Systemic administration of L-Kynurenine
L-Kynurenine (L-KYN) is one of the neuroprotective agents used in cryonics stabilization protocol to limit injury to the brain after cardiac arrest. Administration of L-KYN was perceived to be essential to resuscitate dogs from extended periods (up to 17 minutes) of normothermic ischemia during the Critical Care Research (CCR) cerebral resuscitation experiments in the late 1990s. In cryonics L-KYN has been combined with another neuroprotective agent, niacinamide, to make the compound NiKy.
L-KYN is the precursor of kynurenic acid, the only known endogenous antagonist of the excitatory amino acid receptors. Unlike kynurenic acid, L-KYN can cross the blood brain barrier. Because in cryonics neuroprotective agents are administered to the systemic circulation, the effects of such molecules on blood pressure and cerebral blood flow must be weighed against the benefits as a neuroprotectant.
Katalin Sas et al. investigated the effect of systemic administration of L-Kynurenine on corticocerebral blood flow under normal and ischemic (unilateral carotid artery occlusion) conditions in conscious rabbits. Corticocerebral blood flow (cCBF) was measured using the hydrogen clearance technique (i.e., hydrogen polarography). The investigators observed a significant increase in cCBF for both normal and ischemic animals. In the ischemic animals systemic administration of L-KYN resulted in cCBF that approached or even exceeded the base values measured in the normal animals. Administration of L-KYN did not alter arterial blood pressure or heart rate and its effects were of long duration, peaking between 60 and 240 minutes after administration.
The experiments cannot answer the question of whether L-KYN itself or one of its derivatives (such as kynurenic acid) increases cCBF. Other NMDA receptor antagonists have been found to increase cCBF as well. The authors investigated the possibility that the increase of cCBF might be caused by activation of the ascending cholinergic pathways as a response to NMDA receptor antagonism and found that pre-treatment with atropine prevented the increase of cCBF by L-KYN. The authors also investigated the effect of pre-treatment with the non-specific nitric oxide synthase (NOS) inhibitor L-NAME and found that the increase of cCBF was blocked by this agent as well. This suggests that the L-KYN induced increase in cCBF may be mediated by NMDA antagonist induced NO production. A direct effect of L-KYN on cerebral vessels is doubtful because other studies using either glutumate, NMDA, or agonists and antagonists of the former, failed to affect the tone of isolated cerebral arteries.
If systemic administration of L-KYN enhances cCBF in humans as well, L-KYN might be an attractive agent to treat stroke and cardiac arrest due to its multimodal properties. The beneficial properties of L-KYN on cCBF, instead of (or in addition to) its properties as a neuroprotectant may explain its importance in the CCR cerebral resuscitation experiments. Unlike some neuroprotective agents used in cryonics, such as Propofol and Tempol, L-KYN does not appear to have adverse hemodynamic effects and even improves cerebral blood flow. Although the efficacy of kynurenine as a neuroprotectant in cryonics remains uncertain and investigations into the biochemical and temporal aspects of its metabolism (and the effects of rapid induction of hypothermia on this) are warranted, the drug cannot be ruled out because of adverse effects on blood pressure or cerebral blood flow.