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J Krieglstein

Publications and source records attributed to J Krieglstein.

At least 127 records · Page 7Linked to original sources
PubMed1991

[Pharmacologic basis of therapy for cerebral ischemia].

During the last 5 years neuroprotective effects of drugs have been intensively investigated. Various in vivo and in vitro models are available for testing neuroprotective actions of drugs. Calcium antagonists, glutamate antagonists, oxygen radical scavengers, 5-hydroxytryptamine-1A (5-HT1A) agonists and platelet activating factor (PAF) antagonists are experimentally well characterized as neuroprotectives and, thus, provide a basis for the development of clinically effective drugs.

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PubMed1990

Neuroprotective effect of memantine demonstrated in vivo and in vitro.

The purpose of the present study was to test whether the anticonvulsant, memantine (1-amino-3,5-dimethyladamantane), can protect neurons against hypoxic or ischemic damage. To this end, we used a rat model of transient forebrain ischemia and cultured neurons from chick embryo cerebral hemispheres. Ischemia was induced for 10 min by clamping both carotid arteries and lowering the mean arterial blood pressure to 40 mm Hg; the rats were allowed to recover for 7 days. Cultured neurons were made hypoxic with 1 mmol/l NaCN added to the incubation medium for 30 min followed by a recovery period of 3 days. The possible effects of memantine were compared with those produced by a typical non-competitive NMDA antagonist, dizocilpine. Similar effects were obtained with both drugs. The drugs reduced the damage caused by transient ischemia to neurons of the hippocampal CA1 subfield. Memantine (10 and 20 mg/kg) had a dose-dependent effect when administered intraperitoneally to the rats 1 h before ischemia. Dizocilpine was active in this model at a dosage of 1 mg/kg. When administered after ischemia, 10 mg/kg memantine significantly protected CA1 neurons against ischemic damage. Furthermore, the drugs protected cultured neurons against hypoxic damage. The lowest effective concentration was 0.1 mumol/l for dizocilpine and 1 mumol/l for memantine. Thus, memantine possesses neuroprotective activity but is less potent than dizocilpine.

Adenosine Triphosphate↗
PubMed1990

Cultured neurons for testing antihypoxic drug effects.

Cultured neurons of chick embryo cerebral hemispheres were used as an in vitro system for investigating the influence of several drugs on neuronal cell viability and metabolic activity under hypoxic conditions. Hypoxia was induced by addition of sodium cyanide to the nutrient medium, which led to a rapid depletion of energy stores. The ATP level of the cells and the protein content of the cultures were used to characterize the degree of neuronal damage after cytotoxic hypoxia and recovery, respectively, recovery lasting 15 min or 3 days. Various calcium antagonists, NMDA-antagonists, central depressants, central stimulants, nootropics, and miscellaneous drugs were tested. NMDA-antagonists and central depressants consistently protected the neurons against alterations caused by hypoxia. However, only one (flunarizine) out of five calcium antagonists, two (naftidrofuryl, pyritinol) out of 13 nootropics, the kappa-agonist ketazocine, and the ATPase inhibitor ouabaine exerted neuroprotection. The in vitro model seems to be suitable for testing neuroprotective drug effects and to be a valuable supplement for in vivo experiments, especially when the cellular mechanism of drug action has to be clarified.

Adenosine Triphosphate↗
PubMed1990

Protective effect of nimodipine against ischemic neuronal damage in rat hippocampus without changing postischemic cerebral blood flow.

The purpose of the present study was to investigate the neuroprotective action of nimodipine. Furthermore, the influence of nimodipine on postischemic local CBF (LCBF) was examined. Forebrain ischemia of the rat was performed for 10 min by bilateral carotid clamping, administration of trimethaphan, and blood withdrawal to obtain an MABP of 40 mm Hg. LCBF was measured after 10 min of postischemic recirculation by injecting [14C]iodoantipyrine in saline solution. Nimodipine (0.1, 0.3, and 1.0 mg/kg) was suspended in miglyol oil and applied orally 60 min prior to ischemia. Histological evaluation was performed 7 days after ischemia. Hippocampal neuronal damage was determined as the percentage of necrotic neurons. After preischemic application of nimodipine, neuronal damage was significantly reduced in the hippocampal CA1 subfield. Postischemic LCBF was not affected by treatment with nimodipine. These findings show that nimodipine is able to protect neurons against ischemic damage. The neuroprotective effect of nimodipine was not mediated by a postischemic cerebral vasodilation, but by a direct action on the neurons.

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PubMed1990

PAF antagonist ginkgolide B reduces postischemic neuronal damage in rat brain hippocampus.

We investigated the effect of the known antagonist of platelet-activating factor (PAF), ginkgolide B, on postischemic neuronal damage in the rat. Neuronal necroses were evaluated in the hippocampus 7 days after a 10-min forebrain ischemia. Preischemic application of ginkgolide B (50 mg/kg p.o.) significantly reduced neuronal damage. It is suggested that the antagonism of PAF is responsible for this beneficial effect of ginkgolide B.

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PubMed1990

Effects of delayed administration of methohexital and ketamine on posthypoxic cell damage of primary neuronal cultures.

Primary neuronal cultures from chick embryo cerebral hemispheres received NaCN (cytotoxic hypoxia) for 120 min and were then allowed to recover. Methohexital (300 mumol/l) or ketamine (30 mumol/l) given either before or during the hypoxic period elevated adenosine triphosphate (ATP) content of the cultures 15 min after hypoxia. Prehypoxic administration of ketamine also preserved the structural integrity and ATP content of neurons 20 h later, while methohexital did not. Ketamine elevated ATP content as measured 20 h after hypoxia even when administered 15 min after beginning of recovery. Pharmacokinetic reasons for contradictory effects of ketamine on neuronal cell loss in vivo ischemia studies and our in vitro experiments are discussed.

Adenosine Triphosphate↗
PubMed1990

Effects of vinpocetine on local cerebral blood flow and glucose utilization seven days after forebrain ischemia in the rat.

A marked neuronal cell loss has been determined in the hippocampal CA1-subfield of the rat 7 days after 10 min of ischemia. The purpose of the present study was to evaluate the consequences of ischemia-induced hippocampal neuronal damage on local cerebral glucose utilization (LCGU) and blood flow (LCBF). Forebrain ischemia of 10 min duration was induced in male Wistar rats. Seven days after ischemia LCGU was measured with the [14C]-2-deoxy-D-glucose method, and LCBF was determined with the [14C]-iodoantipyrine technique in sham-operated and in ischemic rats. Furthermore, postischemic LCGU and LCBF were determined in vinpocetine-treated ischemic rats. Vinpocetin (14-ethoxycarbonyl-(3 alpha, 16 alpha-ethyl)-14,15-eburnamine) has already proved to protect hippocampal neurons against ischemic damage. In comparison with sham-operated rats, LCGU increased and LCBF decreased significantly in the CA1-subfield 7 days after ischemia. Both effects were abolished by preischemic vinpocetine treatment supporting the presumption that this drug is protective against ischemic damage.

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PubMed1990

Neuroprotective effect of nimodipine is not mediated by increased cerebral blood flow after transient forebrain ischemia in rats.

In the present study, we investigated the protective effect of nimodipine against postischemic neuronal damage in the rat and considered the question of whether this histologic finding coincides with an improvement of cerebral circulation. Male Wistar rats were subjected to 10 minutes of forebrain ischemia by clamping both common carotid arteries and lowering blood pressure to 40 mm Hg. Histologic evaluation was performed 7 days after ischemia. Local cerebral blood flow was determined with the 14C-iodoantipyrine technique in anatomically defined areas of the brain, including hippocampus. Preischemic application of nimodipine (3.0 mg/kg p.o.) significantly reduced the percentage of damaged neurons in hippocampal CA1 subfield from 78 +/- 4% in controls to 59 +/- 6% in treated rats (mean +/- SEM; p less than 0.05, Mann-Whitney U test). After 10, 60, and 180 minutes of recirculation no differences in local cerebral blood flow between control and drug-treated animals were observed. Our results demonstrate that nimodipine reduces ischemia-induced neuronal damage in rat hippocampus. We did not consider increased cerebral blood flow in the hypoperfusion state in the applied experimental design since improvement of cerebral blood flow seems to bear little relation to the neuroprotective activity of nimodipine.

Animals↗
PubMed1989

Morphine-induced alterations of local cerebral glucose utilization in the basal ganglia of rats.

The actions of various doses of morphine on the local cerebral glucose utilization (LCGU) were studied by means of the autoradiographic [14C]2-deoxyglucose technique. Morphine (1-15 mg/kg i.p.) decreased LCGU in most areas of the basal ganglia (caudate nucleus, globus pallidus, nucleus accumbens), but not in the substantia nigra pars compacta. LCGU was also decreased in limbic nuclei, such as septum, hippocampus and amygdala, and in most thalamic areas. In most cortical regions, a decrease was found as well. Findings in some efferent nuclei seemed of particular interest, namely in the substantia nigra pars reticulata, anteroventral and lateral nucleus of the thalamus and the subthalamic nucleus, where decreases in LCGU were found after administration of 7.5 mg/kg or sometimes lower doses, but not after 15 mg/kg of morphine. The decreases seem to reflect a general depressory effect of morphine on neuronal activity which is known from electrophysiological studies. Part of these effects might be, in addition, due to an activation of dopaminergic neurons, since dopamine mainly acts as an inhibitory neurotransmitter. This dopaminergic activation leads to characteristic behavioral effects after lower doses of morphine. The largest dose used (15 mg/kg) produces muscular rigidity, probably by a direct action on the striatum. This effect antagonizes and masks the dopaminomimetic effects. The results suggest that it also antagonizes the functional alterations in some efferent nuclei of the basal ganglia manifest after lower doses of morphine. Local injections of morphine (15 micrograms) led to decreases of LCGU in the various parts of the striatum, but to increases in lateral and anteroventral thalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Apomorphine-induced alterations in cortical EEG activity of rats. Involvement of D-1 and D-2 dopamine receptors.

EEG activity after activation of dopamine receptors of D-1 and/or D-2 type was studied by using telemetric recordings in rats. Apomorphine, a preferential D-2 agonist, produced a characteristic increase in the power of alpha-1 band (7.00-9.50 Hz) when given in doses mediating stereotypies (0.2 or 0.5 mg/kg s.c.). Low doses produced a general increase in the power of all of the bands except beta-2. In particular, delta activity was enhanced which seems to be in correspondence with the sedation observed after these doses (0.02 and 0.05 mg/kg). Haloperidol in a dose which is assumed to block both D-1 and D-2 receptors (0.1 mg/kg i.p.) completely antagonized the alpha-1 activation produced by apomorphine (0.5 mg/kg). A similar, although not complete inhibition of alpha-1 activation was found after administration of a large dose of the selective D-1 antagonist SCH 23390 (0.2 mg/kg i.p.). The selective agonist at D-2 receptors quinpirole (1.0 mg/kg s.c.) produced a less pronounced activation of the power in the alpha-1 band than apomorphine. In general, there was found to be a good correlation between the activation of the alpha-1 activity and stereotyped behaviour. The results suggest that for the full expression of alpha-1 activation, a pronounced activation of D-2 receptors and at least a minimal activation of D-1 receptors, for instance by the endogenous dopamine, is necessary.

Animals↗
PubMed1989

Testing drug effects against hypoxic damage of cultured neurons during long-term recovery.

Cultured neurons of chick cerebral embryo hemispheres were used to study drug effects against neuronal damage caused by hypoxia during long-term recovery. Sodium cyanide (NaCN, 1 mmol/l) induces hypoxia-like conditions by inhibiting oxydative phosphorylation. The sensitivity of the cultured neurons against this type of hypoxia was determined after 3, 4, 5 and 6 days of cultivation followed by 4, 3, 2 days and 1 day of recovery, respectively. The ATP level and the viability of cells as well as the total cell number and the protein content of the cultures were used to characterize the extent of posthypoxic neuronal damage. A hypoxic period of 30 min after 4 days of cultivation followed by 3 days of recovery seemed to be appropriate for determining protective drug effects. The drug effects obtained were comparable to those from in vivo models of cerebral ischemia or hypoxia. The results suggest that cultured neurons exposed to hypoxia and to long-term recovery could be suitable for studying post-hypoxic neuronal damage as well as neuroprotective drug effects.

Adenosine Triphosphate↗
PubMed1989

Naftidrofuryl protects neurons against ischemic damage.

The effects of naftidrofuryl on postischemic neuronal damage and on local cerebral blood flow (LCBF) were examined in a rat model of forebrain ischemia (occlusion of carotid arteries and hypotension). Ischemia was induced for 10 min. LCBF was measured after 2 and 10 min of recirculation. A histological evaluation of cell loss in the hippocampal areas was performed 7 days after ischemia. Naftidrofuryl (10 mg/kg) was administered intraperitoneally 15 min before ischemia. The drug reduced the percentage of necrotic neurons in the CA1 and CA4 sector of the hippocampus, while the LCBF of these hippocampal sections was not significantly altered. Thus, naftidrofuryl is suggested to protect hippocampal neurons against ischemic damage mainly by a direct effect on brain parenchyma.

Animals↗
PubMed1988

Effects of flunarizine on postischemic blood flow, energy metabolism and neuronal damage in the rat brain.

The effects of flunarizine on local cerebral blood flow, cortical energy metabolism and neuronal necrosis were evaluated in a rat model of forebrain ischemia. The application of flunarizine (2 X 40 mg/kg p.o.) at 24 and 4 h before ischemia accelerated the restoration of cortical high-energy phosphates during early post-ischemic recirculation and also increased the flow in cortical but not in hippocampal areas. Neuronal necrosis was reduced in the hippocampal CA 1 sector but unchanged in the cortex. It is concluded that flunarizine reduces ischemic damage mainly via a direct effect on brain tissue.

Animals↗
PubMed1988

Phencyclidine reduces postischemic neuronal necrosis in rat hippocampus without changing blood flow.

In this report the effects of phencyclidine (PCP) on physiologic variables, local cerebral blood flow (LCBF), and on hippocampal cell damage were measured in a rat model of forebrain ischemia (2-vessel occlusion and hypotension). Ischemia was induced for 10 min. LCBF was determined after 2 min of recirculation, using the [14C]iodoantipyrine technique. Hippocampal cell loss was quantified histologically 7 days postischemia as the percentage of acidic stainable neurons. Intravenous application of PCP (2 mg/kg) at 15 min prior to ischemia left postischemic LCBF unchanged, but neuronal damage was significantly reduced in hippocampal CA1 sector from 46 to 15.7%. PCP is concluded to reduce ischemic damage of neurons mainly via a direct effect on brain tissue.

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