Sensitivity of Rodent Microglia to Kynurenines in Models of Epilepsy and Inflammation In Vivo and In Vitro: Microglia Activation Is Inhibited by Kynurenic Acid and the Synthetic Analogue SZR104

Imre Földesi,Adrienne Mátyás,László Vécsei,Diana Kata,Ferenc Fülöp,Melinda Szabó,András Mihály,Noémi Lajkó,Karoly Gulya,Karolina Dulka

doi:10.3390/ijms21239333

Abstract

Kynurenic acid is an endogenous modulator of ionotropic glutamate receptors and a suppressor of the immune system. Since glutamate and microglia are important in the pathogenesis of epilepsy, we investigated the possible action of the synthetic kynurenic acid analogue, SZR104, in epileptic mice and the action of kynurenic acid and SZR104 on the phagocytotic activity of cultured microglia cells. Pilocarpine epilepsy was used to test the effects of SZR104 on morphological microglia transformation, as evaluated through ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Microglia-enriched rat secondary cultures were used to investigate phagocytosis of fluorescent microbeads and Iba1 protein synthesis in control and lipopolysaccharide-challenged cultures. SZR104 inhibited microglia transformation following status epilepticus. Kynurenic acid and SZR104 inhibited lipopolysaccharide-stimulated phagocytotic activity of microglia cells. Although kynurenic acid and its analogues proved to be glutamate receptor antagonists, their immunosuppressive action was dominant in epilepsy. The inhibition of phagocytosis in vitro raised the possibility of the inhibition of genes encoding inflammatory cytokines in microglial cells.

Highlights

Pharmacological experiments proved that endogenous kynurenic acid (4-hydroxyquinolin-2-carboxylic acid, C10H7NO3; KYNA) exerted a neuroprotective role in different inflammatory/neurodegenerative central nervous system (CNS) disorders [1,2]
KYNA is antagonistic on ionotropic glutamate receptors, especially N-methyl-D-aspartic acid (NMDA)- and α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)/kainate receptors in micromolar concentrations [2,23], whilst quinolinic acid (QUIN) is neurotoxic because it stimulates the synaptic release of glutamate [1,2,23]
We investigated the possible pharmacological effects of the synthetic KYNA analogue SZR104

Summary

Introduction

Pharmacological experiments proved that endogenous kynurenic acid (4-hydroxyquinolin-2-carboxylic acid, C10H7NO3; KYNA) exerted a neuroprotective role in different inflammatory/neurodegenerative central nervous system (CNS) disorders [1,2]. Exogenous KYNA is not able to cross the blood–brain barrier (BBB); efforts are being made to synthesize KYNA analogues which penetrate the BBB, enter the brain and, supposedly, can be used in the pharmacological treatment of some neurodegenerative disorders [3]. One of these KYNA analogues, C19H26N4O3 or N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide (SZR104), has been applied successfully in pentylenetetrazol (PTZ) seizures and significantly decreased the seizure-evoked field potentials [4]. It was proven that the awake epilepsy model was useful for the pharmacological evaluation of some antiepileptic drugs [6]

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