Baicalein reverts L-valine-induced persistent sodium current up-modulation in primary cortical neurons

Abstract

L-valine is a branched-chain amino acid (BCAA) largely used as dietary integrator by athletes and involved in some inherited rare diseases such as maple syrup urine disease. This pathology is caused by an altered BCAA metabolism with the accumulation of toxic keto acids in tissues and body fluids with consequent severe neurological symptoms. In animal models of BCAA accumulation, increased oxidative stress levels and lipid peroxidation have been reported. The aim of this study was to analyze both whether high BCAA concentrations in neurons induce reactive oxygen species (ROS) production and whether, by performing electrophysiological recordings, the neuronal functional properties are modified. Our results demonstrate that in primary cortical cultures, a high dose of valine increases ROS production and provokes neuronal hyperexcitability because the action potential frequencies and the persistent sodium current amplitudes increase significantly compared to non-treated neurons. Since Baicalein, a flavone obtained from the Scutellaria root, has been shown to act as a strong antioxidant with neuroprotective effects, we evaluated its possible antioxidant activity in primary cortical neurons chronically exposed to L-valine. The preincubation of cortical neurons with Baicalein prevents the ROS production and is able to revert both the neuronal hyperexcitability and the increase of the persistent sodium current, indicating a direct correlation between the ROS production and the altered physiological parameters. In conclusion, our data show that the electrophysiological alterations of cortical neurons elicited by high valine concentration are due to the increase in ROS production, suggesting much caution in the intake of BCAA dietary integrators.

Antioxidant Properties of Embelin in Cell Culture. Electrochemistry and Theoretical Mechanism of Scavenging. Potential Scavenging of Superoxide Radical through the Cell Membrane

“…Our results, obtained with embelin in cells in culture, are similar to those of baicalein, known to be an excellent antioxidant compound [18,28,29]. We also evaluated the capability of embelin microglia [32] to be cytotoxic for the cells or modulate proliferation by MTT assay and proliferation curves.…”

“…Since embelin biological antioxidant action needs a longer time with respect to other small molecules scavengers analyzed by our group [18,28], we suspected that the long tail of embelin could slow molecular mobility in the biological environment and be responsible for this delay. Taking advantage of the X-ray crystal structure of embelin [8], we built a model to mimic the cell membrane insertion of this scavenger.…”

“…This indicates that embelin probably acts as an antioxidant through different processes, for example, by the modulation of gene transcription of the antioxidant defense system, as already reported [26,27] or via other mechanisms. In our experiments, we compared the effect of embelin with baicalein, a very good antioxidant with three OH groups [18,28,29], given that our earlier studies had shown that baicalein was the most effective of the different flavone compounds studied, including the flavonol quercetin [18]. A comparison of embelin antioxidant activity with other small plant compounds isolated from the fruits of Ardisia colorata (Myrsinaceae), a Thai medicinal plant, showed it was superior in DPPH radical scavenging activity [30].…”

The Role of Amino Acids in Neurotransmission and Fluorescent Tools for Their Detection

“…LaNoue and colleagues [ 246 ] found that approximately 30% of de novo glutamate synthesis came from transamination of BCAAs in the retina, and the ubiquity of the branched-chain aminotransferase in the CNS suggests that BCAA transamination is a significant contributor to de novo glutamate synthesis in the rest of the CNS as well [ 247 ]. High concentrations of BCAAs, such as those found in patients with maple syrup urine disease, were found to be neurotoxic due to increased excitotoxicity and oxidative stress [ 248 , 249 , 250 ].…”

Inhibition by Thyroid Hormones of Cell Migration Activated by IGF-1 and MCP-1 in THP-1 Monocytes: Focus on Signal Transduction Events Proximal to Integrin αvβ3

“…We also studied the effect of baicalein, a flavonoid from the roots of Scutellaria baicalensis, on THP-1 cell migration. Baicalein is a strong antioxidant also at very low concentrations in THP-1 monocytes, reported to be able to modulate also NO production (Seo et al, 2011;Lombardo et al, 2013;Caioli et al, 2016). Baicalein was able to inhibit significantly the cell migration induced by MCP-1, as well as DPI (Figures 7B,C).…”