Department of Physiology, Anatomy and Neuroscience, University of Szeged, H-6726 Szeged, Közép fasor 52, Hungary; Department of Neurology, University of Szeged, H-6725 Szeged, Semmelweis u. 6, Hungary.
Neurosci Lett. 2013 Oct 11;553:138-41. doi: 10.1016/j.neulet.2013.08.028. Epub 2013 Aug 23.
Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan that acts on different receptors (e.g. those of N-methyl-D-aspartate (NMDA) and presynaptic α7 nicotinic acetylcholine (nACh)), exerts fundamentally antiglutamatergic effects. In view of its antiglutamatergic properties, an elevation of the KYNA level within the brain might result in neuroprotection. However, the use of KYNA as a neuroprotective agent is rather limited, because it crosses the blood-brain barrier (BBB) to only a poor extent. During recent years, new KYNA derivatives have been developed which can readily traverse the BBB and also exert neuroprotection. However, as KYNA and its derivatives are able to interfere with glutamatergic and cholinergic transmission, the potential risks of interfering with cognitive functions cannot be excluded. This in vivo study on anesthetized rats therefore tested the effects of the administration of KYNA and a KYNA derivative (SZR72) (in a dosage that exerted neuroprotection) on long-term potentiation (LTP) and pure field excitatory postsynaptic potentials induced by contralateral CA3 region stimulation and recorded in the pyramidal layer of the CA1 region of the hippocampus. Surprisingly, KYNA and this derivative did not reduce, but rather increased the induceability of LTP. The possible explanation is discussed in detail. In brief: an elevated KYNA level in the perisynaptic area produced, for example, by exogenous prodrug or derivative administration exerts preferential effects on the extrasynaptic NMDA receptors and the nACh receptors on presynaptic glutamatergic terminals, while sparing the currents mediated by synaptic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors. This might be the explanation why the treatment with the prodrug of KYNA or the KYNA derivative in a dosage which induced neuroprotection did not reduce the cognitive functions or the LTP.
犬尿酸（KYNA）是色氨酸的一种神经活性代谢产物，作用于不同的受体（如 N-甲基-D-天冬氨酸（NMDA）和突触前α7 烟碱型乙酰胆碱（nACh）受体），发挥基本的抗谷氨酸作用。鉴于其抗谷氨酸作用，脑内 KYNA 水平升高可能导致神经保护。然而，KYNA 作为神经保护剂的应用相当有限，因为它穿过血脑屏障（BBB）的程度很差。近年来，已经开发出了一些新的 KYNA 衍生物，它们可以很容易地穿过 BBB 并发挥神经保护作用。然而，由于 KYNA 及其衍生物能够干扰谷氨酸能和胆碱能传递，因此不能排除干扰认知功能的潜在风险。因此，本研究在麻醉大鼠中测试了 KYNA 和 KYNA 衍生物（SZR72）（在发挥神经保护作用的剂量下）给药对长时程增强（LTP）的影响，以及对来自对侧 CA3 区刺激诱导的单纯场兴奋性突触后电位的影响，并在海马 CA1 区的锥体层记录。令人惊讶的是，KYNA 和该衍生物不仅没有降低 LTP 的诱导能力，反而增加了它。可能的解释在细节上进行了讨论。简而言之：在突触周围区域中升高的 KYNA 水平，例如通过外源性前药或衍生物给药产生的，优先作用于突触外 NMDA 受体和突触前谷氨酸能末梢上的 nACh 受体，而不影响突触 NMDA 和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的电流。这可能是 KYNA 前药或 KYNA 衍生物治疗剂量诱导神经保护作用而不降低认知功能或 LTP 的原因。
