliters; P < .05) and 8-fold (39 +/- 3 pg/20 microliters; P < .05), respectively, in dialysate NE, whereas a 1-mg/kg dose had no effect. DA was not detected in basal dialysates, but after the administration of 5 or 10 mg/kg of SKF 86466, 3.9 +/- 0.4 and 6.4 +/- 0.6 pg/20 microliters, respectively, was present in the dialysates. The maximum increase in dialysate DA was reached 60 to 90 min after SKF 86466. The DA was not derived from plasma because plasma NE was elevated after the 5 mg/kg dose of SKF 86466 whereas no plasma DA was detected. In order to determine whether DA was present in noradrenergic nerve terminals, the dopamine beta-hydroxylase inhibitor SKF 102698 was administered (50 mg/kg i.p.). The inhibitor decreased dialysate NE but DA was still not detected in the dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1993

Tumor necrosis factor-alpha mediates endotoxin-induced lung injury in platelet activating factor-primed rats.

We have reported recently that lipopolysaccharide endotoxin and platelet activating factor cooperate in priming relationships to elicit lung microvascular injury. Lung injury was associated with elevated serum levels of tumor necrosis factor-alpha (TNF alpha) and histological findings highly reminiscent of the adult respiratory distress syndrome. The present study was designed to examine the role of TNF alpha in lipopolysaccharide/platelet activating factor-induced lung injury by utilizing a highly specific monoclonal antibody which block TNF alpha actions (anti-TNF alpha monoclonal antibody). Pretreatment with anti-TNF alpha monoclonal antibody (2.5-25 mg/kg i.v., n = 5-9) dose-dependently prevented the lipopolysaccharide/platelet activating factor-induced histopathological changes, lung edema (P < .01), lung myeloperoxidase activity (P < .01), elevation of neutrophil count in bronchoalveolar lavage fluid (P < .01) and increased serum thromboxane B2 (P < .01). Indomethacin (6 mg/kg i.v., n = 5) failed to modify the lung injury despite complete inhibition of thromboxane B2 formation (P < .05). These data suggest that TNF alpha might play a key role in initiation of the early inflammatory changes which lead to adult respiratory distress syndrome.

Animals↗

PubMed1993

A new salutary resuscitative fluid: liposome encapsulated hemoglobin/hypertonic saline solution.

Low-volume resuscitation with hypertonic (7.5%) saline (HTS) is an evolving therapeutic modality for patients with hemorrhagic shock. This solution has been shown to exert protective hemodynamic effects in models of controlled hemorrhagic shock and in several clinical trials. However, HTS has no oxygen-carrying capacity and therefore does not improve oxygen delivery directly. One of the leading strategies in developing an oxygen-carrying resuscitative fluid is the encapsulation of hemoglobin within phospholipid vesicles (LEH). This preparation has the advantage of being blood type and antigen free, easily adaptable to scale-up production, and remarkably stable with a long shelf life. We therefore tested the hypothesis that lyophilized LEH reconstituted with HTS will improve tissue oxygenation and survival in rats exposed to a lethal controlled hemorrhagic shock. Shock was induced by withdrawal of 70% of blood volume and therapy (n = 10-16) with HTS (5 mL/kg), LEH (5 mL/kg), lactated Ringer's solution (vol:vol = 1:3), LEH-HTS (5 mL/kg), or oxygen (100%) was initiated 15 minutes later. The LEH-HTS improved skeletal muscle oxygen tension directly measured using a thin-film chamber oxygen sensor (PO2 87 +/- 13 mm Hg vs. 40-50 mm Hg in other groups, p < 0.05). This was associated with improved blood pressure, reduced acidosis, and increased survival at 24 hours (75% vs. 6%-25% in other groups, p < 0.05). In conclusion, the study demonstrates a remarkably salutary effect of LEH reconstituted with HTS as a blood substitute in the treatment of hemorrhagic shock.

Animals↗

PubMed1993

Dermorphin analog Tyr-D-Arg2-Phe-sarcosine-induced opioid analgesia and respiratory stimulation: the role of mu 1-receptors?

Tyr-D-Arg2-Phe-sarcosine4 (TAPS), a mu-selective tetrapeptide analog of dermorphin, induced sustained antinociception and stimulated ventilatory minute volume (MV) at the doses of 3 to 100 pmol i.c.v. The doses of 30 and 100 pmol i.c.v. induced catalepsy. The effect of TAPS on MV was in negative correlation with the dose and the maximal response was achieved by the lowest (3 pmol) dose (+63 +/- 23%, P < .05). Morphine, an agonist at both mu 1 and mu 2 sites, at a dose of 150 nmol i.c.v. (equianalgesic to 100 pmol of TAPS decreased the MV by 30%, due to a decrease in ventilatory tidal volume. The antinociceptive effect of TAPS was antagonized by naloxone and the mu 1 receptor antagonist, naloxonazine. Naloxonazine also attenuated the catalepsy produced by 100 pmol of TAPS i.c.v. and the respiratory stimulation produced by 3 pmol of TAPS i.c.v. Pretreatment with 30 pmol of TAPS antagonized the respiratory depression induced by the mu opioid agonist dermorphin (changes in MV after dermorphin alone at 1 or 3 nmol were -22 +/- 10% and -60 +/- 9% and, after pretreatment with TAPS, +44 +/- 11% and -18 +/- 5%, respectively). After combined pretreatment with naloxonazine and TAPS, 1 nmol of dermorphin had no significant effect on ventilation. In contrast, pretreatment with a low respiratory stimulant dose (10 pmol i.c.v.) of dermorphin did not modify the effect of 1 nmol of dermorphin. In conclusion, the antinociceptive, cataleptic and respiratory stimulant effects of TAPS appear to be a related to its agonist action at the mu 1 opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1992

Neuroprotective effects of carvedilol, a new antihypertensive, at the N-methyl-D-aspartate receptor.

Carvedilol's potent antioxidant activity could explain its protective action in brain ischemia, but may not apply to glutamate-induced excitotoxicity in cultured cerebellar granule cells, since glutamate neurotoxicity was not associated with the formation of lipid peroxidative products. Rather, carvedilol diminished the N-methyl-D-aspartate (NMDA)/glycine-induced increase in intracellular calcium ([Ca2+]i), lowering [Ca2+]i by a maximum of 66 +/- 5% (n = 8) with a 50% inhibitory concentration of 0.8 microM. Prior addition of 5 microM dihydropyridines did not shift the dose-response of carvedilol, but did significantly lower the NMDA/glycine-stimulated response to 64% of untreated (n = 8, P = 0.014). Inclusion of 5 microM carvedilol before the additions of NMDA/glycine prevented 85% of the increase in [Ca2+]i. Furthermore, carvedilol displaced 3[H]MK-801 binding to rat brain cortical membranes with a Kd of 29.4 +/- 2.2 microM (n = 6) and no selectively for the glutamate or glycine binding sites. These data therefore suggest that, in addition to its antihypertensive and anti-lipid peroxidative functions, carvedilol has neuroprotective activity as a calcium channel blocker and as a non-competitive inhibitor at the NMDA receptor.

Animals↗

PubMed1992

Comparison of stimulated tissue factor expression by brain microvascular endothelial cells from normotensive (WKY) and hypertensive (SHR) rats.

The amounts of tissue factor (TF) expressed by brain microvascular endothelial cells (BMECs) from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were compared after stimulating the cells with different doses of lipopolysaccharide (LPS), thrombin, phorbol myristic acid (PMA), Ca(2+)-ionophore (A23187), or tumor necrosis factor (TNF) and interleukin-1 (IL-1). Treatment of cultured BMECs from WKY and SHR with all of these factors dose-dependently increased their total amount of TF; no substantive differences in the levels of enhanced TF expression were observed between WKY and SHR BMECs. We conclude that stimulated endothelium from rats with hypertension, a major stroke risk factor, is not hyperresponsive with respect to TF expression when compared to normotensive controls.

Animals↗

PubMed1992

Role of complement in endotoxin/platelet-activating factor-induced lung injury.

C receptor-1 is a protein involved in the regulation of C3 and C5-convertases. Recombinant human soluble C receptor-1 has recently been produced and shown to reduce infarct size in a rat model of myocardial ischemia/reperfusion injury. The present study aimed to investigate whether recombinant human soluble C receptor-1 exerts any protective effect on pulmonary injury produced in a rodent model of adult respiratory distress syndrome. In this model, Escherichia coli endotoxin (LPS, 0.1 microgram/kg) combined with platelet-activating factor (1 pmol/kg/min over 60 min, n = 10) caused microvascular lung injury characterized by elevation of myeloperoxidase activity, deposition of C3 and C5b-9 on the endothelium of pulmonary vessels, and pulmonary edema. Furthermore, bronchoalveolar lavage revealed increased neutrophil count and elevated protein concentration. These pulmonary responses were associated with elevated serum TNF-alpha. Pretreatment (10 min, i.v.) with recombinant human soluble C receptor-1 at 10 mg/kg (n = 13), but not at 1 mg/kg, prevented the LPS/platelet-activating factor-induced pulmonary edema (p less than 0.01) and changes in the bronchoalveolar lavage fluid cell count (p less than 0.01) and protein concentration (p less than 0.05), and attenuated the deposition of C3 and C5b-9 to lung vessels. There was no effect on lung myeloperoxidase activity and serum TNF-alpha. Also, C depletion by cobra venom factor (500 U/kg, i.v.) eliminated the pulmonary edema and elevated leukocyte count in bronchoalveolar lavage fluid, but had no effect on lung myeloperoxidase activity and serum TNF-alpha. These data suggest that C factors may play an important role in the pathophysiology of adult respiratory distress syndrome.

Animals↗

PubMed1992

Homologous desensitization of calcitonin gene-related peptide response in rat glomerular mesangial cells in culture.

Addition of calcitonin gene-related peptide (CGRP) to rat glomerular mesangial cells in culture resulted in an increase in cyclic adenosine monophosphate (cAMP) accumulation in a concentration-dependent fashion with an EC50 of approximately 3 nM. Inclusion of CGRP8-37, a CGRP1 selective antagonist shifted CGRP concentration-response curve to the right, suggesting the presence of CGRP1 subtype receptors in these cells. Pretreatment of these cells with CGRP followed by washing and rechallenge with CGRP or isoproterenol or forskolin resulted in selective attenuation of CGRP-mediated cAMP accumulation by 55-60% without affecting isoproterenol or forskolin-mediated accumulation, suggesting that CGRP pretreatment of mesangial cells induced homologous desensitization. CGRP-mediated desensitization of cAMP accumulation was found to be both concentration- and time-dependent. Desensitization did not affect the EC50 of CGRP for stimulation of cAMP accumulation, but resulted in a 55-60% reduction in maximal response. CGRP-mediated desensitization was fast, with half-maximal desensitization occurring as early as 5 min after pretreatment with CGRP. In addition, CGRP-mediated desensitization was blocked by the CGRP receptor antagonist, CGRP8-37, when included in the pretreatment protocol. These data suggest that rat mesangial cells display CGRP1 subtype receptors and that prolonged pretreatment of these cells with CGRP resulted in homologous desensitization.

Animals↗

PubMed1992

Pharmacological profile of G619, a new platelet aggregation inhibitor.

G619, a 4-OH-isophthalic acid derivative, was studied for its capacity to inhibit platelet aggregation. G619 dose-dependently inhibited U46619, collagen, ADP, PAF, thrombin and epinephrine-induced platelet aggregation in vitro. The IC50 values for inhibition of U46619-induced human and rabbit platelet aggregation were 39 and 43 microM, respectively. G619, at 100 microM, inhibited high concentration collagen (10 micrograms/ml)-induced aggregation of rabbit platelets pretreated with indomethacin and increased the level of cAMP in washed rabbit platelets by 30% (p less than 0.01 vs basal). However, G619, did not inhibit fibrinogen binding to GPIIb/IIIa receptor, phosphodiesterase, U46619-induced contractile responses on canine saphenous vein or rabbit aorta, calcium-induced vasoconstriction and thrombin or PAF-induced elevation of [Ca++]i in platelets in vitro. In vivo, the U46619-induced maximal thrombocytopenia in rats was reduced from 40% (vehicle) to 22% and 18% by 10 and 30 mg/kg of G619 i.v., respectively. G619 (30 mg/kg) had no effect on the U46619-induced vasopressor response or sudden death in rats, and had no effect on TxB2 formation. Our results indicate that G619 is a broad-spectrum platelet aggregation inhibitor and may have its effect on a common mechanism for platelet aggregation besides an effect on the thromboxane A2 receptor.

Adenosine Diphosphate↗

PubMed1992

Carvedilol, a new beta-adrenoceptor antagonist and vasodilator antihypertensive drug, inhibits superoxide release from human neutrophils.

Carvedilol produced a dose-dependent inhibition of superoxide (O2-) release from human neutrophils (PMNs) (IC50 = 28 microM) and scavenged O2- generated during dihydroxyfumaric acid (DHF) autooxidation (IC50 = 41 microM). Other beta-blockers, such as celiprolol, labetalol and atenolol, or the antioxidant, 'lazaroid', U74500A had no effect on O2- either released from PMNs or generated during DHF autooxidation. Propranolol, at 0.3 mM, inhibited O2- release from PMNs (73%) but failed to scavenge O2- generated from DHF. The novel free radical-scavenging effect of carvedilol may contribute to the cardioprotective activity of the compound.

Adrenergic beta-Antagonists↗

PubMed1992

Neuroprotective effects of phenyl-t-butyl-nitrone in gerbil global brain ischemia and in cultured rat cerebellar neurons.

We examined the ability of phenyl-t-butyl-nitrone (PBN), an electron spin trapper, to attenuate ischemia-induced forebrain edema and hippocampal CA1 neuronal loss in gerbils, and to protect rat cerebellar neurons in primary culture from glutamate-induced toxicity. PBN, given i.p. at 75 or 150 mg/kg 30 min before ischemia (5 min occlusion), increased survival (at 7 days) of CA1 neurons from 60 +/- 14 (vehicle-treated, n = 17) to 95 +/- 15 (P less than 0.05, n = 15) and 145 +/- 3 (P less than 0.01, n = 15), respectively. When gerbils were treated with PBN (50 mg/kg, i.p.) immediately and 6 h after reperfusion, followed by b.i.d. for an additional 2 days, CA1 neurons survival improved from 35 +/- 9 (vehicle, n = 20, 6 min occlusion) to 106 +/- 17 (P less than 0.01, n = 13). In gerbils exposed to a more severe ischemia (10 min), pretreatment with 150 mg/kg PBN increased the survival of CA1 neurons from 6 +/- 6 (vehicle) to 27 +/- 10 (P less than 0.05, n = 11). Pretreatment with PBN, at 150 mg/kg, reduced forebrain edema (following 15 min ischemia) by 24.7% (P less than 0.01, n = 16). PBN at 50 mg/kg, i.p. had no hypothermic effect and at 75 or 150 mg/kg caused a transient hypothermia. The presence of PBN in the brain was confirmed in microdialysis samples and brain tissue extract using HPLC. In vitro, PBN protected rat cerebellar neurons against 100 microM glutamate-induced toxicity with an EC50 value of 2.7 mM. Our results further support the concept that free radicals contribute to brain injury following ischemia and suggest the potential therapeutic application of electron spin trappers in stroke.

Animals↗