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Biomedical subjects

B Penke

Publications and source records attributed to B Penke.

At least 55 records · Page 3Linked to original sources
PubMed1998

Beta-amyloid(Phe(SO3H)24)25-35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation.

Long-term behavioral effects, changes in learning and memory functions and aberrations of cholinergic fibers projecting to the parietal cortex were investigated after bilateral injections of beta-amyloid(Phe(SO3H)24)25-35 peptide in rat nucleus basalis magnocellularis (nbm). The beta-amyloid peptide used in these experiments contained the original beta-amyloid 25-35 sequence which was coupled to a phenylalanine-sulphonate group at position 24. This additional residue serves as a protective cap on the molecule without influencing its neurotoxic properties and results in water-solubility, stability and low rates of peptide metabolism. In this paper, home cage, locomotor and open-field activities, passive shock-avoidance and 'Morris' water maze learning abilities were assessed throughout a 35-day survival period. Subsequently, acetylcholinesterase (AChE) histochemistry was used to visualize alterations of parietal cortical cholinergic innervation. In response to the neurotoxic action of beta-amyloid(Phe(SO3H)24)25-35, a progressive hyperactivity developed in the rats in their home cages which were maintained throughout the 5-week post-injection period. This was accompanied by a significant hypoactivity in the novel environment of a locomotor arena. Beta-amyloid(Phe(SO3H)24)25-35-treated animals showed greatly impaired cortical memory functions in the step-through passive shock-avoidance paradigm, while spatial learning processes remained unaffected. Moreover, beta-amyloid(Phe(SO3H)24)25-35 injections in the nucleus basalis suppressed explorative behavior in rats and inhibited conditioned stress responses 28 days after surgery. Reductions of cortical cholinergic (AChE-positive) projections provided anatomical substrate for the behavioral changes. This indicated extensive, long-lasting neurodegenerative processes as a result of beta-amyloid(Phe(SO3H)24)25-35 infusion.

Acetylcholinesterase↗
PubMed1998

Beta-amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex: reversal by NMDA receptor blockade.

Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex. In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA) receptors, was proposed as a pivotal mechanism in beta-amyloid-induced neurodegeneration. A definite measure of NMDA receptor-mediated processes and subsequent Ca2+ entry is the induction of Ca2+/calmodulin-activated neuronal nitric oxide synthase (nNOS) in nerve cells. In the present account we therefore assessed activation of nNOS in correlation with cholinergic decline after beta-amyloid(1-42) or beta-amyloid(25-35) infusion into the rat nucleus basalis. The results demonstrate the beta-amyloid conformation-dependent enhancement of cortical nitric oxide synthase (NOS) activity. Furthermore, chronic application of the polyamine site NMDA receptor blocker ifenprodil effectively attenuated beta-amyloid neurotoxicity. We propose that nNOS activation reflects the degree of beta-amyloid-induced excitotoxic injury in a proportional manner. Moreover, Ca2+-mediated processes via NMDA receptors, or direct binding of beta-amyloid to this receptor may be a critical step in the neurotoxic mechanisms in vivo.

Amyloid beta-Peptides↗
PubMed1998

Polarographic detection of nitric oxide released from cardiovascular compounds in aqueous solutions.

In order to detect the concentration of nitric oxide, known to be one of the biologically active principles of certain cardiovascular compounds, a highly selective polarographic/amperometric device was used. The nitric oxide-releasing properties of sodium nitroprusside, nitroglycerine, nicorandil, and the molsidomine metabolite, 3-morpholinosydnonimine, were compared in the following cell-free experimental solutions in vitro: in Krebs-Henseleit solution with and without a sulfhydryl donor, L-cysteine, in an acidic, reducing medium, and in Krebs-Henseleit solution with superoxide dismutase enzyme. Sodium nitroprusside released similar concentrations of nitric oxide in Krebs-Henseleit solution and in the acidic, reducing medium. L-Cysteine inhibited the release of nitric oxide at physiological pH. In the presence of nitroglycerine, nitric oxide signals were detected in the acidic, reducing environment and in L-cysteine-rich Krebs-Henseleit solution but not in the absence of the sulfhydryl donor. Amperometric signals could not be detected after adding nicorandil in all the experimental conditions used. 3-Morpholinosydnonimine released nitric oxide only in the presence of the superoxide dismutase enzyme. Our results suggest that the polarographic electrode is able to detect the release of nitric oxide from sodium nitroprusside, nitroglycerine, and 3-morpholinosydnonimine in the absence of biological material. The present observations support the importance of the chemical environment during the detection of nitric oxide from donor compounds in the common in vitro bathing systems.

Cardiovascular Agents↗
PubMed1998

Endothelium-dependent vasorelaxant and anti-aggregatory effect and mechanism of action of some antifibrinogen RGD (Arg-Gly-Asp-containing) peptides.

Vasorelaxation caused by some antifibrinogen RGD (Arg-Gly-Asp-containing) peptides and their basic mechanism of action was studied on rabbit isolated thoracic aortic rings preconstricted with 0.25 microM phenylephrine. GRGDS (Gly-Arg-Gly-Asp-Ser-OH) and RGDV (Arg-Gly-Asp-Val-OH) caused dose-dependent relaxation. RGDS (Arg-Gly-Asp-Ser-OH) had a biphasic effect (a transient relaxation followed by a contraction) while GRGDS-[SE] (Gly-Arg-Gly-Asp-Ser(SO3)-OH) did not change the isometric tone of precontracted aortic preparations. GRGDS and RGDV exerted no relaxing effect on endothelium-denuded blood vessels suggesting that the vascular action of these peptides was entirely dependent on the presence of functionally intact endothelium. L-NG-Nitro-arginine (30 microM) attenuated the relaxation induced by GRGDS and abolished that induced by RGDV. All of the four RGD congeners inhibited ADP-induced aggregation of human platelets. These findings indicate that the relaxant effect of RGDV is mediated exclusively by the nitric oxide pathway, but GRGDS could cause, besides nitric oxide release, the release of another substance which is different from nitric oxide. Because the rank order of the vasorelaxant potencies of RGD peptides differed from that found for their anti-aggregatory activities, a vascular effector mechanism mediated by an RGD-recognizing structure other than the known glycoprotein IIb/IIIa-like RGD-binding site is suggested.

Animals↗
PubMed1997

A putative tetrapeptide antagonist prevents beta-amyloid-induced long-term elevation of [Ca2+]i in rat astrocytes.

Comparative fluorimetric studies on the long-term (8-hour) action of beta[1-42]amyloid and its shorter fragments beta[1-40], beta[25-35] and beta[31-35] on the steady-state intracellular Ca2+ concentration in primary cultures of rat astroglial cells using the Ca2+-sensitive fluorescent probe Fura-2 AM revealed higher 340/380 fluorescence excitation ratios in the treated cells as compared to the untreated controls. All the peptides were found to induce similar cellular effects, suggesting the [31-35] region as the putative active centre of the molecule. No significant alteration was detectable in Fura-2 fluorescence using the Ca2+-insensitive excitation wavelength of 367 nm, indicating that the observed changes reflect a real alteration in the Ca2+ concentration of the cells. Moreover, no considerable difference was observed in the total protein content of treated and untreated cells. Co-treatment of the cells with Pr-Ile-Ile-Gly-Leu-NH2 (Pr-IIGL) peptide, an analogue of the [31-34] region of beta[1-42]-amyloid, was found to effectively antagonize the beta[1-42]-amyloid-induced elevation of the fluorescence excitation ratio, leaving the 367-nm fluorescence unaffected. To the best of the authors' knowledge, this is the first report on an analogue of beta-amyloid peptide capable of blocking one of its physiological effects, thereby raising the possibility that this sequence could prove to be a lead compound for designing effective beta-amyloid antagonists.

Amyloid beta-Peptides↗
PubMed1997

Role of different neurotransmitter systems in the cholecystokinin octapeptide-induced anxiogenic response in rats.

The possible involvement of different neurotransmitter systems in the anxiogenic action of cholecystokinin octapeptide sulphate ester (CCK-8) was investigated in rats. Intracerebroventricularly (i.c.v.) administered CCK-8 induced an anxiogenic response in an elevated plus-maze test. Pretreatment with dopaminergic, muscarinergic acetylcholine receptor blockers and an opiate receptor antagonist blocked the anxiogenic response to CCK-8. The alpha and beta adrenoreceptor, the GABA receptor and the 5-hydroxytryptamine (5-HT) receptor blockers were not able to modulate the 'anxiogenic-like' effect of CCK-8. The results suggest that the anxiogenic effects of CCK-8 are mediated via different neurotransmitters and the anxiogenic action can be prevented by receptor blockers to these transmitters.

Adrenergic alpha-Antagonists↗
PubMed1997

[Synthesis of peptide and pseudo-peptide analogs of cholecystokinin].

We describe selective CCKA receptor antagonists, based on the 1-oxo-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid core. Selectivity A vs B is discussed on the basis of molecular modelling. Chemical preparation uses electrophilic cyclization of isocyanates derivating from unnatural tryptophan esters. A stereoselective version of the reaction is given. A few peptides incorporating unnatural tryptophans are prepared, with a view of SAR.

Cholecystokinin↗
PubMed1996

Ca(2+)- and Al(3+)-induced conformational transitions of amyloid fragment H-Ile-Ile-Gly-Leu-Met-NH2.

The effect of Ca2+ and Al3+ binding on the conformation of the neurotoxic amyloid fragment H-Ile-Ile-Gly-Leu-Met-NH2 [betaA(31-35)NH2] was studied in trifluoroethanol solutions and in the presence of liposomes. Comparative circular dichroism and Fourier-transform infrared spectroscopic studies revealed that the peptide forms a specific 1:1 complex with Ca2+ which coordinates the polar amide carbonyl groups of the peptide backbone. The results suggest the importance of a folded structure in the complexation of Ca2+. On the contrary, the increasing Al3+ concentration causes a gradual shift of the conformational equilibrium toward beta-sheet structure reflecting no specific binding site for Al3+. In the presence of liposomes the peptide adopts a conformation similar to that of the Ca(2+)-peptide complex. The relevance of the stabilization of peptide conformation by Ca2+ and liposome binding to the bioactive conformation of betaA(31-35)NH2 is also discussed.

Aluminum↗
PubMed1996

High-performance separation methods in the analysis of a new peptide family: the galanins.

An analytical investigation of a new peptide family, the human galanins and their fragments, was carried out by reversed-phase HPLC, capillary zone electrophoresis (CZE) at different pH values and micellar electrokinetic capillary chromatography (MECC) in phosphate-borate-sodium dodecyl sulphate buffer. None of the methods seems to be superior to the others. The complementary nature of the electrophoretic methods is obvious when the profiles of peptides are compared; impurities not separated by HPLC are separated by CZE or MECC and vice versa. With these three different separation methods, a more complex analytical control of the synthetic work can be achieved.

Amino Acid Sequence↗
PubMed1996

The involvement of nitric oxide (NO) in the CGRP-induced behavior of rats.

The possible role of nitric oxide (NO) in CGRP-induced passive avoidance, active avoidance, and open field behavior was tested in rats. A specific NO synthase inhibitor, N omega-nitro-L-arginine (L-NA), was used to disrupt NO synthesis. ICV administration of 5 micrograms of L-NA reversed the action of CGRP in passive and active avoidance tests. In an open field, L-NA prevented the action of CGRP on locomotion and grooming. The inactive isomer D-NA had no effect on behavior of animals. The data suggest that NO might contribute to CGRP-induced behavior in rats.

Animals↗
PubMed1995

Beta-amyloid (1-42) affects cholinergic but not parvalbumin-containing neurons in the septal complex of the rat.

beta-Amyloid(1-42) peptide (beta AP(1-42) was injected into the medial septum of rats. After a 14-day survival time, neuronal alterations in the septal cholinergic and GABAergic systems were visualized by means of histo- and immunocytochemical methods. Neurons insulted by the peptide were primary choline acetyltransferase-immunoreactive (ir), while only minor effects of beta AP(1-42) were observed on parvalbumin-ir interneurons. These results indicate that the changes in intracellular Ca2+ level elicited by beta AP(1-42) may contribute to beta-amyloid neurotoxicity, and Ca(2+)-binding proteins may play an important role in the protection against the neurotoxic effects of beta AP(1-42).

Amyloid beta-Peptides↗
PubMed1995

Cholinotoxic effects of beta-amyloid (1-42) peptide on cortical projections of the rat nucleus basalis magnocellularis.

Beta-amyloid(1-42) peptide (betaAP) was injected into the right nucleus basalis magnocellularis (nbm) of rats. After a 14-day survival time, the acetylcholinesterase and choline acetyltransferase activities and the number of muscarinic receptors were found biochemically to be significantly reduced in the ipsilateral frontal cortices. Confirmation of these data with silver staining also revealed degeneration of the projective fibers of the nbm to the frontal cortex. These results demonstrate the cholinotoxicity of betaAP in an in vivo animal model.

Acetylcholinesterase↗
PubMed1995

Effect of selective inhibition of potassium channels on vasorelaxing response to cromakalim, nitroglycerin and nitric oxide of canine coronary arteries.

A comparative study was performed on the sensitivity of in-vitro vasorelaxation by nitroglycerin and cromakalim to block glibenclamide, a blocker of ATP-sensitive potassium channels, and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channels. In isolated canine coronary arteries preconstricted with 25 microM prostaglandin F2 alpha, nitroglycerin (0.005-1.8 microM) and cromakalim (0.15-9.6 microM) produced dose-dependent vasodilations. Glibenclamide (30 microM) had no significant effect on relaxation of the dose-response curve to nitroglycerin and almost completely abolished the relaxation by cromakalim, a known opener of ATP-sensitive potassium channels. Iberiotoxin (90 nM) decreased the maximal response to nitroglycerin and had no effect on the vasodilation induced by cromakalim. The effect of iberiotoxin on the vasorelaxing action of nitric oxide, the active metabolite of nitroglycerin, was also examined. In a low potassium chloride (14.4-20.4 mM) medium, as a contractile stimulus, iberiotoxin inhibited relaxations by exogenous nitric oxide (100-200 nM). Enhancement of potassium concentrations to 35.4-40.4 mM significantly decreased relaxation by nitric oxide and under these conditions the inhibitory action of iberiotoxin disappeared. The present study demonstrated that in canine coronary arteries, the functional role of two potassium channels can be separated by pharmacological means. Nitroglycerin-induced vasorelaxation may be mediated, at least in part, by its enzymatic breakdown product, nitric oxide that activates large-conductance calcium-activated potassium channels.

Animals↗