Kynurenine pathway and cognitive impairments in schizophrenia: Pharmacogenetics of galantamine and memantine

Maju Mathew Koola, Maju Mathew Koola

Abstract

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia, identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the α7 nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. There is a growing body of evidence that excess kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. The α-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA) resulting in cognitive enhancement. Galantamine and memantine through its α-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments. The Single Nucleotide Polymorphisms in the Cholinergic Receptor, Nicotinic, Alpha 7 gene (CHRNA7), Glutamate (NMDA) Receptor, Metabotropic 1 (GRM1) gene, Dystrobrevin Binding Protein 1 (DTNBP1) and kynurenine 3-monooxygenase (KMO) gene may predict treatment response to galantamine and memantine combination for cognitive impairments in schizophrenia in the kynurenine pathway.

Keywords: Cognitive impairments; Kynurenine pathway; Pharmacogenetics; Schizophrenia; α-7 nicotinic receptor and NMDA receptor.

Figures

Fig. 1
Fig. 1
Kynurenine pathway and cognitive impairments in schizophrenia and the association of α-7 nicotinic and the NMDA receptors. Kynurenine pathway metabolism is initiated by the oxidative ring opening of tryptophan by both indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. In the brain, the metabolite L-kynurenine is enzymatically converted in microglial cells and astrocytes. In schizophrenia, there is a persistent reduction of microglial kynurenine 3-monooxygenase activity, along with increased L-kynurenine influx from the circulation. This results in increased kynurenic acid formation in astrocytes (Wonodi and Schwarcz et al., 2010). Galantamine and memantine through its α-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments.

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