Short‐term exposure to the simple polyphenolic compound gallic acid induces neuronal hyperactivity in zebrafish larvae

Abstract

A growing body of evidence suggests that the biological effects of polyphenols are not restricted to antioxidant activity, but they exert a wide range of modulatory effects on metabolic pathways, cellular signaling and gene expression. In this study, we tested the minimum safe concentration of gallic acid (GA) in 72 hpf zebrafish larvae in order to evaluate the effects on the central nervous system and the behavioral response. We showed that a short exposure (30 min) induces the depletion of the two main excitatory and inhibitory neurotransmitters, Glu and GABA, respectively, in the larval nervous system. The acute impairment of GABAergic‐glutamatergic balance was paralleled by an increase of the fosab neuronal activity marker in specific brain areas, such as the forebrain, olfactory bulbs, pallial area, ventral midbrain, tegmentum, and the medulla oblongata ventral area. The neuronal excitation was mirrored by the increased cumulative motor response. The inhibition of the olfactory epithelium with brief cadmium exposition suggests a direct involvement of olfaction in the larvae response to GA. Our results demonstrate that a brief exposure to GA induces motoneuronal hyperexcitability in zebrafish. The behavioral response was probably elicited through the activation of an odorous, or chemical, stimulus. The specificity of the activated neuronal territories suggests the involvement of additional signaling pathways. Although the underlying molecular mechanisms remain to be elucidated, our data support the hypothesis that GA acts as an excitatory molecule, capable of inducing a specific nerve response. These results offer a new vision on potential effects of GA.

Antioxidant, Pro-Survival and Pro-Regenerative Effects of Conditioned Medium from Wharton’s Jelly Mesenchymal Stem Cells on Developing Zebrafish Embryos

“…Remarkably, a number of reports from other authors linked hyperactivity either to exposure to antioxidants or to upregulation of antioxidant gene expression [22][23][24][25][26][27]. In line with this evidence, the hyperactivity observed in CM-treated larvae strictly associates with a reinforced antioxidant performance at the epigenetic and transcription level, as well as in the overall value of their antioxidant capacity.…”

“…According to the literature, the behavioural effects we observed following CM exposure might be attributed either to the downregulation of the brain-derived neurotrophic factor (bdnf ) gene [19][20][21] or to the overexpression of genes involved in redox homeostasis [22][23][24][25][26][27].…”

Overview of Beneficial Effects of (Poly)phenol Metabolites in the Context of Neurodegenerative Diseases on Model Organisms

“…Evidence of neurological modulation by the LMWPM in zebrafish neurophysiological functions ( Table 5 ) or in zebrafish models of NDDs ( Table 6 ) resumes to a small number of molecules. For instance, brief exposure to 3,4,5—trihydroxybenzoic acid in larval zebrafish induced motoneuronal hyperexcitability and hyperactive behavior ( Table 5 ) [ 142 ]. The increased locomotor activity provoked by 3,4,5—trihydroxybenzoic acid was accompanied by the augmented expression of neuronal activity markers like fosab (ortholog for Human c—fos in zebrafish) in specific CNS areas, and by the acute impairment of GABAergic—glutaminergic metabolism in the larval brain ( Table 5 ) [ 142 ].…”

“…For instance, brief exposure to 3,4,5—trihydroxybenzoic acid in larval zebrafish induced motoneuronal hyperexcitability and hyperactive behavior ( Table 5 ) [ 142 ]. The increased locomotor activity provoked by 3,4,5—trihydroxybenzoic acid was accompanied by the augmented expression of neuronal activity markers like fosab (ortholog for Human c—fos in zebrafish) in specific CNS areas, and by the acute impairment of GABAergic—glutaminergic metabolism in the larval brain ( Table 5 ) [ 142 ]. Although the underlying mechanisms must be still clarified, these results suggest that 3,4,5—trihydroxybenzoic acid acts as an excitatory molecule, that is able to induce specific nerve responses.…”

Comparative Study of Condensed and Hydrolysable Tannins during Early Stages of Zebrafish Development

“…Several studies have been carried out on the effect of natural extracts using zebrafish larvae and embryos [28][29][30]. During zebrafish development the early stages are particularly sensitive and the exposure to a plant extract can affect different tissues and organs depending on its content, on the concentration used, and period of exposure [31].…”