Experimental hypothyroidism raises brain kynurenic acid - Novel aspect of thyroid dysfunction

Hypothyroidism frequently manifests with altered mood and disturbed cognition. Kynurenic acid may influence cognition through antagonism of N-methyl-d-aspartate receptors (NMDA) and α7 nicotinic receptors. In here, thyroid hormones effects on kynurenic acid synthesis in rat cortical slices and on kynurenine aminotransferases (KATs) activity in semi-purified cortical homogenates were studied. Furthermore, brain kynurenic acid levels and KATs activities were evaluated in experimental model of hypothyroidism, induced by chronic administration of 0.05% propylthiouracil in drinking water. In vitro, L-thyroxine (T₄) and 3,3,5-triiodothyronine (T₃), reduced kynurenic acid synthesis and KATs activities (IC₅₀ ~ 50-150 μM). In vivo, propylthiouracil increased cortical, hippocampal and striatal, but not cerebellar kynurenic acid content (192%, 142% and 124% of control, respectively), despite uniformly decreased KAT II activity and lower cortical and striatal KAT I activity. T₄ application to hypothyroid animals restored kynurenic acid levels to control values and reversed enzymatic changes. T₄ alone did not change brain kynurenic acid levels, despite increased activities of brain KATs. Hence, thyroid hormones modulate kynurenic acid levels by two opposing mechanisms, stimulation of KATs activity, most probably transcriptional, and direct, post-translational inhibition of KATs. Lack of correlation between KATs activity and kynurenic acid level may reflect the influence of T₄ on organic anion transporter and result from impaired removal of kynurenic acid from the brain during hypothyroidism. Our data reveal novel mechanism linked with thyroid hormones deficiency and imply the potential involvement of increased brain kynurenic acid in the hypothyroidism-related cognitive disturbance.