Manipulating Kynurenic Acid Levels in the Brain – On the Edge Between Neuroprotection and Cognitive Dysfunction

Levente      Szalardy; Denes      Zadori; Jozsef      Toldi; Ferenc      Fulop; Peter      Klivenyi; Laszlo      Vecsei

Abstract

A number of neurodegenerative diseases have been associated with potentially neurotoxic alterations in the kynurenine pathway. Due to the potent inhibitory effect of kynurenic acid on glutamate receptor function, the potential use of the elevation of its concentrations in the brain in the protection against excitotoxic injury has earned an ever greater interest. The first strong preclinical achievements of protection in transgenic murine models of chronic neurodegenerative diseases by kynurenergic approaches have recently been published. Despite the remarkable neuroprotection provided by these molecules, the potential risk of interfering with cognitive functions when dealing with molecules capable of impairing glutamatergic and cholinergic transmission should always be considered. This issue is of particular interest in light of the high affinity of kynurenic acid towards the glycine site of NMDA receptors, the antagonism of which is known to recapitulate key behavioral features of schizophrenia. In the past decade, however, a number of other sites of action have been revealed, most of them being possible contributors of either the neuroprotective or the cognitive deteriorating effects of kynurenic acid. This paper reviews the current understanding about how kynurenic acid can influence cognitive functions in experimental animals, and discusses the possibility of exploiting the neuroprotective potential of kynurenic acid without impairing cognitive functions.

Keywords: Excitotoxicity, Cognitive functions, Glutamate, Glycine co-agonist site, Kynurenic acid, Neuroprotection

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