The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells

Abstract

Six chemicals, 2-halopropionic acids, thiophene, methylhalides, methylmercury, methylazoxymethanol (MAM) and trichlorfon ( Fig. 1), that cause selective necrosis to the cerebellum, in particular to cerebellar granule cells, have been reviewed. The basis for the selective toxicity to these neurones is not fully understood, but mechanisms known to contribute to the neuronal cell death are discussed. All six compounds decrease cerebral glutathione (GSH), due to conjugation with the xenobiotic, thereby reducing cellular antioxidant status and making the cells more vulnerable to reactive oxygen species. 2-Halopropionic acids and methylmercury appear to also act via an excitotoxic mechanism leading to elevated intracellular Ca 2+ , increased reactive oxygen species and ultimately impaired mitochondrial function. In contrast, the methylhalides, trichlorfon and MAM all methylate DNA and inhibit O 6 -guanine-DNA methyltransferase (OGMT), an important DNA repair enzyme. We propose that a combination of reduced antioxidant status plus excitotoxicity or DNA damage is required to cause cerebellar neuronal cell death with these chemicals. The small size of cerebellar granule cells, the unique subunit composition of their N-methyl-D-aspartate (NMDA) receptors, their low DNA repair ability, low levels of calcium-binding proteins and vulnerability during postnatal brain development and distribution of glutathione and its conjugating and metabolizing enzymes are all important factors in determining the sensitivity of cerebellar granule cells to toxic compounds.

High-throughput Functional Genomics Identifies Genes That Ameliorate Toxicity Due to Oxidative Stress in Neuronal HT-22 Cells

“…The described mode of protection consisted of resupplementation of the rate-limiting enzyme, which becomes inactivated at an essential sulfhydryl group by methylmercury (26). For neuronal cells, it is known that methylmercury causes cell death to cerebellar granule cells and other small neurons in the CNS (27,28). Here, its mechanism of toxicity is based in part on the depletion of glutathione, protein modifications and raising the intracellular Ca 2ϩ concentration and in enhancing the production of ROS (27,29).…”

“…For neuronal cells, it is known that methylmercury causes cell death to cerebellar granule cells and other small neurons in the CNS (27,28). Here, its mechanism of toxicity is based in part on the depletion of glutathione, protein modifications and raising the intracellular Ca 2ϩ concentration and in enhancing the production of ROS (27,29). The multiple mode of action of methylmercury (e.g.…”

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

“…Oxidative stress is also implicated in CGN degeneration caused by toxic substances (Fonnum & Lock, 2004). However, in vivo evidence that oxidative stress causes CGN deterioration is lacking.…”

Influence of prenatal exposure to environmental pollutants on human cord blood levels of glutamate

“…During pregnancy, the pollutants accumulated by the women can reach the fetus crossing the placenta. Although the placenta regulates the exchange of nutrients and oxygen between mother and fetus and acts as a barrier of many toxicants, it does not provide protection against certain environmental contaminants (Prouillac and Lecoeur, 2010).The glutamatergic system is one of the targets of several pollutants in the nervous system (Allen et al, 2001;Briz et al, 2010;Fonfría et al, 2005;Fonnum and Lock, 2004;Hogberg et al, 2010;Piedrafita et al, 2008). Glutamate is a non-essential amino acid that has a key role in metabolic pathways, being important for the normal growth and development of the fetus during pregnancy.…”