Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, 6726 Szeged, Hungary.
J Neural Transm (Vienna). 2010 Feb;117(2):183-8. doi: 10.1007/s00702-009-0346-2. Epub 2009 Dec 2.
Kynurenic acid is an endogenous product of the tryptophan metabolism, and as a broad-spectrum antagonist of excitatory amino acid receptors may serve as a protective agent in neurological disorders. The use of kynurenic acid as a neuroprotective agent is rather limited, however, because it has only restricted ability to cross the blood-brain barrier. Accordingly, new kynurenic acid analogues which can readily cross the blood-brain barrier and exert their complex anti-excitotoxic activity are greatly needed. Such a novel analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride, has been developed and tested. In an in vitro electrophysiological study, in which its properties were compared with those of kynurenic acid, the new analogue behaved quite similarly to kynurenic acid: in the micromolar range, its administration led to a decrease in the amplitudes of the field excitatory postsynaptic potentials in the CA1 region of the hippocampus, while in nanomolar concentrations it did not give rise to inhibition, but, in fact, facilitated the field excitatory postsynaptic potentials. Moreover, the new analogue demonstrated similar protective action against PTZ-induced facilitation to that observed after kynurenic acid administration. The findings strongly suggest that the neuroactive effects of the new analogue are comparable with those of kynurenic acid, but, in contrast with kynurenic acid, it readily crosses the blood-brain barrier. The new analogue may therefore be considered a promising candidate for clinical studies.
犬尿酸是色氨酸代谢的内源性产物，作为一种广泛的兴奋性氨基酸受体拮抗剂，可能在神经疾病中作为一种保护剂。然而，犬尿酸作为一种神经保护剂的用途相当有限，因为它只有有限的能力穿过血脑屏障。因此，需要开发和测试能够轻易穿过血脑屏障并发挥其复杂抗兴奋毒性作用的新犬尿酸类似物。已经开发并测试了一种新型类似物，2-(2-N,N-二甲基氨基乙基胺-1-羰基)-1H-喹啉-4-酮盐酸盐。在一项体外电生理学研究中，将其特性与犬尿酸进行了比较，新型类似物的行为与犬尿酸非常相似：在微摩尔范围内，其给药导致海马 CA1 区场兴奋性突触后电位的幅度降低，而在纳摩尔浓度下，它不会引起抑制，而是实际上促进了场兴奋性突触后电位。此外，新型类似物对 PTZ 诱导的易化表现出与犬尿酸给药后观察到的类似的保护作用。这些发现强烈表明，新型类似物的神经活性作用与犬尿酸相当，但与犬尿酸不同的是，它很容易穿过血脑屏障。因此，该新型类似物可被认为是临床研究的有前途的候选物。
