The Mechanism of the Neuroprotective Effect of Kynurenic Acid in the Experimental Model of Neonatal Hypoxia–Ischemia: The Link to Oxidative Stress

Abstract

The over-activation of NMDA receptors and oxidative stress are important components of neonatal hypoxia–ischemia (HI). Kynurenic acid (KYNA) acts as an NMDA receptor antagonist and is known as a reactive oxygen species (ROS) scavenger, which makes it a potential therapeutic compound. This study aimed to establish the neuroprotective and antioxidant potential of KYNA in an experimental model of HI. HI on seven-day-old rats was used as an experimental model. The animals were injected i.p. with different doses of KYNA 1 h or 6 h after HI. The neuroprotective effect of KYNA was determined by the measurement of brain damage and elements of oxidative stress (ROS and glutathione (GSH) level, SOD, GPx, and catalase activity). KYNA applied 1 h after HI significantly reduced weight loss of the ischemic hemisphere, and prevented neuronal loss in the hippocampus and cortex. KYNA significantly reduced HI-increased ROS, GSH level, and antioxidant enzyme activity. Only the highest used concentration of KYNA showed neuroprotection when applied 6 h after HI. The presented results indicate induction of neuroprotection at the ROS formation stage. However, based on the presented data, it is not possible to pinpoint whether NMDA receptor inhibition or the scavenging abilities are the dominant KYNA-mediated neuroprotective mechanisms.

Molecular Docking and Dynamics Simulation revealed the Potential Inhibitory Activity of Piomozide against Kynurenine metabolism targeting the Kynurenine 3-monooxygenase

“…KYNA acts as a neuroprotective agent, blocking the N-methyl-D-aspartate (NMDA) receptor and thus, reducing the excitability of pathways and neuro excitotoxicity in the brain. On the other hand, QUIN functions as an agonist of glutamate receptors, enhancing neuronal excitation and thus, leading to neurotoxicity and oxidative stress (Bratek-Gerej et al 2021).The maintenance of a balance between QUIN and KYNA is essential for normal neuronal function. Imbalances in this pathway have been linked todifferent kinds of diseases, including schizophrenia, depression, and neurodegenerative disorders (Behl et al 2021).…”

Can kynurenine pathway be considered as a next-generation therapeutic target for Parkinson's disease? An update information

“…The neuroprotective action of KA is due to the suppression of the neurotoxicity that is produced by the activation of the NMDA receptor by QUIN overactivation (35). Moreover, KA can also antagonize the noncompetitive α7-nicotinic acetylcholine receptor (α7-nAChR) and reduce the extracellular levels of glutamate and dopamine in the CNS (36). In this regard, the QUIN/KA ratio is commonly used as an index of glutamate receptor activation and neurotoxicity.…”

Associations of the serum kynurenine pathway metabolites with P50 auditory gating in non-smoking patients with first-episode schizophrenia

“…Kynurenic acid (KYNA), a product of the KYN pathway of tryptophan metabolism, may cause glutamate hypofunction through sustained N-methyl D-aspartate (NMDA) receptor antagonism, which may cause psychotic symptoms and cognitive deficits in people with schizophrenia ( 15 , 16 ). Interestingly, due to its antagonistic action on NMDA receptors, effective antioxidant properties and hydroxyl radical scavenging capacity, a highly elevated level of KYNA has also been found to have neuroprotection potential in experimental animals ( 17 , 18 ). In contrast to the replicable findings that cerebrospinal fluid (CSF) levels of KYN and KYNA were significantly higher in patients with schizophrenia than in healthy controls (HC) ( 19 ), either increase ( 20 ) or decrease ( 21 ) in their serum and plasma levels has been found in patients with schizophrenia compared with that in controls.…”