title: Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study.
abstract: 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.
authors: 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.
authors: I
authors: I
authors: Demeter
authors: K
authors: K
authors: Nagy
authors: T
authors: T
authors: Farkas
authors: Zs
authors: Z
authors: Kis
authors: K
authors: K
authors: Kocsis
authors: L
authors: L
authors: Knapp
authors: L
authors: L
authors: Gellert
authors: F
authors: F
authors: Fülöp
authors: L
authors: L
authors: Vecsei
authors: J
authors: J
authors: Toldi
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D007736:Kynurenic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology*; D017208:Rats, Wistar
chemical_list: D018696:Neuroprotective Agents; C533052:SZR 72; D007736:Kynurenic Acid
keywords: Cognitive functions; Hippocampus; KYNA; Kynurenic acid; LTP; Long-term potentiation