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M Rapp

Publications and source records attributed to M Rapp.

57 records · Page 4Linked to original sources

A brief history of time (constants).

That the cerebral cortex processes information at prodigious speeds cannot be doubted. Yet the passive time constant, tau(m), of neurons, often thought of as a measure of the neuron's "response time' to synaptic input, is relatively long. In the 1950s, tau(m) was estimated to be only a few milliseconds for mammalian central neurons; with improvement in recording techniques, its estimated value grew over the years and it now stands near 20-100 msec. However, as we will argue here, the functional meaning of tau(m) is ambiguous. On the basis of a newly introduced definition of local delay, we show that the time window for synaptic integration in passive dendritic trees can be much smaller than the time constant. We argue that the voltage response to very brief synaptic inputs is essentially independent of tau(m). We discuss how tau(m) can change dynamically with the global activity of the network, as well as the difficulties of defining a time constant in structures with voltage-dependent elements. We conclude that the classically defined tau(m) only provides a very rough estimate, typically an overestimate, of the response time of neurons and that alternative measures are required to capture the dependency of the time course of the membrane potential on ligand-gated and/or voltage-dependent membrane conductances.

Animals↗

Disposition and metabolism of O6-alkylguanine-DNA alkyltransferase inhibitor in nude mice bearing human melanoma.

Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG). We have shown that this compound is able to deplete AGT activity on M4Beu human melanoma cells and to enhance the antitumor power of CENU N'-[2-chloroethyl]-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) towards the M4Beu melanoma grafted on nude mice. With a view to determining the best combination BNAG/CENUs conditions, we have studied the distribution and metabolism of BNAG in nude mice bearing M4Beu human melanoma. BNAG, labelled with carbon-14 on the benzyl group, was administered by single i.v. dose of 40 mg/kg. Blood analysis showed that the main radioactive compound was unchanged molecule, and only a small part was found as hippuric acid resulting from the metabolic cleavage of the benzyl group. BNAG and hippuric acid were mainly eliminated in the urine. Unchanged BNAG blood kinetics showed three phases: blood epuration (t1/2 (1) = 13 min), reabsorption and elimination (t1/2 (2) = 1.7 hr). This kinetic profile is probably due to an enterohepatic cycle. BNAG is distributed in several tissues (kidney, liver, skin, duodenum, colon, tumor) but not in the central nervous system, suggesting a poor blood-brain crossing. Because an important part of the administered dose is not metabolized, high unchanged BNAG level remains in most tissues, including M4Beu tumor, and AGT depletion can occur several hours after dosing.

Animals↗

Main urinary metabolites of two cysteamine-containing 2-(chloroethyl) nitrosoureas in rats.

Urine is the major route of excretion of N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]-N'-nitrosourea (CMSOEN2), N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (CMSO2EN2), and their metabolites in the rat. Labeling the two compounds with 14C in three different positions facilitated their metabolic study in animals. The 14C-ethyl species were chosen in order to investigate the presence of unchanged compounds and that of the denitrosated forms. With the same 14C label position, we showed that isolated metabolites derived from this part of the molecule were degradation products of alkylated glutathione and/or cysteine. They are common to both CMSOEN2 and CMSO2EN2, namely thiodiacetic acid and its sulfoxide, the sum of which represents about half of urinary radioactivity. N-acetyl carboxymethylcysteine and N-acetyl hydroxyethylcysteine, accounting for approximately 6% to 7% of the eliminated 14C radioactivity, were also characterized. However, four minor metabolites corresponding to less than 10% of the excreted radioactivity remained unidentified. With the [14C]cysteamine and [14C]carbonyl labels related to the isocyanate moiety behavior, we indirectly showed that more than 60% to 70% of the excreted metabolites were carbamoylation products of endogenous substrates. A small amount of free amines, 2-methylsulfinylethylamine and/or 2-methylsulfonylethylamine, representing 15%-16% of the eliminated radioactivity, was also detected. The total data confirm the predominant function of glutathione and/or cysteine in the detoxifying system of the chloroethyl moieties and reveal the unexpected but important role played by carbamoylation reactions in the metabolic fate of the drug isocyanate moieties.

Animals↗