Kynurenic acid, the only known endogenous antagonist of the excitatory amino acid receptors, exerts neuroprotective effect in focal cerebral ischemia. Kynurenic acid poorly while its bioprecursor, l-kynurenine (L-KYN) completely crosses the blood-brain barrier. The aim of our study was to investigate the effect of intravenous l-KYN (0.3, 1, and 3 mg/kg) on the normal and the unilateral carotid artery occlusion induced ischemic corticocerebral blood flow (cCBF) measured by hydrogen polarography in conscious rabbits. Administration of l-KYN produced a significant increase in the normal cCBF; the peak values were recorded at the dose of 1 mg/kg (187% at 120 and 150 mins. respectively). The cCBF-improving effect of l-KYN was immediate and highly pronounced also in rabbits with carotid occlusion (peak value was 192% at 120 mins. at the dose of 1 mg/kg). Pretreatment with either atropine or Nω-nitro-L-arginine-methyl-ester (L-NAME) prevented the l-KYN induced enhancement of the normal and the ischemic cCBF alike. It is suggested that the cCBF-increasing effect of l-KYN might be mediated by activation of cholinergic and nitric oxide pathways.
Kynurenic acid is the only known endogenous excitatory amino acid receptor blocker with a broad spectrum of antagonistic properties. It can block, in low micromolar concentrations, the glycine allosteric site of the N-methyl-D-aspartate (NMDA) receptor. Its affinity to the glutamate binding site is at least 10 times lower than to the binding site of glycine, 1 whereas it exhibits a weak antagonistic effect on the α-amino-3-hydroxy-5-methyl-isoxasolpropionate (AMPA) and kainate receptors. 2,3 Kynurenic acid is a metabolic product of the tryptophan pathway (Fig. 1). 4,5 Another product of this pathway is quinolinic acid with action opposite to kynurenic acid (i.e., it is an endogenous excitotoxin and an agonist of the NMDA receptor). 4,6 Alterations in their concentrations in the brain were described in several neurologic diseases, (e.g., Huntington disease, temporal lobe epilepsy, neuroinfection, immunologic disorders, brain trauma, and cerebral ischemia as reviewed by Stone 3).
Kynurenic and quinolinic acid cross the blood-brain barrier slowly. In contrast, kynurenine (KYN), the precursor of kynurenic acid possessing a protein carrier, easily enters the brain. 7,8 Systematically administered KYN is able to reach maximal cerebral concentrations within 60 to 120 minutes, 9 and exerts pharmacological effects. 10,11 Production of kynurenic acid in the brain is determined by the amount of l-KYN. 12,13 Peripherally administered l-KYN is able to increase the concentration of cerebral kynurenic acid dose dependently, and the existence of a functional, inducible KYN pathway in the central nervous system has been suggested. 14-16 It has been proposed that by shifting kynurenine metabolism toward kynurenic acid formation, it is possible to reduce glutamate receptor activation and excitotoxic neuronal damage. 17
Kynurenic acid proved to be neuroprotective in neonatal rats by reducing anoxia- 18 or hypoxia-ischemia-19 induced brain edema and in adult rats 20 and gerbils 21 given prior to ischemia induction. Only high doses of kynurenic acid proved to be neuroprotective in all cases investigated.
The aim of our present study was to examine whether peripherally administered l-KYN can influence the normal and the unilateral carotid artery occlusion induced ischemic corticocerebral blood flow (cCBF) in conscious rabbits.