PubMed Health⌕ Search

Biomedical subjects

U Schaeppi

Publications and source records attributed to U Schaeppi.

At least 19 recordsLinked to original sources
PubMed1994

The use of an unbaited tunnel maze in neurotoxicology: I. Trimethyltin-induced brain lesions.

In our laboratory we use an unbaited 6-arm radial tunnel maze (6-arm RTM) to assess working and reference memory in the course of neurotoxicity studies. The 6-arm RTM is believed to measure parameters comparable to those assessed in radial-arm mazes, but without the need of food deprivation and rewarding of animals. This is especially useful in the course of neurotoxicity studies as interferences of e.g. food deprivation with drug pharmacokinetics can be avoided. Since the 6-arm RTM is less evaluated than conventional mazes the aim of this study was to further confirm mean error score as measure of 'working memory', left-right discrimination within each radial arm (expressed as percent "blind-alley" visits) as measure of 'reference memory', and number of arm entries/min as a measure of motor activity. Therefore, hippocampal lesions were induced by injecting animals with the neurotoxicant trimethyltin (TMT). TMT at a dose of 5 mg/kg slightly lesioned hippocampal CA3 pyramidal cells in 3 of 8 animals, but did not affect behavioral measures in the 6-arm RTM. In all surviving animals treated with 7 or 9 mg/kg TMT moderate to marked loss of CA3 pyramidal cells was observed, while in 4 of these 7 rats CA4 pyramidal cells were also affected. Other brain lesions were not observed. TMT-induced brain lesions led to increased mean error score and number of arm visits during the retention phase and after changing maze configuration, whereas percent "blind-alley" visits were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Impaired tunnel-maze behavior in rats with sensory lesions: vestibular and auditory systems.

Maze behavior of rodents provides insight into processes of learning and memory and also serves to assess cognitive functions in neurotoxicity tests. Neurotoxic agents may impair maze behavior by acting upon different parts of the nervous system. To assess the dependence of maze learning upon vestibular and/or auditory input, the two systems were lesioned. Daily treatment of rat pups with streptomycin (400 mg/kg sc) on postnatal day 11 to 22 caused irreversible impairment of vestibular and auditory functions, whereas, 20 injections of neomycin in adult rats (100 mg/kg sc, postnatal weeks 8 to 11) led to hearing loss only. Hearing loss was assessed by absence of Preyer's reflex and impaired vestibular function by loss or shortened duration of postrotatory nystagmus. Learning in the unbaited 6-arm radial maze was tested at the age of 2 to 3 mon using a maze configuration that allowed to assess order of arm entries ("working memory") and left-right discrimination within each arm ("reference memory"). Treatment with streptomycin but not with neomycin led to impaired order of arm entries. Since treatment with streptomycin failed to induce any signs of brain lesions, impaired maze learning is considered to result from destruction of vestibular hair cell receptors with subsequent vestibular impairment and not from hearing loss or cognitive impairment.

Animals↗
PubMed1988

Electroretinography in rats.

Basic mechanisms of the rat ERG were reinvestigated with contemporary methods of recording and photic stimulation via an optic fiber system connected with a contact lens. Flash stimulation and background illuminance were performed with photometrically defined light stimuli. ERGs recorded in darkness, from dark adapted rats, were similar with those observed in earlier work in which light flashes of much longer duration had been used. Flash stimulation carried out under stepwise increased background illuminance gave new information on the characteristics of oscillatory potentials of the ERG. In general the present observations agreed with the notion that the rods of the rat retina are as sensitive as in man, whereas the cones are functionally less efficient with respect to light sensitivity and temporal resolution. Differences in function of the cones from rat to man have to be kept in mind when using the rat ERG as a model for risk assessment in safety studies.

Animals↗
PubMed1988

Detecting functional neurotoxicity in the course of safety evaluations with laboratory animals.

In the course of routinely performed subchronic toxicity studies with laboratory rodents, functional neurotoxicity, i.e. behavioral changes are usually noted first during the daily cage side observations of all animals. Observation and subsequent neurologic examination of a few key animals provide a primary tentative diagnosis. Additional automated testing might include: motor activity, startle response, hurdle stepping and maze behavior. Automated testing provides further refinement of the diagnosis and serves to determine the no observable effect level under conditions of blind testing. Behavioral changes should be assessed as early as possible after initiation of testing, i.e. during acute tests for mortality and the following subchronic range-finding studies. Subsequent subchronic organ toxicity studies are then carried out by following a valid experimental protocol for implementation of automated testing procedures and appropriate neuropathologic evaluation.

Abnormalities, Drug-Induced↗
PubMed1988

Validation of a radial maze test for assessing learning and memory in rats.

Choice behavior of rats in a radially symmetrical 6-arm maze, without food reward, was validated for assessing changes in learning and memory following treatment with 4 psychoactive agents. The test is designed for future use in routine toxicity studies with laboratory rodents. Each radial main arm of the maze leads to a T-shaped choice-point with a blind alley on the left and a long angled alley on the right. Order of choice of the radial main arms served to score within-session working memory, by evaluating relative recency of arm reentries. The choice between blind alley and long-angled alley at the T-intersections provided a measure of between-session reference memory. Maze behavior as an indicator for impairment in learning and memory was validated by testing rats treated with d-amphetamine, chlorpromazine, scopolamine and physostigmine. Based on the above evaluations, working memory was found to be severely impaired by 0.3 and 1.0 mg/kg scopolamine, and reference memory to be improved by 0.02 mg/kg physostigmine and 1.0 mg/kg amphetamine. Locomotor activity, in terms of the total number of arm choices per test session, was altered by all substances as expected from previous reports in the literature. The test appears to be a valid and sensitive method for assessing learning and memory in the rat without the use of food reward, and thus well suited for implementation in routine toxicity studies with rodents.

Animals↗
PubMed1988

Validation of a photobeam system for assessment of motor activity in rats.

To evaluate the validity and sensitivity of test procedures for routine assessment of chemically induced changes in motor activity in rats, studies were carried out with a commercially available photocell cage system. Testing of single, untreated rats showed that motor activity decreased within 10 min to a steady level. Overall activity was the same when testing was repeated at weekly intervals for 6 weeks. In groups of each 10 rats tested immediately after i.p. injection, chlorpromazine HCl (6 or 2 mg/kg) and physostigmine salicylate (0.5 mg/kg) decreased activity. d-Amphetamine sulfate (1.0 mg/kg) caused an increase of virtually all parameters, whereas scopolamine HCl (1.0 mg/kg) and physostigmine salicylate (0.02 mg/kg) led to an increase of particular aspects of motor activity only. Data generated with a mechanical calibrator varied 1-5% between the cages tested. It is concluded that the above procedures of recording of selected parameters of motor activity in groups of 10 rats for periods of up to 20 min would comply with the guidelines recommended by EPA TOSCA.

Animals↗
PubMed1987

Comments on the assessment of neurotoxicity in routine toxicity studies.

Neurotoxicity occurs during administration of high doses of compounds, in testing for acute toxicity (LD50) or on occasion of subchronic treatment for assessment of organ toxicity. Neurotoxicity induces behavioral disturbances, usually first noticed by the animal caretakers, who are observing daily the animals tested according to authorized guidelines. During the following neurological examination a few of the exposed animals, exhibiting distinct behavioral disturbances, are compared with controls. The neurological examination serves to characterize the observed changes, while the observation of the whole group of animals in the home cages gives indications about the highest non-toxic dose level. Further tests for additional clarification of neurotoxicity would be evaluation of neuromotor spontaneous activity in the photocell-cage, behavior in the maze or operant behavior, measurement of the maximum nerve conduction velocity or other especially developed tests.

Animals↗
PubMed1985

Differential vulnerability of 3 rapidly conducting somatosensory pathways in the dog with vitamin B6 neuropathy.

In anesthetized dogs with chronically implanted cortical electrodes somatic sensory-evoked potentials (SEPs) were produced by electrical stimulation at neural, muscular or cutaneous sites of the contralateral hind leg. Stimulation of the tibial nerve at the calcaneus or of the short flexor muscles of the hind paw caused SEPs having characteristics following activation of rapidly conducting afferents from muscle spindles. Stimulation of the glabrous skin of the central pad resulted in SEPs arriving after a more protracted latency evidently related to activation of afferents from Merkel cells, Krause and Pacinian corpuscles known to be located at these sites. Stimulation of the hairy skin from the dorsal surface of the hindpaw produced a further type of SEP presumably resulting from activation of afferents from receptors of tylotrich hair follicles. Vitamin B6-induced neuropathy involves the selective degeneration of the largest neurons in the spinal ganglia and of associated long peripheral and central neurites performing rapid impulse transmission. In the course of vitamin B6 neuropathy the relatively slow impulse transmission following stimulation of the central pad was more severely impaired than the faster one after activation of afferents from muscle spindles or receptors from hair follicles. This allows us to conclude that in the dog afferents from the glabrous skin of the central pad conduct centrally via the dorsal columns, susceptible to vitamin B6 intoxication, while muscle and hair receptor afferents ascend in the dorsal spinocerebellar and spinocervical tract, respectively, which are vitamin B6 resistant.

Animals↗
PubMed1984

What can specific behavioural testing procedures contribute to the assessment of neurotoxicity in laboratory animals?

Subchronic testing of laboratory animals in accordance with present regulatory guidelines involves maximum exposure with the chemical under investigation and serves for the evaluation of systemic toxicity as well as of lesions in organs and organ systems, including neurotoxicity. The primary assessment of neurotoxicity is essentially based on the overall observation of animal behaviour in the course of the customary toxicity studies and on the subsequent neuropathological evaluation with contemporary techniques. Under this maximum exposure the absence of symptoms and signs of neural abnormalities indicates that the material tested would be devoid of neurotoxicity. Any overt or suspicious symptoms for neurotoxicity appearing in the course of subchronic testing may be further characterized with additional functional tests such as neurological examination, electrodiagnostics and possibly with specific behavioural tests. The subsequent neuropathological investigation would have to be expanded to include a detailed evaluation of all neural structures possibly related with the above functional derangements. In case of relevant neurotoxicity subsequent specific behavioural tests might include the evaluation of complex neural functions such as integrated psycho-neuro-motor activity and memory. These behavioural tests might help to explain neurotoxicity and to assess behaviour at low levels of exposure. The implementation of such specific behavioural testing procedures beyond the scope of routine toxicity studies would require a group of investigators capable to carry out appropriate tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Sensory and motor maximum nerve conduction velocity in the peripheral and central nervous system of the beagle dog.

Sensory maximum nerve conduction velocity (MNCV) and motor MNCV were monitored in altogether 14 beagle dogs anaesthetized with pentobarbital. Sensory MNCV was determined by averaging cortically evoked potentials from somatosensory area I (SS I) in response to repeated electrical stimulation of digital paw pads, tibial nerve at calcaneus or sciatic nerve at trochanter. Sensory MNCV determined from paw to tibial nerve at calcaneus was 53 m/sec, from tibial nerve at calcaneus to sciatic nerve at trochanter 64 m/sec and from sciatic nerve at trochanter to crotex SS I 53 m/sec. Motor peripheral MNCV determined in the customary way from sciatic nerve at trochanter to tibial nerve at calcaneus was 68 m/sec and distal latency 3.6 msec. Motor central MNCV from motor cortex to the sciatic nerve at the trochanter in 5 unanaesthetized dogs was 57 m/sec. These testing procedures serve for quantitative assessment of possible impairment of impulse transmission in the central and peripheral sensory and motor pathway of beagle dogs used in routine toxicity studies.

Animals↗
PubMed1982

Pyridoxine neuropathy: correlation of functional tests and neuropathology in beagle dogs treated with large doses of vitamin B6.

Neurologic examination, electrophysiologic testing and microscopic post-mortem examination was used to study the neuropathy induced in the beagle dog by administration of excessive amounts of vitamin B6. Two female dogs received repeated daily oral doses of 3 g. The treatment was ceased when the dogs developed severe general morbidity, including uncoordinated gait and abnormal neurologic symptoms. The symptoms were most severe during and early after cessation of treatment, and in general they regressed during the subsequent 2 months of treatment-free observation. Sensory central and peripheral maximum nerve conduction velocity started to decrease after a considerable delay; the decrease progressed until late after termination of treatment and failed to fully regress. Morphologic lesions were confined to large, first order sensory neurons. The neurologic examination thus revealed the early changes, while electrodiagnostics and microscopic neuropathology were indicators of more advanced stages of toxic neuropathy and disclosed selective lesions in individuals whose gait appeared to be unremarkable.

Action Potentials↗
PubMed1981

Single fiber electromyography. A method for the evaluation of motor axonopathy during toxicity studies in dogs.

In man, single fiber electromyography is used as a very sensitive indicator for the assessment of functional changes in motor nerves. The purpose of the present study was to adapt the above testing procedure to allow repeated investigations of dogs used in subchronic toxicity tests. Experiments were performed on anesthetized pure-bred beagle dogs. Action potentials from single muscle fibers in response to electrical stimulation of motor nerves were recorded with Medelec microelectrodes, amplified with a Medelec system and monitored on a Tektronic oscilloscope. Repeated electrical stimulation with pulses of 0.03 msec and 1 p.p.s. produced characteristic action potentials of single muscle fibers consisting of a positive, followed by a negative, deflection having a duration of from 500 to 800 microseconds altogether. Successive potentials occurred with a variable latency (the jitter) ranging from +/- 5 to 15 microseconds. Quantitative evaluation of the jitter will allow the clinical evaluation of motor axonopathies in dogs.

Action Potentials↗
PubMed1977

Procedures for routine clinical electroretinography (ERG) in dogs.

Following pupillary dilatation and immobilization of the dog with a cataleptic drug (l-Polamivet, Hoechst) the electroretinogram (ERG) was performed with the technique of Ganzfeld stimulation. The head of the dog was kept within a sphere of 60 cm diameter, the white inner surface of which could be indirectly illuminated with a stroboscope producing light flashes of 10 musec duration. The ERG was recorded oscillographically by means of modified contact lenses. Dogs were tested for rod and cone function with luminance curves including white, blue and red stimuli and with trains of repetitive photic stimuli. Tests were performed under dark and light adaptation. The ERG of the dark-adapted dog, an indicator for the electrical activity of the rod system, was similar with that of man with respect to configuration and other characteristics. The electrical activity of the cone system was different from that of man by having a 10-fold lower sensitivity and a reduced capability for discrimination of red versus blue or white stimuli.

Animals↗
PubMed1976

Methyl-CCNU: preclinical toxicologic evaluation of a single iv infusion in dogs and monkeys.

Methyl-CCNU, a compound with marked antitumor activity against the solid Lewis lung tumor in mice, was submitted to a preclinical pharmacologic evaluation. The toxicity of a single iv infusion was tested in 37 beagle dogs and 21 rhesus monkeys. The minimum lethal dose (LD) in dogs was 14 mg/kg and five of six dogs died within 7-10 days after treatment from hematopoietic toxicity with neutropenia, lymphopenia, anemia, and concomitant sepsis. Metaplasia of the intestinal epithelium also occurred. Thrombocytopenia was not observed. Dogs treated with 9.27-1.56 mg/kg exhibited reversible neutropenia and lymphopenia but survived without severe morbidity or histopathologic lesions. In monkeys, interstitial nephritis was the treatment-limiting toxicity and three of six monkeys treated with 45 or 30 mg/kg died, became moribund, or exhibited severe renal histopathologic lesions. One monkey treated with 45 mg/kg had degeneration of the testes. Survivors exhibited reversible toxicity and no histopathologic lesions. Treatment with doses as low as 7.5 mg/kg caused reversible neutropenia, lymphopenia, and anemia. The largest nontoxic dose for a single iv infusion was 3.12 mg/kg (62.40 mg/m2) for the dog and 3.75 mg/kg (45 mg/m2) for the monkey. These and earlier observations showed that methyl-CCNU had approximately one third the toxicity of CCNU. Methyl-CCNU also did not cause the delayed hepatic toxicity which is characteristic of CCNU treatment in the dog.

Animals↗