Hyperhomocysteinemia selectively alters expression and stoichiometry of intermediate filament and induces glutamate‐ and calcium‐mediated mechanisms in rat brain during development

Abstract

The aim of the present work was to investigate the actions of a chemically induced chronic hyperhomocysteinemia model on intermediate filaments (IFs) of cortical and hippocampal neural cells and explore signaling mechanisms underlying such effects. Results showed that in hyperhomocysteinemic rats the expression of neural IF subunits was affected. In cerebral cortex, glial fibrillary acidic protein (GFAP) expression was donwregulated while in hippocampus high and middle molecular weight neurofilament subunits (NF-H and NF-M, respectively) were up-regulated. Otherwise, the immunocontent of IF proteins was unaltered in cerebral cortex while in hippocampus the immunocontent of cytoskeletal-associated low molecular weight neurofilament (NF-L) and NF-H subunits suggested a stoichiometric ratio consistent with a decreased amount of core filaments enriched in lateral projections. These effects were not accompanied by an alteration in IF phosphorylation. In vitro results showed that 500muM Hcy-induced protein phosphatases 1-, 2A- and 2B-mediated hypophosphorylation of NF subunits and GFAP in hippocampal slices of 17-day-old rats without affecting the cerebral cortex, showing a window of vulnerability of cytoskeleton in developing hippocampus. Ionotropic and metabotropic glutamate receptors were involved in this action, as well as Ca(2+) release from intracellular stores through ryanodine receptors. We propose that the mechanisms observed in the hippocampus of 17-day-old rats could support the neural damage observed in these animals.

Intermediate Filaments as a Target of Signaling Mechanisms in Neurotoxicity

“…Moreover, a window of vulnerability of the cytoskeleton of hippocampal cells is evidenced, since misregulated phosphorylation is detected only at postnatal day 17 [30], reflecting an altered activity of the endogenous phosphorylating system associated with the IFs in this brain structure. As expected, NMDA receptors, L-VDCC and extracellular Ca In contrast with hypophosphorylation found in hippocampal slices, the chemically induced chronic hyperhomocysteinemia differently alters the signaling mechanisms directed to the cytoskeleton, producing PP1-, PP2A-and PP2B-mediated hypophosphorylation of NF subunits and GFAP in hippocampal slices of 17-day-old rats without affecting the cerebral cortex [31] through glutamate and Ca…”

Homocysteine Induces Hypophosphorylation of Intermediate Filaments and Reorganization of Actin Cytoskeleton in C6 Glioma Cells

“…, activation of calcineurin, a Ca 2? -dependent protein phosphatase (Wang et al 2005), could be considered, since we have recently demonstrated Hcy-induced IF hypophosphorylation mediated by calcineurin in rat hippocampal slices (Loureiro et al 2009). …”

Advances in Research on the Relationship between Vitamins and Neuropathy

“…The study found that when the concentration of homocysteine increased, the rats will gradually increase growth and cognitive dysfunction, histopathology can also be found in hippocampal neurons atrophy, damage, and the nerve cells placed in high concentrations Homocysteine environmental culture will die, which is directly associated with high concentrations of homocysteine on the toxicity of nerve cells, this evidence was confirmed by Loureiro SO [11]; depression may also occur with low levels of folic acid , high levels of homocysteine, the mechanism is considered folic acid is an antioxidant that can remove oxygen free radicals, protect brain cells from free radical damage, maintain central nervous system function stability, and when folic acid Lack of hyperhomocysteinemia, oxygen free radicals increased, neuronal mitochondrial function damage, the brain antioxidant defense system imbalance, central nervous system dysfunction, causing the corresponding neuropathy and behavior abnormalities Known dysfunction [12].…”