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Biomedical subjects

M Papadopoulos

Publications and source records attributed to M Papadopoulos.

25 records · Page 2Linked to original sources
PubMed1997

Processing of amyloid precursor protein in human primary neuron and astrocyte cultures.

Increased production of amyloid beta peptide (A beta) is highly suspected to play a major role in Alzheimer's disease (AD) pathogenesis. Because A beta deposits in AD senile plaques appear uniquely in the brain and are fairly restricted to humans, we assessed amyloid precursor protein (APP) metabolism in primary cultures of the cell types associated with AD senile plaques: neurons, astrocytes, and microglia. We find that neurons secrete 40% of newly synthesized APP, whereas glia secrete only 10%. Neuronal and astrocytic APP processing generates five C-terminal fragments similar to those observed in human adult brain, of which the most amyloidogenic higher-molecular-weight fragments are more abundant. The level of amyloidogenic 4-kDa A beta exceeds that of nonamyloidogenic 3-kDa A beta in both neurons and astrocytes. In contrast, microglia make more of the smallest C-terminal fragment and no detectable A beta. We conclude that human neurons and astrocytes generate higher levels of amyloidogenic fragments than microglia and favor amyloidogenic processing compared with previously studied culture systems. Therefore, we propose that the higher amyloidogenic processing of APP in neurons and astrocytes, combined with the extended lifespan of individuals, likely promotes AD pathology in aging humans.

Amyloid beta-Protein Precursor↗
PubMed1993

Indium-111-labelled cationic complexes of aminothiols: structure-activity correlation.

In the present work a series of NxS2 ligands were synthesized, investigated for the formation of cationic, indium chelates and evaluated comparatively in experimental animals. The compounds under study formed indium complexes which were stable in vitro and presented myocardial uptake. Animal studies showed that the chemical structure of the ligand plays an important role in biodistribution. A system of one six-membered and two five-membered rings, formed by the metal and the donor atoms of the ligand, may constitute a basic structure for the development of new indium tracers with myocardial affinity.

Animals↗
PubMed1993

Correlation of lipophilicity to biodistribution of 99mTc-labelled aminothiols.

A series of 99mTc-DADT complexes substituted with heterocyclic amines were synthesized and tested for their ability to cross the BBB. Each 99mTc-DADT complex analysed by HPLC was found to consist of two epimers. The more lipophilic epimers were biodistributed in mice. The data demonstrated a significant brain uptake (3-12% dose/g whole brain) and a high lung accumulation (11-85% dose/g) at 2 min p.i. Between the partition coefficients of the technetium complexes, a linear correlation for lung accumulation was observed, while a parabolic curve for brain uptake was found.

Animals↗
PubMed1993

99mTc-DADT complexes substituted with heterocyclic amines: effect of substitution on in vivo reactivity.

Alkylpiperidinyl and alkylpyrrolidinyl 99mTc-DADT complexes were synthesized and tested for their ability to cross the BBB. Each complex was a mixture of two epimers separated by HPLC. More lipophilic epimers were biologically evaluated in mice, at various time intervals. Similar biodistribution patterns were obtained for both piperidinyl and pyrrolidinyl DADT-complexes. Brain uptake or retention was influenced by the heterocyclic amine introduced into the DADT backbone. Subcellular concentration of selected 99mTc-DADT complexes was more profound in crude nuclear and post-microsomal fractions. Moreover, interaction of 99mTc-2,2,6,6,9,9-hexamethyl-4,7-diaza-4-(3-methylpyrroli dinyl)-ethyl-1,10- decanedithiol with either lipids or microsomes of whole brain was almost unaffected by time. This may suggest that a possible selective site of interaction and metabolism for DADT complexes occurs in brain.

Amines↗
PubMed1993

Renal elimination of some 99mTc-labelled cysteamine derivatives.

It is generally believed that -CO-NH-(CH2)n-COOH moiety promotes tubular excretion of organic anions. Recently it was reported that newly developed renal agents, containing the oxotechnetium(V) glycine group, may mimic the carbonyl amide sequence of [131]I-o-iodohippuric acid. In this study the renal excretion of certain carboxy-cysteamine derivatives is investigated in mice, in the presence of renal tubular transport inhibitor. A similar pattern of renal depression was observed for complexes containing the oxotechnetium glycine sequence, suggesting that this group may satisfy structural parameters for tubular secretion of anionic technetium complexes.

Animals↗
PubMed1989

Prolonged incubation with phorbol esters enhanced vasopressin-induced calcium mobilization and polyphosphatidylinositol hydrolysis of vascular smooth muscle cells.

Arginine vasopressin (AVP)-induced formation of inositol phosphates and increased calcium efflux in smooth muscle cells (A-10) were inhibited by short term treatment with phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (Ca2+/phospholipid-dependent protein kinase) (Aiyar, N., Nambi, P., Whitman, M., Stassen, F. L., and Crooke, S. T. (1987) Mol. Pharmacol. 31, 180-184). Here we report that prolonged treatment of A-10 cells (48 h) with PDBu markedly enhanced AVP-induced calcium mobilization but inhibited ATP- and thrombin-induced calcium mobilization. PDBu (400 nM) doubled [Ca2+]i induced with 3 nM AVP, while the basal calcium concentrations before and after AVP were not different from those of untreated cells. The EC50 for a 24-h exposure was 2.3 nM PDBu. Phorbol 12-myristate 13-acetate was also effective, while 4-alpha-phorbol 12,13-didecanoate (48 h at 400 nM) was without effect. 4-alpha-phorbol 12,13-didecanoate also did not affect inositol phosphate formation. PDBu markedly enhanced inositol phosphate formation induced by AVP but not by NaF. PDBu did not affect basal inositol phosphate and polyphosphoinositide levels, and cytosolic and membrane-associated phospholipase C activity. PDBu treatment (48 h, 400 nM) decreased membrane-associated and cytosolic protein kinase C activity by 80 and 90%, respectively. However, the dose response and time course of changes in protein kinase C activity did not correlate with the same curves for PDBu enhancement of AVP-induced calcium mobilization. We conclude that prolonged PDBu treatment selectively enhanced AVP-induced calcium mobilization and polyphosphoinositide hydrolysis. These effects were not caused by an increase in vasopressin receptor number and apparent affinity, an increase in phospholipase C activity, G-protein-phospholipase C coupling, formation of polyphosphoinositide, or inhibition of inositol phosphate metabolizing enzymes. Enhancement of the AVP responses did not correlate with desensitization or activation of protein kinase C. We suggest that prolonged PDBu treatment might sensitize a putative V1 receptor-G-protein-phospholipase C complex.

Animals↗