Preventing Quinolinic acid-induced toxicity in oligodendrocytes with antagonizing monoclonal antibodies and kynurenine pathway inhibitors

Background: Quinolinic acid (QUIN), a downstream metabolite of the kynurenine pathway (KP) and an agonist of the NMDA receptor, has gained interest for its pathophysiological involvement in several major neurological diseases including multiple sclerosis (MS). QUIN is found in pathophysiological concentrations in EAE mice, the most common animal model for MS, sufficient to induce brain cell death especially oligodendrocytes. This study has focused on the strategies to limit QUIN excitotoxicity in oligodendrocytes. Objective: To investigate if the inhibition of QUIN production or the neutralization of QUIN's effects with a monoclonal antibody (mAb) could protect oligodendrocytes. Methods: Mouse oligodendroglial cell lines (N19 and N20.1) were challenged with QUIN secreted from activated microglial cell line BV2. Immunocytochemistry, qRT-PCR, and lactate dehydrogenase assay were used to assess QUIN toxicity and neuroprotection with KP inhibitors or a QUIN mAb. Results: Our data show that QUIN toxicity on oligodendrocytes increases with both time of exposure and concentrations. Treatments of activated BV2 cells with either KP enzyme inhibitors or QUIN mAb were able to protect oligodendrocytes and significantly increase cell survival. Conclusion: We demonstrated that QUIN toxicity on oligodendrocytes could be limited by 1) inhibiting QUIN production by activated monocytic cells with specific KP enzyme inhibitors and 2) using a QUIN mAb neutralizing the cytotoxic effects of exogenous QUIN. The outcomes of this study provide new therapeutic strategies by limiting QUIN-induced neurodegeneration especially in MS.