Abstract
Significant body of evidence suggests that abnormal kynurenic acid (KYNA) level is involved in the pathophysiology of central nervous system disorders. In the brain, KYNA is synthesized from kynurenine (KYN) by kynurenine aminotransferases (KATs), predominantly by KAT II isoenzyme. Blockage of ionotropic glutamate (GLU) receptors is a main cellular effect of KYNA. High KYNA levels have been linked with psychotic symptoms and cognitive dysfunction in animals and humans. As immunological imbalance and impaired glutamatergic neurotransmission are one of the crucial processes in neurological pathologies, we aimed to analyze the effect of anti-inflammatory agents, inhibitors of cyclooxygenase-2 (COX-2): celecoxib, niflumic acid, and parecoxib, on KYNA synthesis and KAT II activity in rat brain in vitro. The influence of COX-2 inhibitors was examined in rat brain cortical slices and on isolated KAT II enzyme. Niflumic acid and parecoxib decreased in a dose-dependent manner KYNA production and KAT II activity in rat brain cortex in vitro, whereas celecoxib was ineffective. Molecular docking results suggested that niflumic acid and parecoxib interact with an active site of KAT II. In conclusion, niflumic acid and parecoxib are dual COX-2 and KAT II inhibitors.
Highlights
Schizophrenia is a common psychiatric disorder affecting about 1% of the general population (Janoutová et al 2016)
We showed that COX-2 inhibitors, niflumic acid and parecoxib, decreased kynurenic acid (KYNA) production in rat cortical slices in vitro
Both COX-2 inhibitors lowered kynurenine aminotransferase (KAT) II activity, an enzyme that is directly involved in brain KYNA production
Summary
Schizophrenia is a common psychiatric disorder affecting about 1% of the general population (Janoutová et al 2016). Elevated levels of proinflammatory cytokines have been found in cerebrospinal fluid of schizophrenia patients (Wang and Miller 2017). This was accompanied by impaired blood-brain barrier structure (Schwarz et al 1998) and changes in postmortem brain tissue (van van Kesteren et al 2017). The expression of COX2 could be markedly increased in astroglia and microglia in the presence of inflammatory stimuli (Font-Nieves et al 2012). COX-2 inhibitors were demonstrated to alleviate memory impairment in diabetic rat model (Yang and Gao 2017), Alzheimer’s disease rat model (Mhillaj et al 2018), and in humans with first manifestation of schizophrenia (Müller et al 2010). Neuroprotective effect of COX-2 inhibitor, 5,5dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl2((5)H)-furanone (DFU) against NMDA-mediated damage of cerebellar granule cells has been presented (Strauss and Marini 2002)
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