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Biomedical subjects

G Feuerstein

Publications and source records attributed to G Feuerstein.

At least 109 records · Page 6Linked to original sources
PubMed1991

Control of bleeding is essential for a successful treatment of hemorrhagic shock with 7.5 per cent sodium chloride solution.

Small volume hypertonic saline (HTS) solution resuscitation has been shown to restore hemodynamic derangements and to protect against mortality in "controlled" hemorrhagic shock (CHS), but it exacerbates the shock state in "uncontrolled" hemorrhagic shock (UCHS). To study the mechanisms associated with the divergent outcome of HTS treatment in CHS versus UCHS, HTS was administered to anesthetized rats (n = 7) subjected to 15 per cent resection of the tail followed by controlled or uncontrolled bleeding. HTS treatment of UCHS increased bleeding (13.3 +/- 1.6 milliliters, p less than 0.05), dropped mean arterial pressure (MAP) (-84.5 +/- 8.9 millimeters of mercury, p less than 0.001), central venous pressure (zero millimeters of mercury, p less than 0.001) and cardiac index (CI) (41 per cent of basal value, p less than 0.001) and increased acidosis (pH 7.23 +/- 0.12, p less than 0.05) and mortality (mean survival time 75 +/- 15 minutes versus 122 +/- 23 minutes of untreated rats, p less than 0.05). In contrast, when administered after application of a ligature proximal to the resection site (at 15 minutes), HTS completely reversed the changes in MAP, CI and total peripheral resistance index (TPRI), and improved mean survival time (172 +/- 7 minutes, p less than 0.05). These data support the assumption that HTS should be used in the treatment of hemorrhagic shock only after bleeding was controlled.

Acidosis↗
PubMed1990

Excitatory amino acid neurotoxicity at the N-methyl-D-aspartate receptor in cultured neurons: protection by SKF 10,047.

SKF 10,047 (N-allylnormetazocine) was found to be neuroprotective against glutamate-induced excitotoxicity in our model system of energy-stressed neurons which rapidly succumb to glutamate via N-methyl-D-aspartate (NMDA) receptor-mediated events. The 50% protective concentration (PC50) of the (+) and (-) enantiomers was 3.3 microM and 9 microM, respectively, against the toxic action of 100 microM glutamate. Protection by SKF 10,047 seemed to be mediated by the lower-affinity phencyclidine (PCP) binding site rather than the higher-affinity sigma-site since the potent sigma-ligand (+)-3-(3-hydroxyphenyl-N-1-propyl)piperidine [+)-3-PPP) did not protect at concentrations up to 2 mM. A reversed stereoselectivity was apparent for neuroprotection since (-)-3-PPP was weakly protective with a PC50 of 1.5 mM. These data suggest that energy-stressed rat cerebellar granule cells are a useful model for identifying neuroprotective agents, as shown by SKF 10,047.

Animals↗
PubMed1990

Selective hippocampal lesion following omega-conotoxin administration in rats.

Histopathological evaluation of rat brains 3 days following unilateral i.c.v. injections of omega-conotoxin GVIA (omega-ctx), 0.032 and 0.1 nmol/kg, was performed. An isolated unilateral lesion confined to the injected hemisphere was found in the hippocampal CA3 neurons. Morphometric analysis of these cells revealed a significant reduction in cell area in both dose groups compared to i.c.v. injected vehicle, and to the contralateral hemisphere. These data indicate a specific degenerative process and suggest that CA3 cells possess omega-ctx-sensitive Ca2+ channels which are essential to their viability.

Animals↗
PubMed1990

Assessment of damage from implantation of microdialysis probes in the rat hippocampus with silver degeneration staining.

We used a sensitive silver degeneration staining method to study the effects of insertion of microdialysis probes in rat dorsal hippocampus and neocortex. Nine animals were sacrificed 24 h, 3 days or 7 days after implantation of dialysis tubing. Although mild neuronal cell death and small petechial hemorrhages were seen in close proximity to the implantation site, the striking finding was the presence of degenerating axons both adjacent to the implantation site and in remote sites such as the corpus callosum and contralateral hippocampus. The observed changes could alter brain function near or remote from the implantation site and should be considered in analysis of dialysis experiments.

Animals↗
PubMed1990

The influence of cold or isolation stress on resistance of mice to West Nile virus encephalitis.

The effect of cold or isolation stress on mortality rate and brain virus level were investigated in mice infected with West Nile virus (WNV). Exposure of mice for 5 min/day to cold water (1 +/- 0.5 degrees C) for 8-10 days resulted in 92% mortality as compared to 47% in control mice (p less than 0.001). Mice housed in individual cages (isolation stress) were also more susceptible to WN viral infection, as shown by increased mortality rate reaching 85% as compared to 50% in mice housed 6 per cage (p less than 0.01). Cold or isolation stress increased blood brain and spleen virus levels as early as 2 days after inoculation. After 8 days of isolation or cold stress, mice inoculated with WNV had 8.9 and 9.0 log10 plaque forming units in the brain, respectively, as compared to 6.9 in the control (p less than 0.01-0.001). Furthermore, lymphoid organs such as spleen and thymus showed severe mass loss. These data suggest that physical or non-physical stress situations enhance WNV encephalitis by accelerating virus proliferation and increase mortality in mice.

Animals↗
PubMed1990

Monoclonal antibodies against the presynaptic calcium channel antagonist omega-conotoxin GVI A from cone snail poison.

Monoclonal antibodies have been prepared against omega-conotoxin GVI A, a peptide isolated from marine snails of the genus Conus (Conus geographus and Conus magus). This toxin is a blocker of select presynaptic Ca2+ channels in the central nervous system. Antigenic omega-conotoxin GVI A was synthesized as a covalent conjugate with bovine serum albumin and injected s.c. An ELISA assay combined with a competitive inhibition assay was used to select and characterize monoclonal antibodies able to recognize and bind the free toxin. Several of the antibodies were found to block omega-conotoxin GVI A inhibition of 45Ca transport into rat brain synaptosomes and to block omega-conotoxin GVI A binding to membranes from the same preparation. The antibodies recognize native, synthetic toxin, and are useful for analysis of toxin in biological fluids.

Animals↗
PubMed1990

Prominent white matter lesions develop in Mongolian gerbils treated with 100% normobaric oxygen after global brain ischemia.

Carotid arteries were occluded bilaterally for 15 min in two groups of Mongolian gerbils. The first group received 100% oxygen during the first 3 h of reperfusion. During that period, room air was given to the second group. After 3 h, both groups received room air. Brains of gerbils that died within 14 days after occlusion were removed, fixed in formalin and embedded in paraffin. Gerbils that survived 15-28 days were perfused with formalin before their brains were removed and embedded in paraffin. Adjacent, serially cut sections were stained with luxol fast blue (LFB)-H&E, cresyl violet, according to the Bodian method, or immunocytochemically with antisera raised against myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP). In brain sections of gerbils receiving 3 h of 100% oxygen, there were circumscribed white matter lesions in the corpus striatum, lateral thalamus, mesencephalon and posterior limb of the internal capsule. Myelin sheaths were swollen, fragmented and were less intensely stained by MBP antiserum. MBP and LFB-stained myelin fragments were present extracellularly and in macrophages. Many axons in these areas appeared undamaged. Previously described ischemic changes were found in gray matter and some areas of white matter in both groups. However, neurons in the deeper laminae of the cerebral cortex appeared to be better preserved in gerbils given oxygen. The results suggest that hyperoxia, if present immediately after transient brain ischemia, may damage myelin more severely than other cellular elements.

Animals↗
PubMed1990

Cardiovascular effects of anatoxin-A in the conscious rat.

The effects of anatoxin-A on mean arterial pressure (MAP), heart rate, cardiac index (CI), and blood flow (BF) in hindquarter (HQ), renal (R), and mesenteric (M) vascular beds were studied after intravenous (iv) and intracerebroventricular (icv) administration in the conscious rat. The pharmacological profile of anatoxin-A was further compared to nicotine administered iv and icv. MAP and heart rate were measured from femoral artery, CI by thermodilution method, and blood flow by Doppler velocimetry. Anatoxin-A and nicotine (30, 100 and 300 micrograms/kg iv) produced an increase in MAP with concomitant bradycardia. The highest doses increased CI. MBF and RBF decreased due to a vasoconstriction in M and R vasculature. These effects were attenuated by the ganglion blocker chlorisondamine (5 mg/kg, iv). Anatoxin-A (100 micrograms/kg, iv) increased plasma epinephrine levels by 2-fold with virtually no effect on norepinephrine whereas nicotine (100 micrograms/kg, iv) increased plasma epinephrine and norepinephrine by 20- to 30-fold. Central administration of anatoxin-A and nicotine (30-100 micrograms/kg icv) increased MAP with no effect on heart rate and produced M and R vasoconstriction. In summary, the present study demonstrates that anatoxin-A acts as a nicotinic cholinergic agonist in the conscious rat after both systemic and central administration. Anatoxin-A and nicotine produced pressor and reno-splanchnic vasoconstrictor responses and at high doses increased cardiac output. These effects were mediated by activation of the nicotinic receptors in the adrenal medulla and sympathetic ganglia. However, marked differences were found in the potency of anatoxin-A versus nicotine to stimulate the sympathoadrenomedullary axis.

Animals↗
PubMed1990

Pharmacologic profile of BN 50739, a new PAF antagonist in vitro and in vivo.

The effect of a new PAF antagonist BN 50739 was studied on PAF-induced [3H]-serotonin release from washed rabbit platelets in vitro and on PAF-induced hypotension in vivo. BN 50739 competitively inhibited PAF-induced [3H]-serotonin release from the platelets in a dose-dependent manner. In the presence of 4, 10 and 50 nM of BN 50739, the concentration of PAF inducing 50% maximal [3H]-serotonin release from the platelets (EC50) increased from 2.15 nM to 5.10, 45.10 and 900 nM, respectively. The IC50 of BN 50739 for PAF (10 nM) induced [3H]-serotonin release was 3.67 nM. Under the same experimental condition, the IC50s of BN 50726, BN 50730, BN 50741, WEB 2086, SRI 63-441 and BN 52021 were 5.40, 4.61, 6.88, 5.98, 40.90 nM and 14.90 microM, respectively. PAF-induced hypotension in conscious rats was also inhibited dose-dependently by i.p. pretreatment of BN 50739 (3 and 10 mg/kg). PAF-induced hypotension was diminished both in magnitude and duration in rats pretreated with BN 50739. These data taken together indicate that BN 50739 is a most potent PAF antagonist in vitro and in vivo.

Animals↗
PubMed1990

Identification of endothelin receptors in various regions of rat brain.

Endothelins (ET) are a family of 21 amino acid peptides which carry a high degree of hemology. ET-1, originally isolated from porcine endothelium in culture, is an unusually potent vasoconstrictor. Recent studies indicated the presence of ET-1 and ET-3 in the CNS, and autoradiographic evidence supported the presence of specific ET-1 binding sites. The present study aimed to raise evidence in support for the presence of ET-1 and ET-3 receptors in the rat CNS, to establish their spatial distribution, and gain insight on the molecular species which could be associated to ET-1 and ET-3 binding. The data support the presence of specific binding sites for ET-1 and ET-3 and a heterogeneous distribution of these sites in the CNS. The highest densities were found in the cerebellum (greater than 2200 fmol-mg protein) and the lowest in the cerebral cortex (500 fmol/mg protein). Our data also suggest that ET-1 and ET-3 labelled two different proteins of 45 Kd and 37 Kd molecular weight, but no evidence for separate ET-1 and ET-3 receptors could be noted. These data provide further evidence in support for the possible role of ET-1 and ET-3 in neuromodulation/neurotransmission in the CNS.

Animals↗
PubMed1990

Effect of endothelins on cytosolic free calcium concentration in neuroblastoma NG108-15 and NCB-20 cells.

The effects of endothelin(ET)-1, ET-2, ET-3 and Big ET on intracellular level of Ca2+ ([Ca2+]i) were studied in neuroblastoma NG108-15 and NCB-20 cells. All ETs, except Big ET, induced an increase in [CA2+]i in NG108-15 cells in a dose-dependent manner, with EC50: 6.7, 11.2 and 71 nM, respectively. However, none of the ET increased [Ca2+]i in NCB-20 cells. Calcium channel blockers diltiazem or nicardipine had no effect on ET-induced increase in [CA2+]i, but extracellular Ca2(+)-depletion significantly reduced the response of NG108-15 cells to ETs. NG108-15 cells exhibited a homologous desensitization to sequential addition of ETs, but no heterologous desensitization among ET, bradykinin and PAF was observed. These data suggest that ET-induced receptor activation results in increased intracellular Ca2+ via a non voltage calcium channel mechanism and intracellular Ca2+ release.

Animals↗
PubMed1990

Production of platelet-activating factor from rat cerebellar granule cells in culture.

Platelet-activating factor (PAF) is a potent lipid mediator implicated in various pathological conditions, including CNS neuronal injury. However, the production of PAF by mammalian CNS neurons has not as yet been demonstrated. In the present study, we demonstrate that PAF is produced by cultured rat cerebellar granule cells. PAF was identified on the basis of chemical and enzymatic characteristics, biological activities with washed rabbit platelets, and behavior on TLC and HPLC. PAF was detected both in the cells and in the incubation medium, a result indicating the release of PAF from cultured neurons. The amount of PAF produced during a 30-min incubation was as follows: 1.02 +/- 0.10 and 0.93 +/- 0.09 pmol/4 X 10(7) cells in incubation buffer and cells, respectively (n = 10). The calcium ionophore A23187 (2.5 microM) had only a mild stimulatory effect on PAF production, a finding indicating that the neuron-generated PAF might be synthesized mainly by the de novo pathway of PAF production.

Animals↗
PubMed1990

Integrated autonomic and behavioral responses to L/N Ca2(+)-channel blocker omega-conotoxin in conscious rats.

omega-Conotoxin (omega-ctx) was used as a probe for studying the putative role of brain L/N-type Ca2+ channels in regulation of autonomic functions. Rats were injected intracerebroventricularly (icv) with omega-ctx, and hemodynamic, biochemical and behavioral variables were monitored. omega-Ctx (0.032-10 nmol/kg) caused a persistent, dose-dependent shaking behavior, complex thermoregulatory changes, and motor deficits lasting up to 48 h. Cardiovascular responses to omega-ctx included tachycardia (+71 +/- 16%, P less than 0.01) and elevated arterial blood pressure (+16 +/- 1%, P less than 0.05) associated with increased circulating levels of norepinephrine and epinephrine. Higher doses, 1 or 10 nmol/kg, resulted in circulatory shock and death. Central administration of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8), diltiazem (100 or 1,000 nmol/kg), neomycin (100 nmol/kg, each), nifedipine (10 nmol/kg), and CdCl2 (100 nmol/kg), which represent intracellular, non-specific N-, L-, and L/N-type Ca2(+)-channel blockers, respectively, did not cause any behavioral or hemodynamic effects, whereas the L-channel agonist BAY K 8644 (100 nmol/kg icv) caused a mild transient pressor response. Pretreatment with the gamma-aminobutyric acid (GABA) agonist muscimol (icv) or a combined intravenous pretreatment with propranolol and N-methylatropine blocked the omega-ctx effects. Our data suggest that omega-ctx actions in the brain involve central GABAergic mechanisms modulated by yet a different type of Ca2+ channels not characterized by any of the known voltage-operated Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Evidence for platelet-activating factor as a novel mediator in experimental stroke in rabbits.

Platelet-activating factor is a potent mediator of inflammation, which has untoward effects on cerebrovascular and neural elements. While several investigators have reported attenuation of ischemic damage after treatment with antagonists of platelet-activating factor, no study has proved endogenous production of platelet-activating factor in ischemia of the central nervous system. We hypothesized that endogenous production of platelet-activating factor participates in the early pathologic manifestations of deteriorating stroke. In 12 rabbits, we found tissue levels of platelet-activating factor measured by the release of serotonin from washed platelets to be elevated by approximately 20-fold in spinal cord injured by 25 minutes of ischemia and 2 hours of reperfusion (2.80 +/- 0.98 ng/g) compared with that in normal spinal cord (0.15 +/- 0.06 ng/g, p less than 0.01). Given during ischemia to seven rabbits, 10 mg/kg i.p. of a highly selective and potent antagonist of platelet-activating factor (BN 50739) accentuated the early postischemic hyperemia and prevented the delayed hypoperfusion measured by on-line laser-Doppler flowmetry (-35 +/- 7% of baseline [n = 7] without versus 33 +/- 14% with treatment, p less than 0.01) and the edema formation measured as the increase in tissue water content (4.4 +/- 0.7% without [n = 6] versus 2.1 +/- 0.6% with [n = 7]treatment, p less than 0.05) after 2 hours of reperfusion. This neurochemical and pharmacologic evidence emphasizes a new perspective of ischemia-induced phospholipid degradation and suggests an important role for platelet-activating factor in the early manifestations of stroke.

Animals↗
PubMed1990

Effect of endothelin on cortical microvascular perfusion in rats.

We used laser-Doppler flowmetry to study the effects of endothelin-1 on local cortical microvascular perfusion and resistance in 29 pentobarbital-anesthetized rats. Intravenous administration of 10-300 pmol endothelin-1 reduced arterial blood pressure and microvascular resistance and increased microvascular perfusion. However, intracarotid administration of low doses of endothelin-1 increased microvascular perfusion and reduced microvascular resistance and arterial blood pressure, whereas high doses (greater than or equal to 300 pmol) reduced microvascular perfusion and increased microvascular resistance and arterial blood pressure. Only the high dose/low flow response was associated with attenuation of the electrocorticogram. The low dose/high flow and high dose/low flow responses to endothelin-1 were not altered by blockade of muscarinic and adrenergic receptors. In addition, systemic metabolic changes (arterial pH, PaCO2, PaO2, and plasma glucose concentration) did not account for the cerebrovascular effects of endothelin-1. Platelet hyperaggregability also did not appear to be a causative factor in the high dose/low flow response to endothelin-1. In fact, ex vivo rat platelet aggregation was inhibited by intracarotid administration of 300 pmol endothelin-1. In conclusion, the cerebral vasculature exhibits extreme sensitivity to the vasodilator properties of endothelin-1 at low doses. The ischemic vasoconstrictor effects observed at high doses implicate endothelin-1 as an important mediator of cerebral vasospasm and/or postischemic hypoperfusion.

Animals↗
PubMed1990

Respiratory and locomotor stimulation by low doses of dermorphin, a mu1 receptor-mediated effect.

The selective opioid mu receptor agonist dermorphin increased the locomotor activity of rats dose dependently at 10 to 100 pmol/kg i.c.v. Respiratory rate, relative tidal volume and respiratory minute volume also increased unrelated to changes in locomotor activity. Higher doses, on the other hand, produced catalepsy and respiratory depression. Pretreatment of the rats with the mu1-selective antagonist naloxonazine (10 mg/kg i.v.) blocked the stimulant locomotor and respiratory effects of low doses of dermorphin (10-100 pmol/kg), but potentiated the respiratory depressant effect of a high dose (10 nmol/kg) of dermorphin. The selective benzodiazepine antagonist flumazenil (5 mg/kg), which has been shown previously to antagonize catalepsy and respiratory depression produced by relatively high doses of dermorphin, did not antagonize the respiratory or locomotor stimulant effect of dermorphin. The data suggest that mu1-opioid receptors are responsible for the low dose stimulant effects of dermorphin on locomotor activity and respiration whereas mu2 receptors mediate the respiratory depressant effect of dermorphin.

Analgesics, Opioid↗
PubMed1990

Effect of gram-negative endotoxin on levels of serum corticosterone, TNF alpha, circulating blood cells, and the survival of rats.

The relationship between serum tumor necrosis factor (TNF alpha), circulating blood cells, plasma corticosterone (CS), and survival was studied in conscious rats injected intravenously with E. coli lipopolysaccharide (LPS, 0.0001-28.8 mg/kg). The TNF alpha response was dose-related, peaked at 90-120 min after LPS injection, and subsided 6 hr later. The CS response showed an earlier onset, prolonged (greater than 12 hr) duration, and a broader dose-response pattern. White blood cells (WBC) and platelet depletion peaked at 2-4 and 24-48 hr post-LPS, respectively; however, no changes in the cell count were observed at LPS doses which produced greater than 50% maximal increase in TNF alpha levels. Survival curves for each of the LPS doses were significantly different from the doses of LPS which elicited TNF alpha release. Systemic injection of human recombinant TNF alpha (h-rTNF alpha), which produced plasma levels of TNF alpha 10 x 10(7) U/ml, much higher than the maximal TNF alpha levels produced by LPS, 1-2 x 10(5) U/ml, failed to affect survival, plasma WBC, or hematocrit. Our data suggest that factors other than TNF alpha produced by high doses of LPS are essential in eliciting LPS-induced death.

Animals↗