Divergent Effects of the N-Methyl-D-Aspartate Receptor Antagonist Kynurenic Acid and the Synthetic Analog SZR-72 on Microcirculatory and Mitochondrial Dysfunction in Experimental Sepsis

Abstract

Introduction: Sepsis is a dysregulated host response to infection with macro- and microhemodynamic deterioration. Kynurenic acid (KYNA) is a metabolite of the kynurenine pathway of tryptophan catabolism with pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenously administered KYNA or the synthetic analog SZR-72 affects the microcirculation and mitochondrial function in a clinically relevant rodent model of intraabdominal sepsis.Methods: Male Sprague–Dawley rats (n = 8/group) were subjected to fecal peritonitis (0.6 g kg−1 feces ip) or a sham operation. Septic animals were treated with sterile saline or received ip KYNA or SZR-72 (160 μmol kg−1 each) 16 and 22 h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic dysfunctions (PaO2/FiO2 ratio, mean arterial pressure, urea, AST/ALT ratio and lactate levels, respectively) based on the Rat Organ Failure Assessment (ROFA) score. The ratio of perfused vessels (PPV) of the ileal serosa was quantified with the intravital imaging technique. Complex I- and II-linked (CI; CII) oxidative phosphorylation capacities (OXPHOS) and mitochondrial membrane potential (ΔΨmt) were evaluated by High-Resolution FluoRespirometry (O2k, Oroboros, Austria) in liver biopsies. Plasma endothelin-1 (ET-1), IL-6, intestinal nitrotyrosine (NT) and xanthine oxidoreductase (XOR) activities were measured as inflammatory markers.Results: Sepsis was characterized by an increased ROFA score (5.3 ± 1.3 vs. 1.3 ± 0.7), increased ET-1, IL-6, NT and XOR levels, and decreased serosal PPV (65 ± 12% vs. 87 ± 7%), ΔΨmt and CI–CII-linked OXPHOS (73 ± 16 vs. 158 ± 14, and 189 ± 67 vs. 328 ± 81, respectively) as compared to controls. Both KYNA and SZR-72 reduced systemic inflammatory activation; KYNA treatment decreased serosal perfusion heterogeneity, restored PPV (85 ± 11%) and complex II-linked OXPHOS (307 ± 38), whereas SZR-72 improved both CI- and CII-linked OXPHOS (CI: 117 ± 18; CII: 445 ± 107) without effects on PPV 24 h after sepsis induction.Conclusion: Treatment with SZR-72 directly modulates mitochondrial respiration, leading to improved conversion of ADP to ATP, while administration of KYNA restores microcirculatory dysfunction. The results suggest that microcirculatory and mitochondrial resuscitation with KYNA or the synthetic analog SZR-72 might be an appropriate supportive tool in sepsis therapy.

Kynurenic Acid and Its Synthetic Derivatives Protect Against Sepsis-Associated Neutrophil Activation and Brain Mitochondrial Dysfunction in Rats

“…The animals were randomly divided into sham-operated (n ∑ =15) and septic groups (n ∑ =62). Polymicrobial sepsis was induced with intraperitoneally (ip)-administered fecal inoculum, as described before ( 17 , 26 ). Briefly, fresh feces samples were randomly collected from healthy rats (n=4–5), suspended and incubated in physiological saline (37°C, 5h).…”

“…In addition to glutamate receptor antagonism, KYNA acts as an agonist for G protein-coupled receptor GPR35 and the aryl hydrocarbon receptor and regulates glutamatergic neurotransmission and immune activation (25). Previously, we have already shown that KYNA and its synthetic analogue, termed SZR-72, ameliorated sepsis induced mitochondrial dysfunction (decreased oxygen consumption and DYmt) in the rat liver (17). Nevertheless, the mitochondrial effects of these compounds in the CNS have not been examined before.…”

“…Along with BBB injury and immune activation, cerebral mitochondria are also affected soon after an inflammatory insult (~12–24h) at least in rodent experiments. Functional and morphological changes within the organelles and changes in microglial energy metabolism ( 15 ) have been demonstrated, manifested by decreased respiratory chain function and oxidative phosphorylation (OXPHOS) ( 16 ) and loss of mitochondrial membrane potential (ΔΨmt) ( 17 ). These events may ultimately lead to a release of mitochondrial damage-associated molecular patterns to the extracellular space, which further stimulate the immune response.…”

Kynurenic Acid Analog Attenuates the Production of Tumor Necrosis Factor-α, Calgranulins (S100A 8/9 and S100A 12), and the Secretion of HNP1–3 and Stimulates the Production of Tumor Necrosis Factor-Stimulated Gene-6 in Whole Blood Cultures of Patients With Rheumatoid Arthritis

“…There is evidence that KYNA could only poorly cross the BBB, while SZR-72 is BBB-permeable due to a water-soluble side chain with an extra cationic center ( 9 , 18 , 21 ). Furthermore, a facilitated membrane crossing of SZR-72 is suspected, which could influence intracellular signaling, including the activation of antioxidative and anti-apoptotic pathways ( 22 ). On the other hand, a distinct binding to the glycine site of the NMDA receptor has a higher affinity to SZR72 than KYNA ( 22 ).…”

“…Furthermore, a facilitated membrane crossing of SZR-72 is suspected, which could influence intracellular signaling, including the activation of antioxidative and anti-apoptotic pathways ( 22 ). On the other hand, a distinct binding to the glycine site of the NMDA receptor has a higher affinity to SZR72 than KYNA ( 22 ).…”