Biomedical subjects

K H Sontag

Publications and source records attributed to K H Sontag.

At least 19 recordsLinked to original sources

PubMed1992

Retinal ischemia induced by occlusion of both common carotid arteries in rats as demonstrated by electroretinography.

In 2 models of reduced cerebral blood flow-permanent occlusion of the vertebral arteries plus transient occlusion of the common carotid arteries (4VO) and transient clamping of the common carotid arteries (BCCA)-the acute effects on the electrical function of the retina were monitored by recording the photopic electroretinogram. During both 4VO and BCCA the amplitude of the b-wave was reduced. Within 30 min of reperfusion after 4VO and after BCCA the b-wave had fully recovered. In contrast, the a-wave was not affected by either treatment. The data suggest that occlusion of common carotid arteries leads to retinal ischemia and might represent a useful model of amaurosis fugax.

Animals↗

PubMed1992

N-methyl-D-aspartate (NMDA)-mediated muscle relaxant action of memantine in rats.

The present study examined in vivo whether memantine exerts muscle relaxant activity via an antagonistic action at N-methyl-D-aspartate (NMDA) receptors. Intraperitoneal (i.p.) administration of memantine, 50-100 mumol/kg, reduced the tonic activity in the electromyogram recorded from the gastrocnemius muscle of spastic mutant rats. This effect was prevented by coadministration of NMDA. Memantine, while not affecting monosynaptic Hoffmann (H)-reflexes, depressed polysynaptic flexor reflexes in anaesthetized rats following i.p. (6.25-100 mumol/kg) or intrathecal (i.t., 10-500 nmol) administration. The latter effect was prevented by i.t. coadministration of NMDA, but not of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). These observations suggest that NMDA receptors might be involved in the mediation of the muscle relaxant activity of memantine.

Animals↗

PubMed1992

Abnormalities of somatosensory evoked potentials in the quinolinic acid model of Huntington's disease: evidence that basal ganglia modulate sensory cortical input.

Intrastriatal injection of quinolinic acid (QA) in rats provides an animal model that mimics some of the neuropathological and neurochemical alterations observed in the striatum of patients with Huntington's disease (HD). One of the very early neurophysiological signs in HD is a diminution of amplitude of early somatosensory evoked potentials (SEPs) recorded over the parietal cortex. The present study investigated whether the QA model exhibits similar neurophysiological abnormalities. Two weeks after unilateral intrastriatal injection of QA (240 nmol) or of the solvent, early SEPs were recorded with chronically implanted electrodes from the somatosensory cortex or from the ventrobasal nucleus of the thalamus of lightly pentobarbital-anesthetized rats, in response to single-shock electrical stimulation of the contralateral forepaw. Whereas intrastriatal injection of solvent did not influence SEPs, the striatal QA lesion significantly reduced the amplitude of early cortical SEPs by about 40% without affecting the latency. SEPs recorded from the ventrobasal nucleus were unchanged after QA lesion. Histological examination and glial fibrillary acid protein staining after intrastriatal injection of QA revealed no evidence for damage in the somatosensory system. It is concluded that (1) the QA animal model of HD mimics some of the SEP abnormalities of patients, and (2) a striatal lesion modulates somatosensory transmission to the cortex in rats.

Animals↗

PubMed1992

Transient reduction of cerebral blood flow leads to longlasting increase in GABA content in vulnerable structures and decreased susceptibility to bicuculline induced seizures.

Rats were exposed for 24 min to bilateral clamping of the common carotid arteries (BCCA) in pentobarbital anaesthesia. The GABA content was measured 24 hours, 48 hours, 4 days, 14 days and 3 months after BCCA. In other groups of rats seizures were elicited by i.p. injection of (+)-bicuculline (3 mg/kg) 24 hours, 48 hours, 4 days, 14 days and 3 months after BCCA. Analysis of the GABA content revealed significant increase compared with controls in the hippocampus, frontal cortex and substantia nigra from 24 hours up to 3 months. Bicuculline treatment induced tonic/clonic seizures and status epilepticus in sham operated animals; these effects were drastically diminished at various time points after BCCA. The present results suggest that BCCA produces a longlasting increase in GABA content and as a consequence protection from bicuculline-induced seizures.

Animals↗

PubMed1992

Behavioural effects after cholinergic stimulation of the reticular thalamic nucleus in rats.

This study investigated the functional relationship between the experimentally induced changes in the activity of the cholinergic, muscarinergic system of the rostral area of the nucleus reticularis thalami (TRN) and the motor behaviour. The effect of direct stimulation of the rostral TRN by the cholinergic agonist carbachol on the behaviour of freely moving rats was observed. Unilateral injection of carbachol (0.2-3.2 micrograms/0.5 microliters) into the rostral TRN caused catalepsy which appeared rapidly and was short-lasting. Furthermore, it induced impairment of the performance on the rota rod. Both effects were dose-dependent. The cholinergic antagonist scopolamine (6.66 micrograms) coadministered with the equimolar dose of carbachol (3.2 micrograms) antagonized the effects of carbachol on both behavioural tests. The described effects seem to be cholinergic- and site-specific within the rostral TRN. The present results suggest that activation of the cholinergic, muscarinergic receptors in the rostral TRN modulate the motor function of rats.

Animals↗

PubMed1992

In vitro and in vivo experiments--what is more informative?

In-vitro experiments offer a lot of informations but if in-vitro technics would be used exclusively for drug research and screening of new substances the complete pharmacological profile would be unknown. It is always necessary to integrate knowledge of basic research into living and active animals. The fruitful co-operation between theoretical and clinical disciplines--as demonstrated by the L-DOPA story here--demonstrates how to achieve real progress in medical research and the question which type of experiments is more informative is not relevant.

Animals↗

PubMed1991

Transient occlusion of rat carotid arteries decreases susceptibility to pilocarpine seizures.

Bilateral clamping of the carotid arteries (BCCA) for 24 min protects animals against convulsive effects of intraperitoneal injection of 300 mg/kg of pilocarpine when administered 14 days after surgery. Electrographic recordings from hippocampus, frontal cortex, striatum and substantia nigra demonstrate that (1) no spontaneous spiking activity is caused by the BCCA when observed for up to 10 days after surgery, (2) spiking activity can only be recorded in limbic structures but not in the frontal cortex after systemic administration of pilocarpine. These observations suggest that the propagation of seizure activity from subcortical limbic structures to the neocortex is affected by BCCA.

Animals↗

PubMed1991

Neuronal degeneration in hippocampus and cerebellum of mutant spastic Han-Wistar rats.

The neuropathology of the brain of mutant spastic Han-Wistar rats (Han-Wist SPA/SPA) was investigated using histological techniques. A surprising result was the detection of neuronal degeneration in the hippocampus and cerebellum of mutant spastic rat brains, whereas other regions, e.g. neocortex, isocortex, basal ganglia and thalamus, were overall normal. The CA3 sector in the septal third of the hippocampus including the cell band reaching into the hilus ('CA3c') showed a severe neuronal degeneration, whereas the granule cells of the dentate gyrus, several hilar neurons ('CA4') and the pyramidal cells in CA1 were found normal. In the cerebellum, a variable patchy degeneration of Purkinje cells was detected while the general layering was normal and granule cells and Golgi cells appeared preserved.

Animals↗

PubMed1991

Paradoxical anticonvulsant activity of the gamma-aminobutyrate antagonist bicuculline methiodide in the rat striatum.

Bicuculline methiodide (BMI), a gamma-aminobutyrate (GABA) antagonist, is a powerful convulsant agent when injected into the cerebral ventricles, amygdala, hippocampus, thalamus, neocortex, and deep prepiriform cortex in rats. In contrast, bilateral microinjection of BMI into the rat striatum confers protection against seizures induced by the cholinergic agonist pilocarpine (380 mg/kg, i.p.), with an ED50 of 94 fmol (range 45-195 fmol). No topographical variation in the anticonvulsant action of BMI was detected throughout rostrocaudal and dorsoventral aspects of the striatum. The anticonvulsant action of BMI in the striatum was reversed by coadministration of the GABA agonist muscimol or by blocking GABA-mediated inhibition in either the substantia nigra pars reticulata or in the entopeduncular nucleus. The results show that blockade of GABA-mediated inhibition in the striatum has a powerful anticonvulsant effect in the pilocarpine model, suggesting that GABAergic transmission in the striatum modulates the seizure propagation in the forebrain.

Animals↗

PubMed1991

Damage of substantia nigra pars reticulata during pilocarpine-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation.

The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of pilocarpine in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific calcium-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial calcium-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus.

Animals↗

PubMed1991

Decreased susceptibility to seizures induced by bicuculline after transient bilateral clamping of the carotid arteries in rats.

Rats were exposed for 24 min to bilateral clamping of the common carotid arteries (BCCA) in pentobarbital anaesthesia. 14 days later the animals were subjected to subcutaneous injection of (+)-bicuculline (3 or 4 mg/kg). A significantly decreased susceptibility to bicuculline-induced seizures could be observed in BCCA treated rats compared with sham operated controls. It is suggested that BCCA treatment protects animals against status epilepticus and lethal toxicity produced by bicuculline. Electrographic recordings of the BCCA animals revealed no ictal activity within 1 h after bicuculline injection. An analysis of the GABA content showed a significant increase in the hippocampus (HPC), frontal cortex (FCX), parietal cortex and substantia nigra in BCCA animals compared with controls. It is therefore possible that an increase in GABA content postsynaptically counteracts the GABAA antagonistic effect of bicuculline in BCCA animals thus preventing the normal seizure inducing effect of this substance.

Animals↗

PubMed1991

Effects of bilateral clamping of carotid arteries on hippocampal kindling in rats.

Moderate reduction of cerebral blood flow by bilateral clamping of carotid arteries (BCCA) in pentobarbital anaesthetized Wistar rats induces decreased PO2 and temperature values in vulnerable brain structures such as hippocampus and frontal cortex during the acute phase of clamping. Up to two weeks chronic increased GABA contents in hippocampus, substantia nigra and frontal cortex could be observed. During this time the development of hippocampal kindling was difficult. These results demonstrated an acute and chronic influence of GABA on most vulnerable brain structures which, however, do not lead to ischemic impacts as histological analyses demonstrate.

Animals↗

PubMed1991

Reduction of ocular blood flow results in glial fibrillary acidic protein (GFAP) expression in rat retinal Müller cells.

Reduction of blood flow to the rat retina was achieved by either clamping both carotid arteries briefly (24 min) or combining clamping of the carotid arteries with permanent occlusion of the vertebral arteries. Analysis of retinas 6 days after operations showed that GFAP immunoreactivity is expressed throughout the retinal Müller cells, although this was variable in retinas from animals where only the carotid arteries were clamped. GFAP immunoreactivity was not associated with retinal Müller cells from control animals and no obvious neuronal damage was observed in retinas from operated animals. These data suggest that Müller-cell GFAP expression may be used as an index to follow possible processes leading to an ischemic insult.

Animals↗

PubMed1990

Spatial learning is affected by transient occlusion of common carotid arteries (2VO): comparison of behavioural and histopathological changes after '2VO' and 'four-vessel-occlusion' in rats.

Place learning in the Morris water maze following transient (24 min) occlusion of the common carotid arteries (2VO), and following permanent occlusion of both vertebral arteries plus transient (20 min) clamping of the carotids (4VO) was investigated in rats 6-9 days after occlusion. Both 2VO and 4VO treatment increased the latency to find the hidden platform during escape trials; spatial bias, tested in a probe trial, was decreased. Histological analysis revealed neural necrosis in the CA1 sector of the hippocampus in 4VO rats but not in 2VO animals. The data suggest that an experimentally induced reduction in cerebral blood flow of 50% (after 2VO) or 95% (after 4VO) produces persistent functional changes even in absence of actual neural damage.

Animals↗

PubMed1990

Blockade of excitatory neurotransmission in the globus pallidus induces rigidity and akinesia in the rat: implications for excitatory neurotransmission in pathogenesis of Parkinson's diseases.

Bilateral microinjections of the selective N-methyl-D-aspartate (NMDA) antagonist, (-)-2-amino-7-phosphonoheptanoate (AP7), 0.02-0.5 nmol, into the globus pallidus and ventral-posterior portions of the caudate-putamen result in an increase in the muscle tone (rigidity) and catalepsy (akinesia) in rats. NMDA blocked the actions of AP7 on motility in sensitive regions of the globus pallidus and caudate-putamen. Topographical differences in the action of AP7 in the striatum were detected in the dorsal-ventral and rostral-caudal direction. Microinjections of AP7 into the nucleus accumbens induced neither an increase in the muscle tone nor catalepsy in rats, while ventral regions of the caudate-putamen were sensitive to both actions of AP7. Microinjections of AP7 into the dorsal caudate-putamen resulted in a moderate or no increase in the muscle tone. AP7 failed to induce catalepsy from dorsal regions of the caudate-putamen. These data identify the globus pallidus and a defined subregion of the caudate-putamen as crucial sites where excitatory neurotransmission acts to regulate the final set-point of the respective output neurons providing modulation of the passage of motor information through the basal ganglia.

2-Amino-5-phosphonovalerate↗

PubMed1990

The entopeduncular nucleus regulates muscle tone in genetically spastic rats: role of substance P and gamma-aminobutyric acid.

Microinjections of the substance P (SP) antagonist (D-pro2,D-phe7,D-trp9)-SP, or the gamma-aminobutyric acid (GABA) agonist, muscimol, into the entopeduncular nucleus reduced muscle tone in genetically spastic rats in a dose- and time-dependent manner. Similar injections into the ventral thalamus, zona incerta or amygdala had no effect on muscle tone. The muscle relaxant effect of (D-pro2,D-phe7,D-trp9)-SP injected into the entopeduncular nucleus was blocked by co-injections of SP, and that of muscimol by the GABAA antagonist, bicuculline methiodide. These results suggest that SP- and GABA-dependent mechanisms in the entopeduncular nucleus mediate regulation of the muscle tone.

Animals↗

PubMed1990

Substantia nigra: a site of action of muscle relaxant drugs.

Sites of action of centrally active muscle relaxant drugs are not well defined. Clinical experience with such drugs suggests that the spinal cord may be one of the important regions from which pathologically increased muscle tone may be relieved. Supraspinal centers that may also be involved in the expression of muscle relaxant action have not yet been defined. We report here that microinjections of therapeutically relevant muscle relaxants into the midbrain tegmentum of genetically spastic rats decrease muscle tone. The substantia nigra is the region from which midazolam, baclofen, and tizanidine (drugs used clinically in the treatment of spasticity), or gamma-vinyl-GABA, (-)-2-amino-7-phosphonoheptanoate, and [D-pro2-D-phe7-D-trp9]-substance P (experimental drugs active in animal models of spasticity), reduce muscle tone in genetically spastic rats and Hoffmann reflexes in normal rats. The effects of muscle relaxant drugs are topographically restricted to the substantia nigra pars reticulata and are receptor specific. These observations disclose a previously unknown function of the substantia nigra in mediating muscle relaxation.

Animals↗

PubMed1990

S-emopamil ameliorates ischemic brain damage in rats: histological and behavioural approaches.

Transient ischemia induced by 4 vessel occlusion (4VO) in rats is known to produce neuronal damage to particular brain structures such as the CA1 sector of the hippocampus. Behavioural changes associated with ischemic lesioning of this brain region are an impairment in spatial learning of rats tested in a water maze (14). In the present study, it was investigated whether pretreatment with S-emopamil, a Ca2(+)-channel blocker as well as a 5-HT2 antagonist, prevents the occurrence of hippocampal cell damage and/or spatial learning impairments in rats subjected to 4VO. Neuronal lesioning in the hippocampus was significantly reduced following pretreatment with S-emopamil in 4VO rats. In addition, S-emopamil treated animals showed an improved spatial learning ability compared to saline treated 4VO rats. It is suggested that S-emopamil may exert a protective effect under ischemic conditions. The possible mechanisms involved are discussed.

Animals↗