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Biomedical subjects

H J Tobler

Publications and source records attributed to H J Tobler.

17 recordsLinked to original sources
PubMed1986

Muscarinic cholinergic receptor subtypes in the human brain. II. Quantitative autoradiographic studies.

The distribution and characteristics of M1 and M2 muscarinic cholinergic receptors as defined by their affinity for the antagonist pirenzepine were studied in the human brain using in vitro quantitative autoradiographic techniques. The binding of N-[3H]methylscopolamine ([3H]NMS) to cortical and striatal microtome tissue sections was saturable and presented a Kd of 0.25 nM. The sensitivity of [3H]NMS-binding sites to 100 microM carbachol and 300 nM pirenzepine was analyzed in 30 brain areas. In selected brain regions, complete competition curves using carbachol, pirenzepine and atropine were analyzed. Finally, the regional distribution of M1 sites was studied using [3H]pirenzepine ([3H]PZ) as ligand. The binding of [3H]NMS to striatum, hippocampus and amygdala was very sensitive to pirenzepine but not to carbachol. The opposite situation was found in thalamus, hypothalamus, substantia innominata, pons and medulla, while intermediate sensitivity to both displacers was observed in different layers of the cortex and in the claustrum. Competition experiments showed that [3H]NMS binding was displaced with the same affinity by atropine in all the regions studied, while the IC50 of carbachol varied from 5 microM in the nucleus facialis to 830 microM in the caudate. Pirenzepine IC50 values for [3H]NMS sites varied from 66 nM to 1 microM. Results using [3H]PZ further confirm this pattern of distribution, with high densities of binding observed in the striatum, hippocampus and amygdala and very low in thalamic and brainstem areas. These results show that the putative M1 and M2 muscarinic receptor subtypes present a differential anatomical distribution in the human brain. This differential distribution is comparable to that observed in the rat brain. Some basal ganglia and limbic areas are enriched in M1 sites, while thalamus, brainstem, medulla and also the hypothalamus and substantia innominata contain predominantly receptors of the M2 type. The cerebral cortex is an example of a region containing a mixed population of M1 and M2 sites. These results provide an anatomical description of the distribution of subtypes of the muscarinic receptor in the human brain, which can be related to the known pharmacological effects of muscarinic agents in brain function.

Aged↗
PubMed1984

Classification of drugs according to receptor binding profiles.

The affinity for eight different neurotransmitter receptors of about forty drugs, used for the treatment of various central nervous system disorders, was determined following in vitro receptor binding assays. Our findings indicate that, in spite of widely varying chemical structures and often poorly understood mechanisms of action, the similarities in the "affinity profiles" permit a clinically meaningful classification of these drugs. Such an approach would thus be useful in the assessment of newly synthesized compounds at an early stage of drug development.

Animals↗
PubMed1984

[What do glaucomatous visual fields really look like?].

Analysis of the visual fields of 20 glaucoma patients using 229 F2 programmes consisting of 30 degrees long profiles with 1 degree resolution and double measurements of the light sensitivity threshold, revealed that there is a positive correlation between mean loss and mean short-term fluctuations; short-term fluctuations tend to be larger with increasing loss of sensitivity. However, small short-term fluctuations were also seen in areas of greatly reduced sensitivity. Analysis of the F2 programmes showed 12 different abnormal patterns. The pattern most frequently found, "increased scatter with normal sensitivity", appears to be the earliest perimetric sign of glaucoma. Progression of the glaucomatous damage produces a "gray area of increased scatter", usually accompanied by reduced sensitivity with a poorly defined lower and upper threshold.

Computers↗
PubMed1984

The effect of age on the microheterogeneous pattern of human myelin basic protein.

Dry weight, total basic protein and myelin basic protein (MBP) in human corpus callosum tissue were found to be significantly reduced with age, confirming other reports. The heterogeneous patterns of the MBP samples were investigated and could be classified into three groups: a normal one with peak 1 larger than peak 3; an old-age pattern with peak 1 smaller than peak 3; and a pathological pattern with peak 1 greatly reduced. Because peak 1 is the only one which is significantly reduced with age, it is suggested that future investigations could be simplified. The physiological and pathophysiological role of MBP heterogeneity is discussed.

Adult↗
PubMed1983

Affinity spectra: a novel way for the evaluation of equilibrium binding experiments.

For equilibrium binding isotherms of radioreceptor assays, the affinity spectrum is defined as a plot of the number of binding sites against their corresponding dissociation constants. A numerical procedure for direct calculation of affinity spectra from untransformed binding data is presented and illustrated with experimental values. The advantage of the new method in comparison to non-linear regression analysis is the fact that no starting values and mathematical models have to be supplied and that statistical assessment of the results is straightforward from a detailed graphical display of a likelihood function. Affinity spectra thus show directly all information formerly obtained by means of both graphical plots and regression analysis.

Animals↗
PubMed1982

DSIP-induced changes of the daily concentrations of brain neurotransmitters and plasma proteins in rats.

The influence of delta sleep-inducing peptide (DSIP) on the brain neurotransmitters 5-HT, dopamine and norepinephrine and plasma proteins/corticosterone concentrations for four time points within the 24 hr following IV injection of 30 nmol/kg was investigated in rats. DSIP administered in the morning or in the evening respectively induced changes in nearly all measured parameters. Different effects were observed for different times of administration. The most marked changes were found in the level of serotonin during daytime. In view of the multivariate results obtained by measuring several parameters at multiple time points, a method was developed to describe the time-dependent changes. By means of "circadian rhythm statistics" based on a statistical likelihood analysis we found that multiple and different changes within the factor's daily variation are induced by one injection of DSIP. A multidimensional scaling of the results provides further insights into the correlations of the DSIP-induced effects on plasma and brain factors which are therefore tentatively termed "programming functions." These apparently involve not just sleep induction but also act on multiple parameters within the 24 hr rest-activity period.

Animals↗
PubMed1981

Effects of repeated DSIP and DSIP-P administration on the circadian locomotor activity of rats.

Daily intravenous evening injections of 30 nmol/kg DSIP (Delta Sleep-Inducing Peptide) in rats adapted to a constant 24 hr light:dark cycle produced changes in the circadian locomotor behavior. After 3 days the normally high locomotor activity during the dark phase was reduced while during the light (sleeping) phase the animals became relatively more active. Similar, but more rapid and more marked changes were observed (with the same schedule of injections) after 0.1 nmol/kg DSIP-P (the analogue of DSIP phosphorylated at the serine in position 7). In fact the peptide and its analogue induced a relative reversal or shift of the circadian locomotor activity phases opposite to the persisting light:dark conditions (=Zeitgeber). This suggests that DSIP exerts rather complex "programming" effects on the circadian activities and has more than just a sleep-inducing activity.

Animals↗
PubMed1980

Peptides isolated from human liver with specific inhibitory effects on reassociation/reactivation of in vitro dissociated lactic dehydrogenase (LDH-M4 and -H4) isozymes.

Two different peptides have been purified from human liver, similar to those previously reported (Schoenenberger, G.A., and Wacker, W.E.C. (1966) Biochemistry 5, 1375--1379) to be present in human urine, which may serve as metabolic regulators of lactate dehydrogenase (EC 1.1.1.27) isoenzymes (LDH-M4 = muscle type; LDH-H4 = heart type). By trichloroacetic acid precipitation, ultrafiltration, Sephadex G-25 and Bio-Gel P-2 columns, affinity chromatography on immobilized LDH-isozymes and HPLC two peptides which differed with respect to molecular weight, retention on the affinity columns and amino acid composition were isolated. No effect was observed when native, tetrameric lactate dehydrogenase was incubated with these peptides. However, when lactate dehydrogenase was dissociated to monomers at low pH and allowed to reassociate by adjusting the pH to 7.5 complete inhibition of the reactivation occurred when the inhibitors were incubated together with respective reassociating monomeric isozymes. The two peptides showed no cross-specificity, i.e. each peptide exhibited inhibitory activity only on one of the two isozymes LDH-M4 or LDH-H4. From the amino acid analyses, gel filtrations and PAGE + SDS, molecular weights of 1800 for the M4 and approximately 2700 for the H4 inhibitor were calculated. An apparent Ki of approximately 3 X 10(-5) mM for the H4 and approximately 7 X 10(-5) mM for the H4 inhibitor was estimated. The interaction of the inhibitors with the enzyme system showed strong cooperativity with Hill coefficients of 2.9 (LDH-M4-specific) and 2.4 (LDH-H4-specific). Mathematical modelling of the reassociation and reactivation of lactate dehydrogenase and its specific inhibition by the peptides led to the conclusion that the peptides react with monomers, dimers or a transition state during the tetramerisation process. kappa 1 for the dimerisation step of M4 = 2.0 X 10(5) M-1 . S-1 and of H4 = 8.2 X 10(4) M-1 . S-1; kappa 2 for the tetramerisation step of M4 = 2.8 X 10(5) M-1 . S-1 and of H4 = 1.2 X 10(5) . M-1 S-1, were calculated, the second step still being the faster one (Rudolf, R. and Jaenicke, R. (1976) Eur. J Biochem. 63, 409--417).

Amino Acids↗
PubMed1978

The delta EEG (sleep)-inducing peptide (DSIP). XI. Amino-acid analysis, sequence, synthesis and activity of the nonapeptide.

A peptide which induces slow-wave EEG (sleep) after intraventricular infusion into the brain has been isolated from the extracorporeal dialysate of cerebral venous blood in rabbits submitted to hypnogenic electrical stimulation of the intralaminar thalamic area. It was shown by amino-acid analysis and sequence determination to be Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu and named "Delta Sleep-Inducing Peptide" (DSIP). This compound was synthesized as well as 5 possible metabolic products (1--8, 2--9, 2--8, 1--4 and 5--9), 2 nonapeptide analogues (with one and two amino-acids exchanged) and a related tripeptide (Trp-Ser-Glu). All 9 synthetic peptides were infused intraventricularly in rabbits (6 nmol/kg in 0.05 ml of CSF-like solution over 3.5 min) and tested under double-blind conditions. A total of 61 rabbits including controls were used. The EEG from the frontal neocortex and the limbic archicortex were subjected to direct fast-Fourier transformation and analyzed by an 1108 computer system. A highly specific delta and spindle EEG-enhancing effect of the synthetic DSIP could be demonstrated. The mean increase of EEG delta activity reached 35% in the neocortex and limbic cortex as compared to control animals receiving CSF-like solution or any of the other 8 peptides. The final chemical characterization of the synthetic DSIP revealed that only the pure alpha-aspartyl peptide is highly active in contrast to its beta-Asp isomer. A neurohumoral modulating and programming activity was suggested.

Amino Acid Sequence↗
PubMedDate not supplied

Stereological changes in the capillary network and nerve cells of the aging human brain.

Stereologic parameters of the capillaries and nerve cells of the brain cortex and putamen were investigated. Thirty-eight brains from subjects aged between 19 and 94 years were examined. All cases were free of metabolic, neurologic and psychiatric diseases. It is demonstrated that the capillary diameter remains unchanged during aging in both brain cortex and putamen. However, in the putamen the total capillary length per unit volume and the capillary volume fractions increase (approximately 60%) progressively with age. Consequently the mean inter-capillary distances in the putamen decrease (approximately 15%). These age-induced changes in the putamen indicate shrinking of subcortical brain structures. In contrast to those of the putamen, the morphometric data of the capillaries in the cortex remain unchanged during the aging process. Stereologic investigations of nerve cells in the brain cortex and putamen revealed that only in brains over 85 years of age can a significant decrease in nerve cell size be demonstrated. A correlation of all the data by a correspondence analytical procedure showed that only the surface/volume ratio of the capillaries correlates with the nerve cell size. This observation suggests a functional interaction between the nerve cells and the capillaries. From the data presented it becomes apparent that the shrinkage of the gyri in the aging brain is not a change in the volume of the cortex, but a decrease in the volume of subcortical structures.

Adult↗
PubMedDate not supplied

Isoenzyme specific inhibition of the reactivation of in vitro dissociated lactic dehydrogenase isoenzymes by two different peptides isolated from human liver.

The catalytic activity of the LDH-isoenzymes depends on their tetrameric structure. Low pH or other denaturants leads to dissociation into monomers and to the loss of the specific activity. After removal of the denaturing conditions reassociation and reactivation occur spontaneously. Neither NADH nor NAD+ shows a significant effect on the reactivation. We have isolated two different peptides which isoenzyme specifically inhibit the reactivation of dissociated LDH. Inhibition was abolished by treating with proteases. Additionally, NAD+ and NADH were found to be antagonists of the inhibitors. The heart-type enzyme-inhibitor system is especially susceptible for NADH whereas NAD+ affects the inhibition only slightly. The muscle-type system shows the opposite behavior, e.g., the completely inhibited system can be fully reactivated by NAD+ but not by NADH. These findings together with first kinetic studies suggest a possible specific regulatory function of these peptides.

Amino Acids↗