Kynurenic acid and kynurenine aminotransferase are potential biomarkers of early neurological improvement after thrombolytic therapy: A pilot study.

BACKGROUND: Biomarkers for predicting treatment response to thrombolysis in acute ischemic stroke are currently lacking. Both, animal models and clinical studies have provided evidence that the kynurenine (KYN) pathway is activated in ischemic stroke. OBJECTIVES: In our pilot study, we aimed to investigate whether KYN pathway enzymes and metabolites could serve as potential biomarkers for treatment response in the hyperacute phase of ischemic stroke. MATERIAL AND METHODS: We included 48 acute ischemic stroke patients who received thrombolysis. Blood samples were taken both before and 12 h after treatment. Concentrations of 11 KYN metabolites were determined using ultra-high-performance liquid chromatography-mass spectrometry. To assess the treatment response, we used early neurological improvement (ENI), calculated as the difference between the admission and discharge National Institutes of Health Stroke Scale (NIHSS) scores. We performed receiver operating characteristic (ROC) analysis for KYN pathway metabolites and enzymes that showed a correlation with ENI. RESULTS: In the samples taken before thrombolysis, significantly lower concentrations of kynurenic acid (KYNA) and kynurenine aminotransferase (KAT) activity were found in patients who had ENI (p = 0.01 and p = 0.002, respectively). According to the ROC analysis, the optimal cut-off value to predict ENI for KYNA was 37.80 nM (sensitivity (SN) 69.2%, specificity (SP) 68.4%) and 0.0127 for KAT activity (SN 92.3%, SP 73.7%). CONCLUSIONS: Our research is the first clinical pilot study to analyze changes in the KYN pathway in ischemic stroke patients who received thrombolytic treatment. Based on our results, baseline KYNA concentration and KAT activity could serve as potential biomarkers to predict early treatment response to thrombolysis.

Detailed severity assessment of Cincinnati Prehospital Stroke Scale to detect large vessel occlusion in acute ischemic stroke.

BACKGROUND: Selecting stroke patients with large vessel occlusion (LVO) based on prehospital stroke scales could provide a faster triage and transportation to a comprehensive stroke centre resulting a favourable outcome. We aimed here to explore the detailed severity assessment of Cincinnati Prehospital Stroke Scale (CPSS) to improve its ability to detect LVO in acute ischemic stroke (AIS) patients. METHODS: A cross-sectional analysis was performed in a prospectively collected registry of consecutive patients with first ever AIS admitted within 6 h after symptom onset. On admission stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and the presence of LVO was confirmed by computed tomography angiography (CTA) as an endpoint. A detailed version of CPSS (d-CPSS) was designed based on the severity assessment of CPSS items derived from NIHSS. The ability of this scale to confirm an LVO was compared to CPSS and NIHSS respectively. RESULTS: Using a ROC analysis, the AUC value of d-CPSS was significantly higher compared to the AUC value of CPSS itself (0.788 vs. 0.633, p < 0.001) and very similar to the AUC of NIHSS (0.795, p = 0.510). An optimal cut-off score was found as d-CPSS≥5 to discriminate the presence of LVO (sensitivity: 69.9%, specificity: 75.2%). CONCLUSION: A detailed severity assessment of CPSS items (upper extremity weakness, facial palsy and speech disturbance) could significantly increase the ability of CPSS to discriminate the presence of LVO in AIS patients.

Structural Evaluation and Electrophysiological Effects of Some Kynurenic Acid Analogs.

Kynurenic acid (KYNA), a metabolite of tryptophan, as an excitatory amino acid receptor antagonist is an effective neuroprotective agent in case of excitotoxicity, which is the hallmark of brain ischemia and several neurodegenerative processes. Therefore, kynurenine pathway, KYNA itself, and its derivatives came into the focus of research. During the past fifteen years, our research group has developed several neuroactive KYNA derivatives, some of which proved to be neuroprotective in preclinical studies. In this study, the synthesis of these KYNA derivatives and their evaluation with divergent molecular characteristics are presented together with their most typical effects on the monosynaptic transmission in CA1 region of the hippocampus of the rat. Their effects on the basic neuronal activity (on the field excitatory postsynaptic potentials: fEPSP) were studied in in vitro hippocampal slices in 1 and 200 µM concentrations. KYNA and its derivative 4 in both 1 and 200 µM concentrations proved to be inhibitory, while derivative 8 only in 200 µM decreased the amplitudes of fEPSPs. Derivative 5 facilitated the fEPSPs in 200 µM concentration. This is the first comparative study which evaluates the structural and functional differences of formerly and newly developed KYNA analogs. Considerations on possible relations between molecular structures and their physiological effects are presented.