Abstract 15237: Inhibition of the Kynurenine Pathway Improves Neurological Recovery in a Rat Model of Cardiac Arrest
Introduction: Kynurenine pathway (KP), the major route of the tryptophan (TRP) catabolism, is involved in the pathogenesis of numerous cerebral disorders. We have previously demonstrated that KP is activated following cardiac arrest (CA) and correlates with neurological injury both in animals and humans. We thus hypothesized that inhibition of the enzyme initiating the TRP catabolism into kynurenine (KYN), i.e. indoleamine-2,3-dioxygenase (IDO), could prevent KP activation and improve neurological recovery.
Methods: Twenty-two rats received oral administration of 1-Methyl-Tryptophan (1-MT, 800mg/Kg of racemate) (n=10) or corresponding vehicle (n=12), 24h and 2h before CA. Ventricular fibrillation was induced and untreated for 8 min. CPR was then performed for additional 8 min prior to defibrillation. Blood samples were obtained for assay of plasma levels of: 1-MT, TRP, KYN, high-sensitive cardiac troponin T (hs-cTnT), and neuron specific enolase (NSE). Rats were observed up to 96h for assessment of neurological recovery by the neurological deficit score (NDS).
Results: High plasma levels of 1-MT were observed up to 96h after drug administration (Fig). CA induced a significant and long-lasting KP activation (reported as KYN/TRP) and this was significantly reduced in rats treated with 1-MT (Fig). 90% of animals treated with 1-MT were successfully resuscitated compared to 75% of those treated with vehicle. Lower levels of hs-cTnT (5186 vs. 9207 ng/L) and NSE (0.44 vs. 0.76 ng/mL) were observed in treated animals compared to vehicles. 1-MT also significantly reduced the KP activation in the hippocampus, restoring the KYN/TRP ratio to the values observed in naïve rats. The severity of CA-induced neurological deficit was significantly reduced by 1-MT (Fig), and correlated with level of KP activation, both in plasma (Fig) and in the hippocampus (r=0.73, p=0.019).
Conclusions: In this model, inhibition of KP was feasible and improved neurological recovery after CA.
Author Disclosures: R. Affatato: None. J. Lucchetti: None. S. Ceriani: None. F. Fumagalli: None. C. Fracasso: None. L. Staszewsky: None. T. Letizia: None. S. Masson: None. M. Gobbi: None. R. Latini: None. G. Ristagno: Research Grant; Modest; Associazione "Amiche del Mario Negri", Milano.
- © 2015 by American Heart Association, Inc.