Abstract

Simple phenolic compounds can act as antioxidants or prooxidants depending on their structure and environmental conditions. Glutamate-induced excitotoxicity leads to neurodegeneration, astrocyte dysfunction, oxidative stress, and neuroinflammation. This study examined six phenolics: catechol, phloroglucinol, resorcinol, pyrogallol, hydroquinone, and hydroxyquinol, assessing their effects on astrocyte survival in a glutamate-excitotoxic model. Mouse astrocytes (C8-D1A) were exposed to 20 mM glutamate, with phenolics added before, during, or after treatment. Cell viability, morphology, nuclear condensation, ROS levels, and inflammatory cytokines were measured using the MTT assay, microscopy, CellROX, and RT-qPCR. Simultaneously, treatment improved astrocyte survival and preserved morphology, whereas pre- or post-treatment did not confer protection and worsened toxicity at higher doses. Resorcinol showed the strongest protective effect, followed by hydroxyquinol and hydroquinone at lower doses. Resorcinol and hydroxyquinol decreased ROS levels, whereas pyrogallol and hydroquinone increased cell survival without reducing ROS. All four lowered IL-6 and TNF-α. These findings demonstrate that the effects of phenolics, whether protective or toxic, depend on concentration, structure, and timing, underscoring their dual role in excitotoxic environments. They also identify resorcinol as a promising candidate for further preclinical study.

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