Analog of Kynurenic Acid Decreases Tau Pathology by Modulating Astrogliosis in Rat Model for Tauopathy

ABSTRACT Background and purpose Kynurenines have immunomodulatory and neuroactive properties and can influence the central nervous system. Previous studies showed the involvement of the kynurenines in the pathogenesis and progression of neurodegenerative disease. In neurodegenerative disorders, including tauopathies, the tryptophan metabolism is shifted toward neurotoxic agents and the reduction of neuroprotectant products. Astrocyte-derived kynurenic acid serves as a neuroprotectant. However, systemic administration of kynurenic acid is not effective because of low permeability across the blood-brain barrier (BBB). Experimental Approach We used a kynurenic acid analog with similar biological activity but higher brain permeability to overcome BBB limitations. In the present study, we used amide derivate of kynurenic acid N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamid (KYNA-1). We administered KYNA-1 for three months to tau transgenic rats SHR-24 and analyzed the effect on tau pathology and activation of glial cells. Primary glial cell cultures were applied to identify the mechanism of the KYNA-1 effect. Key results KYNA-1 was not toxic to rats after chronic three-month administration. When chronically administered, KYNA-1 reduced hyperphosphorylation of insoluble tau in the brain of transgenic rats. Noteworthily, the plasma total tau was also reduced. We determined that the effect of KYNA-1 on tau pathology was induced through the modulation of glial activation. KYNA-1 inhibited LPS induced activation of astrocytes and induced transformation of microglia to M2 phenotype. Conclusion and Implications We identified that the administration of KYNA-1 reduced tau hyperphosphorylation and neuroinflammation. KYNA-1 may serve as a promising treatment for tauopathies. What is already known? Studies showed tryptophan-kynurenine pathway changes in neurodegenerative disorders including tauopathies Kynurenines exert immunomodulatory and neuroactive properties and have influence on the central nervous system What does this study add? Chronic administration of synthetic analog of kynurenic acid (KYNA-1) reduces tau phosphorylation and astrogliosis in a transgenic rat model for tauopathies The analog reversed LPS-induced inflammatory changes in glial cell cultures What is the clinical significance? Administration of KYNA-1 analog shifted the tryptophan metabolism in the neuroprotectant direction Neuroprotective analogs KYNA-1 can serve as a new and effective potential therapeutic approach for tauopathies