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A Witter

Publications and source records attributed to A Witter.

35 records · Page 2Linked to original sources
PubMed1977

Distribution of a behaviorally highly potent ACTH4-9 analog in rat brain after intraventricular administration.

Distribution within the brain of a 3-fold modified ACTH4-9 analog with a remarkably potentiated behavioral activity, 4-MET (O2), 8-d-Lys, 9-Phe-ACTH4-9, was investigated. The radioactive labeled [7-3H-Phe]ACTH4-9 analog was administered intraventricularly in urethane anesthetized rats in a dose of approximately 170 ng. Total radioactivity in CSF, measured in samples drawn from the cisterna magna, decreased over the period of 0.5-4 h after injection from 51 to 2% of the injected dose. Intraventricular injection of the ACTH4-9 analog resulted in high intact peptide levels in the brain. At 2 h after injection the distribution of radioactivity over 2500 micronm and 300 micronm frontal cut brain slices was rather homogenous. Data from distribution studies over topographically defined gross brain structures indicated that the septal area, which is involved in eliciting behavioral activities of ACTH-like neuropeptides, accumulated most of the injected radioactivity per gram wet weight. The distribution profiles within the brain of the [3H]ACTH4-9 analog and [3H]Phe showed considerable differences. Uptake studies in various brain nuclei after intraventricular administration of the [3H]ACTH4-9 analog demonstrated that the greatest part of the investigated nuclei exhibited relative low or medium uptake of radioactivity. This was also true for hippocampal and thalamic nuclei, which have been suggested as effected sites of action for ACTH peptides. Very high accumulation of radioactivity occurred only in the septal nuclei, particularly the dorsal and fimbrial septal nuclei. The results indicate selective uptake of the ACTH4-9 analog in the septal area, suggesting a possible significance of this area as a site of action of ACTH neuro-peptides.

Adrenocorticotropic Hormone↗
PubMed1976

In vivo fate of a behaviorally active ACTH 4-9 analog in rats after systemic administration.

In vivo fate of a threefold substituted ACTH 4-9 analog with a markedly potentiated behavioral activity, 4-Met(O2), 8-D-Lys, 9-Phe-ACTH 4-9, was investigated. The radioactive labeled [7-3H-Phe] ACTH 4-9 analog was administered IV, SC and orally in a dose of approximately 40 mug. Plasma concentrations of total radioactivity and intact peptide were determined at various periods after administration in urethane anesthetized rats. Oral administration was also performed with conscious animals. Maximal plasma concentrations were found 8 min after SC injection. After oral administration in anesthetized rats maximal plasma levels were reached 8 hr after administration; in conscious animals this took 4 hr. The initial volume of distribution was 5.9% of body weight and the initial half-life (t1/2) for intact peptide 4 min. Shortly after IV and SC administration relatively high and stable plasma levels of intact peptide were obtained, reflecting metabolic stability. This stability was also apparent from the metabolite patterns, which were determined in trichloroacetic acid extracts of plasma and brain by paperchromatography and paperelectrophoresis. The plasma profiles indicated increased stability of the labile 8Lys-9Phe bond by the introduction of an 8D-Lys residue in the peptide analog. Enzymatic attack of the analog took place predominantly at 6His-7Phe and 7Phe-8D-Lys. Formation of tritiated water occcurred in brain and the gastro-intestinal tract and was considerable; proteolysis in these compartments was higher than in plasma. High uptake of radioactivity was found in the kidney, but urinary excretion was low during the first 30 min. Uptake in brain was low and paralleled uptake in cerebrospinal fluid. Intact peptide concentrations/g fresh tissue were in the order of 10(-5)-10(-4) times the administered dose for all three routes.

Adrenocorticotropic Hormone↗
PubMed1975

Correlation between structure, behavioral activity and rate of biotransformation of some ACTH4-9 analogs.

The effect of substitutions in adrenocorticotropin (ACTH4-9) on extinction of pole-jumping avoidance behavior in intact rats was investigated systemically at two-dose levels. Simultaneous introduction of 4-methionine sulfoxide and 5-D-lysine, in combination with 9-phenylalanine, led to a 1000-fold increase in behavioral potency. The same substitutions induced a 1000-fold decrease in melanocyte-stimulating hormone activity. Incubations of 14-C-labeled ACTH4-9 analogs, prepared by reductive methylation, were carried out with plasma and brain extracts. The resulting metabolites were separated by paper electrophoresis and paper chromatography. The concentrations of nonmetabolized hexapeptides, which appeared to be almost entirely responsible for behavioral activity, were determined as a function of incubation time. The in vitro half-life of intact hexapeptides correlated with their behavioral activity. Therefore, the increase in behavioral potency as a result of amino acid substitutions can be explained, at least partly, by increased resistance against biotransformation.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Des-Tyr1-gamma-endorphin (DT gamma E) and des-enkephalin-gamma-endorphin (DE gamma E): plasma profile and brain uptake after systemic administration in the rat.

The plasma disappearance, metabolism and uptake in the brain of [3H-Phe4]-DT gamma E and [3H-Lys9]-DE gamma E were investigated following systemic administration of these neuroleptic-like peptides to rats. 3H-DT gamma E, 3H-DE gamma E and their radioactive metabolites in plasma and brain extracts were determined by reversed-phase HPLC. Plasma disappearance of DT gamma E upon intravenous (IV) dosing followed a biphasic pattern with half-lives of 0.7 min (distribution phase) and 5.5 min (elimination phase). For DE gamma E the plasma disappearance curve was best characterized by a one-compartment model since a second elimination phase was hardly detectable by our methods. The corresponding half-life was 0.6 min, probably representative for the initial distribution phase of DE gamma E. Both neuropeptides distributed rapidly over the larger part of the extracellular fluid. Following the IV route of administration, brain uptake of DT gamma E and DE gamma E appeared to be low. Brain levels of DT gamma E decreased from 0.0075% to 0.0031% of the administered dose/g tissue at 2-15.5 min after injection, whereas those of DE gamma E decreased very rapidly from 0.0174% of the dose/g brain tissue to below the detection limit at 2-4.5 min after injection. As compared to the IV route of administration, subcutaneous (SC) injection of DE gamma E resulted into lower but remarkably longer-lasting peptide concentrations in plasma as well as in brain, possibly because of a sustained release from the SC site of injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Autoradiographic studies with a behaviorally potent 3H-ACTH4--9 analog in the brain after intraventricular injection in rats.

Autoradiographic studies aimed at identifying target cells in the brain for ACTH-like peptides were performed using (3H-7-Phe)-4-Met(O2),8-D-Lys, 9-Phe-ACTH4--9, a behaviorally potent analog of ACTH4--9. The 3H-peptide was injected into the lateral ventricle of hypophysectomized rats that were sacrificed 5, 30, 60, 180, and 240 min later. Dry-mount autoradiograms of brain showed the highest density of silver grains in the ventricular lumen and choroid plexus. In addition, radioactivity penetrated brain tissue as far as 100 microns from the ventricles, and was distributed predominantly over neuropil. Within 5 min after the injection, an intracellular concentration of radioactivity above background levels was observed in a small proportion of cells near the ventricles in the septum, caudate-putamen, preoptic area, hypothalamus, thalamus, amygdala, and hippocampus. The cellular labeling decreased in intensity at greater distances from the injection site and at longer survival intervals, and was no longer evident 4 hr after the injection. The labeled cells were usually small, dark, and often elongated, suggesting that ACTH peptides may act preferentially upon a morphologically distinct class of cells in the brain.

Adrenocorticotropic Hormone↗