Systemic administration of l-kynurenine sulfate induces cerebral hypoperfusion transients in adult C57Bl/6 mice

Abstract

The kynurenine pathway is a cascade of enzymatic steps generating biologically active compounds. l-kynurenine (l-KYN) is a central metabolite of tryptophan degradation. In the mammalian brain, l-KYN is partly converted to kynurenic acid (KYNA), which exerts multiple effects on neurotransmission. Recently, l-KYN or one of its derivatives were attributed a direct role in the regulation of the systemic circulation. l-KYN dilates arterial blood vessels during sepsis in rats, while it increases cerebral blood flow (CBF) in awake rabbits. Therefore, we hypothesized that acute elevation of systemic l-KYN concentration may exert potential effects on mean arterial blood pressure (MABP) and on resting CBF in the mouse brain. C57Bl/6 male mice were anesthetized with isoflurane, and MABP was monitored in the femoral artery, while CBF was assessed through the intact parietal bone with the aid of laser speckle contrast imaging. l-KYN sulfate (l-KYNs) (300mg/kg, i.p.) or vehicle was administered intraperitoneally. Subsequently, MABP and CBF were continuously monitored for 2.5h. In the control group, MABP and CBF were stable (69±4mmHg and 100±5%, respectively) throughout the entire data acquisition period. In the l-KYNs-treated group, MABP was similar to that, of control group (73±6mmHg), while hypoperfusion transients of 22±6%, lasting 7±3min occurred in the cerebral cortex over the first 60-120min following drug administration. In conclusion, the systemic high-dose of l-KYNs treatment destabilizes resting CBF by inducing a number of transient hypoperfusion events. This observation indicates the careful consideration of the dose of l-KYN administration by interpreting the effect of kynurenergic manipulation on brain function. By planning clinical trials basing on kynurenergic manipulation possible vascular side effects should also be considered.

Keywords: C56Bl/6 mice; Cerebral blood flow; Hypoperfusion; Laser speckle flowmetry; Mean arterial blood pressure; l-Kynurenine.