Dual Effect of Methylglyoxal on the Intracellular Ca2+ Signaling and Neurite Outgrowth in Mouse Sensory Neurons

Abstract

The formation of advanced glycation end products is one of the major factors involved in diabetic neuropathy, aging, and neurodegenerative diseases. Reactive carbonyl compounds, such as methylglyoxal (MG), play a key role in cross-linking to various proteins in the extracellular matrix, especially in neurons, which have a high rate of oxidative metabolism. The MG effect was tested on dorsal root ganglia primary neurons in cultures from adult male Balb/c mice. Lower MG doses contribute to an increased adherence of neurons on their support and an increased glia proliferation, as proved by MTS assay and bright-field microscopy. Time-lapse fluorescence microscopy by Fura-2 was performed for monitoring the relative fluorescence ratio changes (ΔR/R(0)) upon depolarization and immunofluorescence staining for quantifying the degree of neurites extension. The relative change in fluorescence ratio modifies the amplitude and dispersion depending on the subtype of sensory neurons, the medium-sized neurons are more sensitive to MG treatment when compared to small ones. Low MG concentrations (0-150 μM) increase neuronal viability, excitability, and the capacity of neurite extension, while higher concentrations (250-750 μM) are cytotoxic in a dose-dependent manner. In our opinion, MG could be metabolized by the glyoxalase system inside sensory neurons up to a threshold concentration, afterwards disturbing the cell equilibrium. Our study points out that MG has a dual effect concentration dependent on the neuronal viability, excitability, and neurite outgrowth, but only the excitability changes are soma-sized dependent. In conclusion, our data may partially explain the distinct neuronal modifications in various neurodegenerative pathologies.

Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

“…Such promoting effect of carbonyl stress in cancer is inferred for the first time from our data and certainly awaits more comprehensive studies before confirmation. In a non-tumoral context, MG dual effect has been shown recently for neurons where MG is favorable to neurons development and activity while high MG levels are toxic (Radu et al, 2012). …”

Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress

“…However, Cai et al [117] demonstrated a biphasic elevation of intracellular Ca 2+ in MDA-incubated (30 min) hippocampal neurons with an early phase assigned to Ca 2+ release from SR via IP 3 R and a late phase from Ca 2+ influx through L-type VDCC. Methylglyoxal-treated (24 h) sensory neurons upon KCl mediated plasma membrane depolarization showed a dual effect on Ca 2+ influx with an increase of intracellular Ca 2+ at low methylglyoxal concentrations (up to 150 µM) and a decrease at higher concentrations (250–750 µM) [118]. Albano et al demonstrated a correlation between elevation of intracellular Ca 2+ and lipid peroxidation in isolated rat hepatocytes stimulated with FeCl 3 [119].…”

Glycolytic metabolite methylglyoxal inhibits cold and menthol activation of the transient receptor potential melastatin type 8 channel

“…However, we did not observe any changes in neuronal viability with prolonged MG treatment in our DRG cultures, which rules out neuronal cell death as a possible explanation for the effects reported in this study. Other studies have indicated that survival of DRG neurons is decreased after 24 hr of incubation with MG only at concentrations above 750 µM (Radu et al, ).…”