NeuroAid™-II (MLC901) provides neuroprotection and enhances neuronal cell survival against kainic acid-induced excitotoxicity in vitro by activating the PI3K/AKT pathway

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Abstract In the twenty-first century, in vitro models of excitotoxic injury, leveraging advanced cellular and molecular technologies, offer a promising alternative to animal studies. These models provide a more precise understanding of injury mechanisms. Method: This study utilizes kainic acid (KA), a potent glutamate receptor agonist, to induce excitotoxicity, oxidative stress, and mitochondrial dysfunction, resulting in motor neuron (MN) degeneration. Mature, differentiated NSC-34 MNs were exposed to different concentrations of KA (0.1, 0.5, and 1 mM) to induce neurodegeneration and apoptosis. Following KA treatment, cells were either treated with MLC901 (NeuroAiD™ II) or left untreated. The effects were assessed through cell viability assays, immunocytochemistry with antibiotic staining, and analysis of key markers in the PI3K/AKT signaling pathway. KA exposure resulted in significant neurodegeneration and apoptosis, as indicated by a reduction in cell viability, a decrease in Tubulin beta-III expression, and downregulation of regenerative markers, including AKT, p-AKT, and GAP43. Additionally, the apoptotic marker p-GSK3β was upregulated in KA-treated cells. In contrast, MLC901 treatment alleviated these detrimental effects. MLC901 restored Tubulin beta-III expression and reversed the downregulation of PI3K/AKT signaling markers (AKT, p-AKT, GAP43). Furthermore, MLC901 treatment led to a reduction in the apoptotic marker p-GSK3β. This study demonstrates that KA induces necrotic and apoptotic cell damage, mimicking secondary injury mechanisms typical of neurodegenerative diseases. MLC901 shows promise as a neuroprotective agent, counteracting KA-induced excitotoxicity and highlighting its potential therapeutic application in neuroprotection.

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