The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

Exp Neurol. 2016 Aug;282:99-118. doi: 10.1016/j.expneurol.2016.05.005. Epub 2016 May 6.

Abstract

Dysregulation of the kynurenine (Kyn) pathway has been associated with the progression of Huntington's disease (HD). In particular, elevated levels of the kynurenine metabolites 3-hydroxy kynurenine (3-OH-Kyn) and quinolinic acid (Quin), have been reported in the brains of HD patients as well as in rodent models of HD. The production of these metabolites is controlled by the activity of kynurenine mono-oxygenase (KMO), an enzyme which catalyzes the synthesis of 3-OH-Kyn from Kyn. In order to determine the role of KMO in the phenotype of mouse models of HD, we have developed a potent and selective KMO inhibitor termed CHDI-340246. We show that this compound, when administered orally to transgenic mouse models of HD, potently and dose-dependently modulates the Kyn pathway in peripheral tissues and in the central nervous system. The administration of CHDI-340246 leads to an inhibition of the formation of 3-OH-Kyn and Quin, and to an elevation of Kyn and Kynurenic acid (KynA) levels in brain tissues. We show that administration of CHDI-340246 or of Kyn and of KynA can restore several electrophysiological alterations in mouse models of HD, both acutely and after chronic administration. However, using a comprehensive panel of behavioral tests, we demonstrate that the chronic dosing of a selective KMO inhibitor does not significantly modify behavioral phenotypes or natural progression in mouse models of HD.

Keywords: Huntington's disease; Inhibitor; Kynurenic acid; Kynurenine; Neurodegeneration; Pharmacodynamic; Q175; Quinolinic acid; R6/2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Electrophysiological Phenomena / drug effects*
  • Electrophysiological Phenomena / genetics
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Hippocampus / drug effects
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease / drug therapy*
  • Huntington Disease / genetics
  • Huntington Disease / physiopathology*
  • In Vitro Techniques
  • Kynurenic Acid / metabolism
  • Kynurenine 3-Monooxygenase / antagonists & inhibitors*
  • Kynurenine 3-Monooxygenase / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Microdialysis
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Quinolinic Acid / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transfection
  • Trinucleotide Repeats / genetics
  • alpha7 Nicotinic Acetylcholine Receptor / genetics
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism

Substances

  • CHDI-340246
  • Enzyme Inhibitors
  • HTT protein, human
  • Huntingtin Protein
  • Pyrimidines
  • Receptors, N-Methyl-D-Aspartate
  • alpha7 Nicotinic Acetylcholine Receptor
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Kynurenine 3-Monooxygenase
  • Quinolinic Acid
  • Kynurenic Acid