Kynurenic Acid Promotes Hippocampal Remyelination and Reduces Seizure Susceptibility in the Cuprizone Model of Demyelination
Abstract number :
1.078
Submission category :
1. Basic Mechanisms / 1F. Other
Year :
2022
Submission ID :
2204086
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:23 AM
Authors :
Yuanyuan Yao, PhD – Medical School of Southeast University; Xinjian Zhu, Ph.D – Medical School of Southeast University
Rationale: Demyelination in the central nervous system (CNS) contributes to axon injury and leads to neurological deficits that can be partially reversed by remyelination. Kynurenic acid (KYNA), a metabolite of kynurenine pathway is reported to play an important role in CNS remyelination. However, it remains unclear how KYNA modulates remyelination process in the context of demyelination. Here in this study, we sought to determine the role of KYNA might play in the remyelination process and the mechanisms involved.
Methods: Adult male C57BL/6J mice were fed with 0.2% (w/w) cuprizone mixed with ground chow for 5 weeks to induce demyelination. At the end of 5 weeks, the cuprizone diet was excluded and from the sixth week onwards, the mice participated in the remyelination phase for 4 weeks. Immunohistochemical and biochemistry measurements were performed to analyze the demyelination and remyelination process, whereas high performance liquid chromatography (HPLC) was used to quantify the metabolites of the kynurenine pathway. Adenovirus vectors carrying AADAT gene (AAV-AADAT) were bilaterally injected into the hippocampus to induce overexpression of kynurenine aminotransferase 2 (KAT-2), the primary enzyme for KYNA synthesis. The specific KAT-2 inhibitor PF-04859989 was administered following demyelination to suppress KYNA synthesis. Mice were subjected to different doses of pentylenetetrazole (PTZ) and exposed to continuous video monitoring to record the latency to onset of seizures and the seizure intensity to investigate seizure susceptibility.
Results: Our results demonstrated that KYNA production was significantly reduced in the hippocampus of cuprizone-treated mice. Overexpression of hippocampal KAT-2 promoted hippocampal KYNA production and remyelination and decreased seizure susceptibility in this cuprizone model of demyelination. Pharmacological inhibition of KAT-2 activity, however, suppressed KAT-2 overexpression-induced remyelination and diminished anti-seizure predisposition.
Conclusions: These results suggested that kynurenic acid promotes hippocampal remyelination and reduces seizure susceptibility in the cuprizone model of demyelination.
Funding: This work was supported by grants from the National Natural Science Foundation of China (81872846 and 81673413 to Xinjian Zhu).
Basic Mechanisms