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Synergistic Toxicity of the Neurometabolites Quinolinic Acid and Homocysteine in Cortical Neurons and Astrocytes: Implications in Alzheimer’s Disease

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The brain of patients affected by Alzheimer’s disease (AD) develops progressive neurodegeneration linked to the formation of proteins aggregates. However, their single actions cannot explain the extent of brain damage observed in this disorder, and the characterization of co-adjuvant involved in the early toxic processes evoked in AD is essential. In this line, quinolinic acid (QUIN) and homocysteine (Hcy) appear to be involved in the AD neuropathogenesis. Herein, we investigate the effects of QUIN and Hcy on early toxic events in cortical neurons and astrocytes. Exposure of primary cortical cultures to these neurometabolites for 24 h induced concentration-dependent neurotoxicity. In addition, QUIN (25 μM) and Hcy (30 μM) triggered ROS production, lipid peroxidation, diminished of Na+,K+-ATPase activity, and morphologic alterations, culminating in reduced neuronal viability by necrotic cell death. In astrocytes, QUIN (100 μM) and Hcy (30 μM) induced caspase-3-dependent apoptosis and morphologic alterations through oxidative status imbalance. To establish specific mechanisms, we preincubated cell cultures with different protective agents. The combined toxicity of QUIN and Hcy was attenuated by melatonin and Trolox in neurons and by NMDA antagonists and glutathione in astrocytes. Cellular death and morphologic alterations were prevented when co-culture was treated with metabolites, suggesting the activation of protector mechanisms dependent on soluble factors and astrocyte and neuron communication through gap junctions. These findings suggest that early damaging events involved in AD can be magnified by synergistic toxicity of the QUIN and Hcy. Therefore, this study opens new possibilities to elucidate the molecular mechanisms of neuron-astrocyte interactions and their role in neuroprotection against QUIN and Hcy.

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This work was supported by grants of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and INCT (EN 465671/2014-4)/CNPq, Brazil.

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Correspondence to Paula Pierozan.

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Pierozan, P., Biasibetti-Brendler, H., Schmitz, F. et al. Synergistic Toxicity of the Neurometabolites Quinolinic Acid and Homocysteine in Cortical Neurons and Astrocytes: Implications in Alzheimer’s Disease. Neurotox Res 34, 147–163 (2018).

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