Age-dependent changes in NMDA-induced excitotoxicity and neuromodulatory effects of kynurenic acid and its analogue in mouse brain slices.

Kynurenic acid (KYNA) is one of the main neuroprotective substances of the kynurenine pathway. KYNA plays an important role in various neurodegenerative and psychiatric diseases. Although KYNA has been shown to have neuroprotective effects, it cannot be used as a peripherally administered drug due to its poor ability to cross the blood-brain barrier. To address this limitation, chemically modified KYNA analogues are being developed: SZR72 is one such analogue and has been shown to be protective in various animal models. Glutamate-induced excitotoxicity is a key factor in many neurodegenerative diseases. Therefore, we used the N-methyl-D-aspartate (NMDA)-induced excitotoxicity model to investigate the neuromodulatory agents. Using acute hippocampal slices from mouse brains, we investigated the potential neuroprotective effect of KYNA and its analogue, SZR72 on NMDA-induced excitotoxicity across different age groups of mice. The degree of tissue damage was assessed using biochemical and histological methods. In young animals (1- and 4-week-old), NMDA treatment caused no significant changes, and the cells were found to be resistant. However, in older animals (8-week-old and 1-year-old), NMDA caused significant damage in cells and tissue structure, which was reduced by KYNA and SZR72 treatment. To our knowledge, this is the first study to compare the neuroprotective effects of KYNA and SZR72 in animals of different ages using an in vitro NMDA excitotoxicity model.