Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington's disease

Department of Neurology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis u. 6, Szeged 6725, Hungary.
Journal of Neural Transmission (Impact Factor: 2.4). 12/2010; 118(6):865-75. DOI: 10.1007/s00702-010-0573-6
Source: PubMed


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.

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Available from: Gabor Nyiri, Jan 08, 2014
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    • "There is evidence that it can also affect nociception (Mecs et al. 2009; Nasstrom et al. 1992; Pardutz et al. 2012), probably due to an antagonistic effect on N-methyl-D-asparate (NMDA), a-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA), kainate and a7-nicotinic acetylcholine receptors (Pereira et al. 2002; Birch et al. 1988; Kessler et al. 1989) or an agonistic action on G-protein-coupled receptor-35 (Wang et al. 2006). Due to the poor ability of kynurenic acid to cross the blood– brain barrier (Fukui et al. 1991), its various derivatives with a better central nervous system action and a suggested similarity regarding their pharmacological effect were synthesized and successfully used under experimental conditions (Demeter et al. 2012; Gellert et al. 2012; Zadori et al. 2011). An earlier synthesized kynurenic acid derivative was more effective than the parent compound reducing the second-order trigeminal activation, as previously shown (Knyihar-Csillik et al. 2008) and experimental evidence suggests that this analogue has a similar pharmacological action as kynurenic acid with a presumed better blood–brain barrier penetrance (Marosi et al. 2010). "
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