Biomedical subjects

K H Sontag

Publications and source records attributed to K H Sontag.

At least 19 recordsLinked to original sources

PubMed1995

Injection of a minuscule dose of FeCl3 within the ventrolateral striatum causes a chronic disturbance of the integrative function within the limbic part of the ventral striatum.

The present study shows that low amounts of applied iron have a potent effect on the ventrolateral striatum. This is reflected by an influence on spontaneous night activity, cognitive behaviour during the water maze navigation task, exploratory activity and in response to postsynaptic apomorphine stimulation. Such functional disturbances could be observed up to months after a single application of either 0.3 microgram or 1.5 micrograms FeCl3. The low dose of iron stimulates while 1.5 micrograms inhibits the spontaneous dopaminedependent locomotor night and explorative activity. The low concentration of ionic iron injected intrastriatally also increases lipid peroxidation in striatal and hippocampal tissues. These results suggest that the functional integrity of the ventral striatum and the regulation of the iron metabolism are critical for the sensorimotor performance.

Animals↗

PubMed1995

Posttreatment with EPC-K1, an inhibitor of lipid peroxidation and of phospholipase A2 activity, reduces functional deficits after global ischemia in rats.

In this study the effect of an inhibitor of lipid peroxidation and of phospholipase A2 activity, EPC-K1, on spatial learning deficit and neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel occlusion (4VO) for 20 min in rats. EPC-K1 (10 mg/kg IP) was administered either a) 15 min before induction of ischemia, b) immediately after, or c) 30 min after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. EPC-K1 reduced the deficit in spatial learning when given immediately or 30 min after the onset of reperfusion but not when applied 15 min before ischemia. Neuronal damage in the CA1 sector of the hippocampus produced by 4VO was slightly, but not significantly attenuated by posttreatment. The present data demonstrate that posttreatment with EPC-K1 exerts a protective effect on deficits in spatial learning induced by 4VO. These results support the hypothesis that lipid peroxidation and activation of phospholipase A2 contribute to functional alterations of the brain during reperfusion following forebrain ischemia.

Animals↗

PubMed1995

Altered pattern of immunohistochemical staining for glial fibrillary acidic protein (GFAP) in the forebrain and cerebellum of the mutant spastic rat.

The spastic rat is a neurological mutant of the Han-Wistar strain with prominent spasticity, tremor, and ataxia. Neurodegeneration is found in the CA3 sector of the hippocampus and in Purkinje cells of the cerebellum. We examined the forebrain and cerebellum of spastic rats for glial reactions by using immunolabelling for the astrocytic marker, glial fibrillary acidic protein (GFAP). First, a map of the GFAP-distribution was made representing a systematic series of frontal sections in controls. Reactive astrocytes with increased GFAP should occur in the areas with established neuronal degeneration, but they could also demarcate further regions with pathology in this rat strain. Since the baseline levels of GFAP-immunoreactivity differ between brain regions, control rats and clinically normal littermates served as controls to judge relative increases in major structures. In the CA3 sector and hilus of the dorsal hippocampus, a massive gliosis was detected. In the cerebellum, a patchy increase of GFAP labelling in Bergmann glia was found. Further increases of GFAP-labelling in reactive astrocytes occurred in fiber tracts, the ventral thalamic nuclei, medial geniculate nuclei, pontine region and optic layer of the superior colliculus. Inconsistent changes were noted in cortex and pallidum. No defects of glial labelling or malformations in glial architectonics were found. The reactive changes of astroglial cells in hippocampus and cerebellum are in proportion to the neuronal degeneration. The glial reactions in the other brain regions possibly reflect a reaction to fiber degeneration and incipient neuronal degeneration or functional alterations of glial cells in response to neuronal dysfunction.

Animals↗

PubMed1995

Memantine prevents progressive functional neurodegeneration in rats.

The aim of this study was to examine whether the non-competitive NMDA-antagonist memantine might have neuroprotective properties in an animal model of pro-gressive functional neurodegeneration, without producing NMDA-specific learning and memory deficiencies. Rats were subjected to bilateral clamping of the carotid arteries (BCCA) under pentobarbital anaesthesia for 24 min, and 8-10 days later estimates of their escape latency in finding a hidden platform in a Morris water maze indicated a significant increase. This BCCA-induced increase in escape latency is maximally ameliorated by preinjection of 5 mg/kg of memantine, while higher doses have a lesser effect. BCCA for 60 min produces deficiencies in the maze performance during the second experimental day only, when animals were tested 8-10 days after surgery, but results in severe deficits 6 months later. Intraperitoneal injection of 30 mg/kg memantine 10 minutes before BCCA prevents the development of these deficiencies. In parallel experiments, the apomorphine-induced hypersensitivity of the post-synaptic dopamine receptors, observed 12 months after BCCA, was also prevented by the memantine pre-treatment. No neuronal necrosis was observed after BCCA of either 24 minutes' or 60 minutes' duration. The results suggest that memantine complements the therapeutic value of NMDA antagonists. Further, they lend support to the idea that the glutamatergic NMDA-receptor might play a significant role in the BCCA-induced development of progressive "functional neurodegeneration", i.e. behavioural disturbances and dopamine-receptor hypersensitivity.

Analysis of Variance↗

PubMed1995

Cerebral oligemic hypoxia and iron toxicity in the mesolimbic system of rats.

60 min of bilateral clamping of the carotid arteries (BCCA) in pentobarbital anaesthetized adult Wistar rats increases the lipid peroxidation in hippocampal tissue as estimated four weeks later. 1.5 micrograms FeCl3 in 2 microliters buffer injected unilaterally in the ventrolateral striatum enforced the effect when applicated one week after the BCCA treatment. During ageing, the explorative and locomotor behaviour of BCCA rats decreased earlier than the behaviour activities of the controls. These activities show no more changes 9 months after surgery but the BCCA treated rats were more sensitive to 2 mg/kg apomorphine s.c., demonstrated by the distance travelled during 1 hour of habituation in a new environment. BCCA treated rats rotate in response to apomorphine after an intrastriatal and ventrolateral injection of 0.3 microgram FeCl3 15 and 14 weeks, respectively, after BCCA and iron instead of 1.5 micrograms after iron injection alone. Transient BCCA leads to a dramatical increase of released DA. We assume, therefore, that during the autooxidation of released DA, free radicals trigger the increase of lipid peroxidation. Predamaged tissue due to increased lipid peroxidation reacts to very small amounts of iron and iron seems to be more toxic in such cerebral tissue.

Animals↗

PubMed1995

Effect of lazaroid U-74389G on iron-induced reduction of striatal dopamine metabolism.

The substantia nigra of parkinsonian brains is reported to contain increased amounts of iron as compared with age-matched controls. Since iron might be cytotoxic via radical mechanisms, we analyzed the effect of intranigral iron infusion on the dopaminergic activity in the striatum of the rat. The striatal dopamine metabolism of the rat was followed 1, 3, and 6 weeks after unilateral intranigral iron (III) (1.5 micrograms) application. A progressive decrease of extraneuronal 3,4-dihydroxyphenylacetic acid (DOPAC) levels was observed in the ipsilateral striatum by means of in vivo pulse voltammetry. The significant reduction of the DOPAC signal could be attenuated by pretreatment of the animals with the lazaroid U-74389G, applied ip 20 minutes before unilateral intranigral iron application. Our data indicate that a single iron application into the substantia nigra leads to a progressive loss of dopaminergic activity in the striatum, also observed in Parkinson patients. Furthermore, the Lazaroid U-74389G seems to be beneficial in this model of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

The TaClo concept: 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a new toxin for dopaminergic neurons.

Due to its structural analogy to the neurotoxin MPTP, "TaClo" (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline), a compound readily originating in vitro from tryptamine ("Ta") and chloral ("Clo"), is discussed as a potential natural inducer of parkinsonian-like symptoms. Its spontaneous formation in man has to be taken into account after application of the drug chloral hydrate or after exposure to the solvent trichloroethylene. This first representative of chloral-derived heterocycles could now indeed be demonstrated to be formed in vivo after application of its putative precursors to rats. In vivo analysis of the nigrostriatal dopamine metabolism, behavioural studies, and histochemical findings as well as a strong inhibition of the complex I of the mitochondrial respiratory chain revealed the neurotoxic potential of TaClo on the dopaminergic system.

Animals↗

PubMed1995

Biochemical lesions of the nigrostriatal system by TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) and derivatives.

In vivo voltammetry with carbon fibre electrodes was used to study the effects of highly halogenated tetrahydro-beta-carbolines on the striatal dopamine (DA) metabolism of the rat. As representatives of chloral-derived heterocycles, "TaClo" (1-trichloro-1,2,3,4-tetrahydro-beta-carboline) and its N-methylated derivative. "N-methyl-TaClo", were investigated. After intranigral injection of 10 micrograms TaClo, the DA activity in the ipsilateral striatum was reduced compared with the intact side. Application of N-methyl-TaClo (10 micrograms) resulted in a nearly total reduction of the DOPAC signal. Furthermore, also "TaBro" (1-tribromomethyl-1,2,3,4-tetrahydro-beta-carboline), the bromal-derived analogue of TaClo, was tested. The impairment of the DA metabolism in rats achieved with 10 micrograms TaBro was found to be between that observed after application of TaClo and N-methyl-TaClo, respectively. The results demonstrate the toxic potential of chloral- and bromal-derived beta-carbolines towards dopaminergic neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Long-term behavioural effects of TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) after subchronic treatment in rats.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), which shows a great structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when administered to rats lead to enhanced spontaneous locomotion when they were tested 4-9 days after subchronic injection at a daily dose of 0.2 mg/kg over a seven week period. However, 9 weeks after the end of the course of injections animals walked more slowly during 12 hours of nocturnal activity, and apomorphine-induced locomotion was decreased 12 weeks later. These results suggest that the drug may exert a progressive neurotoxic effect.

Analysis of Variance↗

PubMed1994

Influence of short-lasting bilateral clamping of carotid arteries (BCCA) on GABA turnover in rat brain structures.

We have previously shown that short-lasting reduction of cerebral blood flow by bilateral clamping of carotid arteries (BCCA) results in long-lasting increase in regional GABA concentration and decrease in seizure susceptibility in rats. In the present experiments, the effect of BCCA on GABA turnover and the enzymes involved in GABA synthesis and degradation were studied in rats. Regional GABA turnover was measured by means of GABA accumulation induced by the GABA-transaminase (GABA-T) inhibitor aminooxyacetic acid (AOAA). Fourteen days after BCCA, GABA turnover was significantly increased in hippocampus, substantia nigra and cortex, but not different from sham-operated controls in several other brain regions, including striatum, hypothalamus and cerebellum. The activity of glutamate decarboxylase (GAD) measured ex vivo did not show any changes in investigated structures, while the activity of GABA-T was slightly increased in hippocampus. The increased GABA turnover in some brain regions may explain our previous findings of increased GABA content in these brain regions and decreased sensitivity of BCCA treated animals to the GABAA-receptor antagonist bicuculline.

4-Aminobutyrate Transaminase↗

PubMed1994

Reference memory is affected by transient bilateral clamping of the carotid arteries in rats (BCCA).

Rats were subjected to 60 min of bilateral clamping of the carotid arteries (BCCA) in pentobarbital anaesthesia and tested in a hole board with 8 of the 25 holes baited with food pellets hidden in a serial order. All rats learned to recognize the pattern as a reference during an acquisition period at 2-14 days post surgery, i.e. reference memory. During the recall tests 29-37, 165-175 and 240-250 days later BCCA animals showed a decrease in memory revealing a significant increase in reference memory errors. The number of working memory errors, i.e. reexamination of inspected previously baited holes, did not differ from those of sham operated controls. The number of pellets eaten in serial order from hole 1 to hole 8 was significantly decreased in BCCA animals compared with controls, while the number of holes inspected by the animals in the two groups were the same. Thus the observed behaviour changes appear not to be caused by motor or motivation deficiencies.

Analysis of Variance↗

PubMed1994

Levemopamil injection after cerebral oligemia reduces spatial memory deficits in rats.

Transient reduction of cerebral blood flow to oligemic levels as produced by bilateral clamping of carotid arteries (BCCA) in pentobarbital anesthetized Wistar rats leads to spatial orientation deficiencies in a water maze test 8-10 days after surgery. These deficiencies are more pronounced in 4-month-old than in 6-week-old animals. Levemopamil [(2S)-2-isopropyl-5-(methylphenethylamino)-2-phenylvaleronitril e hydrochloride], a Ca2+ channel blocker and 5-HT2 antagonist, prevents the deficiencies in groups of animals of both ages, even when administered 24 h after the transient vessel occlusion. Levemopamil did not influence the maze performance of sham-operated control rats. Levemopamil, therefore, appears to modulate mechanisms that are altered specifically either by, or as a consequence of, the BCCA procedure. Levemopamil did not influence the altered GABA or ACh content in different vulnerable brain structures following BCCA, showing that the substance acts via additional mechanisms affected by the BCCA procedure.

Acetylcholine↗

PubMed1994

Effect of transient reduction of cerebral blood flow on membrane anisotropy and lipid peroxidation in different rat brain areas.

Light-microscopical studies revealed that oligemic hypoxia for 24 and 60 min as produced by bilateral clamping of the carotid arteries (BCCA) in normotension does not produce neuronal cell necrosis in the vast majority of rat brain. Less than 5% of cases showed a pattern of mild selective neuronal necrosis as would be expected in ischemia. However, significant changes in both lipid peroxidation (as measured by MDA formation) and membrane anisotropy (measured by DPH or TMA-DPH, respectively, as a fluorescence probe) in cortical and striatal, but not in hippocampal, membrane fractions could be measured in ex vivo studies. Twenty-four and 60 min of BCCA without reperfusion decreased lipid peroxidation in the cerebral cortex but not in the striatum. BCCA, either for 24 or 60 min, and 60 min of reperfusion produced no changes in lipid peroxidation in either structure. However, 24 and 60 min of BCCA followed by 14 days of reperfusion led to a significant increase in MDA formation in the striatum, while lipid peroxidation in the cortex was only increased after 60 min of BCCA. Cortical as well as striatal membrane anisotropy increased significantly 14 days later in rats submitted to BCCA for 24 or 60 min. The study shows an increased lipid peroxidation 2 weeks after a transient reduction in cerebral blood flow although no neuronal necrosis could be observed in general.

Animals↗

PubMed1994

Differential effects of transient occlusion of common carotid arteries in normotensive rats on the somatosensory and visual system.

The effect of transient occlusion of both carotid arteries in normotensive rats (BCCA) on the electrical function of the central nervous system was monitored by recording somatosensory evoked potentials (SEPs), visual evoked potentials (VEPs) and electroretinogram (ERG). The amplitude and latency of cortical SEPs were not affected by BCCA. In contrast, the latency of P1 and N1 of VEPs were increased and the peak-to-peak amplitude (P1-N1) decreased. The amplitude of the b-wave of the ERG was reduced and its latency increased during BCCA. These changes in VEPs and ERG were limited to the period of BCCA. During the first hour of reperfusion VEPs and the b-wave of the ERG revealed no differences between former occluded animals and sham-operated controls. The present results suggest that both sensory pathways display a different susceptibility to BCCA.

Animals↗

PubMed1993

The glia-derived protease nexin 1 persists for over 1 year in rat brain areas selectively lesioned by transient global ischaemia.

The re-expression of the developmentally regulated serine protease inhibitor glia-derived nexin (GDN) was investigated 1 year after transient global ischaemia induced by the four-vessel occlusion technique in rats. The CA1 sector of the hippocampus was severely shrunken due to the absence of pyramidal cells, but still clearly discernible due to the continued presence of the parvalbumin-containing GABAergic neurons. In this partially neuron-depleted hippocampus, GDN immunoreactivity was found in reactive astrocytes containing glial fibrillary acidic protein. GDN-positive astrocytes were also found in other lesioned areas, the reticular thalamic nucleus and the cerebellar cortex. Thus, the re-expression of GDN in the adult excitotoxically lesioned brain described previously in the gerbil model of ischaemia persists. The continued presence of the protease inhibitor might disturb the proteolytic balance and lead to the deposition of pathological breakdown products of proteins, e.g. beta-amyloid.

Amyloid beta-Protein Precursor↗

PubMed1993

Effect of transient reduction of cerebral blood flow in normotensive rats on striatal dopamine-release.

Bilateral Clamping of both Carotid Arteries (BCCA) in normotensive rats is known to cause a transient reduction in cerebral blood flow. Using in vivo trans-striatal microdialysis and HPLC/ECD we measured the release of dopamine and DA-metabolites under these oligemic conditions. BCCA caused a substantial stimulation of striatal DA-release (40-fold) and a decrease of the outflow of DA-metabolites. The elevated DA-release returned to baseline levels before the onset of reperfusion. Upon reperfusion, DA-metabolites rose above their initial baseline values. Trans-striatal administration of glutamate-diethylester (GDEE, 10 mM) attenuated the oligemia-induced DA-release. A sudden reduction of blood flow appears to disrupt the compartmentation of dopamine in striatal dopaminergic nerve endings in a similar but more moderate manner as compared to ischemia.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Functional studies on monoaminergic transmitter release in parkinsonism.

1. In vivo pulse voltammetry and apomorphine induced circling behaviour were used to study the effect of antiparkinsonian drugs and neurotoxins on striatal, extraneuronal dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations which are a measure of dopamine (DA) release/DA metabolism and serotonin (5-HT) release, respectively. 2. The DA precursor dihydroxyphenylalanine (DOPA, i.p.) increased extraneuronal DOPAC and reduced 5-HIAA levels whereas the opposite effect was induced by the 5-HT precursor 5-hydroxytryptophan (5-HTP, i.p.). Tryptophan, i.p., decreased the extraneuronal DOPAC levels without significant effect on 5-HT release. 3. The monoamine oxidase (MAO) inhibitors pargyline, i.p., and deprenyl, i.p., as well as the DA agonist apomorphine, i.p., decreased the catechol signal. The DA antagonist haloperidol, i.p., increased extraneuronal DOPAC. 4. In longterm studies unilateral application of the neurotoxins 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetra-hydroxypyridine (MPTP), and 1-methyl-4-phenylpyridinium cation (MPP+) into the substantia nigra pars compacta abolished the DOPAC signal in the striatum at the lesioned side. This effect can be partially or fully restored by DOPA depending on the time elapsed after neurotoxin administration. 5. In accordance with the voltammetric recorded unilateral lesion of the dopaminergic system the apomorphine stimulated circling behaviour was significantly enhanced in MPTP and MPP+ treated rats as compared with controls. 6. The results obtained indicate that antiparkisonian drugs and neurotoxins besides their effect on total catecholamine and 5-HT concentrations change specifically the extraneuronal levels of the transmitter (metabolites). Moreover the results suggest that neurotoxin-treated rats can be used as a model to study Parkinson-like effects with regard to the pathogenesis and treatment of this disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1993

Metabolic changes during and after transient clamping of carotid arteries in normotensive rats.

In the present experiments changes of local metabolism in the striatum, hippocampus, and frontal cortex during and after transient clamping of carotid arteries in normotensive rats (BCCA) were studied by continuous measurement of local cerebral temperature, partial oxygen tension (PO2), and extracellular levels of lactate. Local temperature in the striatum, hippocampus, and frontal cortex fell between 1.7 and 2.3 degrees C upon occlusion and quickly returned to preocclusion values after free flow had been established. Local PO2 was reduced in the striatum, hippocampus, and frontal cortex to values between 70 and 30% during BCCA. Immediately after termination of BCCA the PO2 showed a tendency to recover in the striatum and frontal cortex, whereas in the hippocampus, this process started later. Extracellular levels of lactate within these three structures increased during BCCA and went down to preocclusion values within the observed period of reperfusion. The results suggest that BCCA induces a transient anaerobic metabolism that seems to be sufficient to evoke functional changes without neuronal damage.

Animals↗