Manganese neurotoxicity: cellular effects and blood-brain barrier transport.

Publisher Summary This chapter discusses biological significance of manganese in mammalian systems. For manganese in mammalian systems, more information is now available on the sites of action and interaction at the molecular and cellular levels, due to an explosion of new findings within the past decade. Although, this has produced more viable hypotheses, manganese exhibits such a multiplicity and complexity of action that no single, unifying concept or model is likely to emerge. First, it is important to distinguish conceptually between ‘manganese activated (or inhibited)’ and ‘manganese containing’ enzyme systems—the latter being in the minority, with arginase and manganese superoxide dismutase being the best known examples. Manganese-activated systems are the general rule, typically having tight, rapidly reversible, manganese-specific sites involved with either catalytic or regulatory function. The limited number of redox enzymes reported to involve Mn(II) or Mn(III) directly in catalysis include catalase, a peroxidase, a hydroxylase, and manganese superoxide dismutase, all of which utilize one-electron redox reactions.

Biological significance of manganese in mammalian systems.

Base excision repair and the central nervous system.

Very low incorporation of 3H-thymidine (TdR) into neurons and non-proliferating glial and endothelial cells in various brain areas of the adult mouse after 3H-TdR injection and subsequent X-irradiation of the head with 45 Gy has been demonstrated autoradiographically after exposure times of 250 days. In accordance with biochemical studies this incorporation of 3H-TdR represents DNA repair synthesis or UDS (unscheduled DNA synthesis). However, 3H-TdR incorporation into nuclear DNA of non-proliferating cells in the brain was not only found in X-irradiated but also in sham-irradiated mice. This suggests that spontaneous UDS also occurs. Up to now spontaneous UDS has been shown only in HeLa cells in vitro. Nearly all the various types of brain cells tested exhibited UDS after X-irradiation as well as spontaneous UDS. After correcting the mean grain numbers per nucleus not only for background but also for β-self-absorption, substantial differences became apparent in the extent of UDS between the individual types of cells. After X-irradiation, UDS was highest in Purkinje cells and hippocampal granular cells but comparable UDS was also found in endothelial cells, regardless of the different brain areas studied. The extent of spontaneous UDS is also quite different in the various cell types, being highest in neurons of different sites and considerably lower in endothelial and glial cells.

Unscheduled DNA synthesis in various types of cells of the mouse brain in vivo.

DNA-polymerase α, β, δ and ε activities in isolated neuronal and astroglial cell fractions from developing and aging rat cerebral cortex

DNA-polymerases alpha and beta were studied in neuron and glial cells of mouse during developing and aging brain Maximum activity of alpha-enzyme was found to be prenatal, though a very low but significant level could be detected in aging brain Furthermore, this pattern was found to be dependent upon cell types that shift in peak activity just before birth in glial cells in contrast to neurons DNA-polymerase-beta remained high throughout the period studied though a second peak of activity was also observed at day 30 in both cell types, suggesting a possible role in DNA-replication in addition to DNA-repair It was found that beta-enzyme from glial cells behaves differently than the same enzyme from neurons

DNA-polymerases in neuron and glial cells of developing and aging mouse brain.

Addition of an N-substituted indole without any substitution in the 2 and 3 positions to 1,4-naphtoquinone leads to the expected, 2-(3-indolyl)-1,4-naphtoquinone. The latter reacts with some dienophiles via a Diels - Alder reaction and gives new N-substituted naphto-[2,3-C]-carbazole-5-13-quinones.

Action de Divers Dienophiles Sur Quelques 2‐(3‐Indolyl)‐1,4‐Naphtoqui‐Nones‐N‐Substituees. Synthese D'une Nouvelle Serie de Naphto‐[2,3‐c]‐Carbazole‐5,13‐Quinones

When living organisms are exposed to deleterious conditions, such as physical or chemical agents, their cellular DNAs are subject to damage. In order to survive and to maintain genetic continuity, living organisms have developed very efficient repair processes. If a DNA damage is defined as any modification of the normal chemistry or any change in the sequence of the nitrogenous bases of DNA, DNA repair processes are biological mechanisms by which the damage is reversed or removed from the DNA. An error-free repair mode will restore the correct base sequence while an error-prone repair mode will give rise to a base sequence different from the original one.

Michel Philippe

Papers

DNA-polymerases in neuron and glial cells of developing and aging mouse brain.

Action de Divers Dienophiles Sur Quelques 2‐(3‐Indolyl)‐1,4‐Naphtoqui‐Nones‐N‐Substituees. Synthese D'une Nouvelle Serie de Naphto‐[2,3‐c]‐Carbazole‐5,13‐Quinones

DNA Polymerases and DNA Repair in Eukaryotic Cells