title: Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder, the pathomechanism of which is not yet fully understood. Excitotoxicity is known to be involved in the development of HD and antiglutamatergic agents may, therefore, have beneficial neuroprotective effects. One of these agents is the tryptophan metabolite kynurenic acid (KYNA), which is an endogenous NMDA receptor antagonist. However, its pharmacological properties rule out its systemic administration in CNS disorders. We have tested a novel KYNA analogue, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride, in the N171-82Q transgenic mouse model of HD. The analogue exhibited several significant effects: it prolonged the survival of the transgenic mice, ameliorated their hypolocomotion, prevented the loss of weight and completely prevented the atrophy of the striatal neurons. The beneficial effects of this KYNA analogue are probably explained by its complex anti-excitotoxic activity. As it did not induce any appreciable side-effect at the protective dose applied in a chronic dosing regime in this mouse model, it appears worthy of further thorough investigations with a view to eventual clinical trials.
authors.affiliation: Department of Neurology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis u. 6, Szeged 6725, Hungary.
authors.forename: Dénes
authors.initials: D
authors.lastname: Zádori
authors.forename: Gábor
authors.initials: G
authors.lastname: Nyiri
authors.forename: András
authors.initials: A
authors.lastname: Szonyi
authors.forename: István
authors.initials: I
authors.lastname: Szatmári
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: József
authors.initials: J
authors.lastname: Toldi
authors.forename: Tamás F
authors.initials: TF
authors.lastname: Freund
authors.forename: László
authors.initials: L
authors.lastname: Vécsei
authors.forename: Péter
authors.initials: P
authors.lastname: Klivényi
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D007736:Kynurenic Acid