Thioperamide, antagonist of histamine H3 receptors, increases brain production of kynurenic acid

Brain histamine plays the role of neuromodulator and neurotransmitter in a variety of physiological and pathological processes. Kynurenic acid (KYNA) is an antagonist of the glycine site within the N-methyl-D-aspartate (NMDA) receptor complex, and of nicotinic α7 receptors in the brain of mammals. Here, we report that thioperamide, H3 receptor antagonist/inverse agonist is capable of increasing KYNA synthesis in vitro. The eff ective concentrations were within the range of 0.25-1.0 mM in rat brain cortical slices, and 50-100 μM in mixed glial cultures. An inhibitor of protein kinase A, KT 5720 (0.5 μM) prevented the stimulatory eff ect of 0.5 mM thioperamide. Thioperamide also increased the activity of KYNA biosynthetic enzyme, KAT I, but not of KAT II. The above data suggest that the neuroprotective action of thioperamide may, at least in part, depend on an enhanced synthesis of KYNA.