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

Abstract

Background and AimsThe systemic host response in sepsis is frequently accompanied by central nervous system (CNS) dysfunction. Evidence suggests that excessive formation of neutrophil extracellular traps (NETs) can increase the permeability of the blood–brain barrier (BBB) and that the evolving mitochondrial damage may contribute to the pathogenesis of sepsis-associated encephalopathy. Kynurenic acid (KYNA), a metabolite of tryptophan catabolism, exerts pleiotropic cell-protective effects under pro-inflammatory conditions. Our aim was to investigate whether exogenous KYNA or its synthetic analogues SZR-72 and SZR-104 affect BBB permeability secondary to NET formation and influence cerebral mitochondrial disturbances in a clinically relevant rodent model of intraabdominal sepsis.MethodsSprague–Dawley rats were subjected to fecal peritonitis (0.6 g kg-1 ip) or a sham operation. Septic animals were treated with saline or KYNA, SZR-72 or SZR-104 (160 µmol kg-1 each ip) 16h and 22h after induction. Invasive monitoring was performed on anesthetized animals to evaluate respiratory, cardiovascular, renal, hepatic and metabolic parameters to calculate rat organ failure assessment (ROFA) scores. NET components (citrullinated histone H3 (CitH3); myeloperoxidase (MPO)) and the NET inducer IL-1β, as well as IL-6 and a brain injury marker (S100B) were detected from plasma samples. After 24h, leukocyte infiltration (tissue MPO) and mitochondrial complex I- and II-linked (CI–CII) oxidative phosphorylation (OXPHOS) were evaluated. In a separate series, Evans Blue extravasation and the edema index were used to assess BBB permeability in the same regions.ResultsSepsis was characterized by significantly elevated ROFA scores, while the increased BBB permeability and plasma S100B levels demonstrated brain damage. Plasma levels of CitH3, MPO and IL-1β were elevated in sepsis but were ameliorated by KYNA and its synthetic analogues. The sepsis-induced deterioration in tissue CI–CII-linked OXPHOS and BBB parameters as well as the increase in tissue MPO content were positively affected by KYNA/KYNA analogues.ConclusionThis study is the first to report that KYNA and KYNA analogues are potential neuroprotective agents in experimental sepsis. The proposed mechanistic steps involve reduced peripheral NET formation, lowered BBB permeability changes and alleviation of mitochondrial dysfunction in the CNS.

Kynurenic Acid and Its Analog SZR104 Exhibit Strong Antiinflammatory Effects and Alter the Intracellular Distribution and Methylation Patterns of H3 Histones in Immunochallenged Microglia-Enriched Cultures of Newborn Rat Brains

“…KYNA and SZR104 not only attenuated tumor necrosis factor-α (TNF-α) production and increased tumor necrosis factor-stimulated gene-6 mRNA expression in U-937 cells stimulated with heat-inactivated Staphylococcus aureus [8] but they also inhibited the LPS-stimulated phagocytotic activity of microglial cells in vitro while suppressing microglial activity in an in vivo model of epilepsy [5]. Another potent proinflammatory citokine, interleukin-1β, was elevated in sepsis but was ameliorated by KYNA and its synthetic analogues SZR72 and SZR104 [44]. Furthermore, SZR72 inhibited the production of the inflammatory mediators TNF-α, calprotectin, S100A12, and HNP1-3 in blood cultures of rheumatoid arthritis patients [45].…”

A Review of the Health Benefits of Food Enriched with Kynurenic Acid

“…Moroni et al (2012) were the first to communicate that KYNA administered subcutaneously at doses of 500 mg/kg (single injection) or 200 mg/kg three times at 0, 3, and 6 h after LPS dramatically reduced LPS-induced death in mice [ 98 ]. The Hungarian group confirmed that KYNA protects against LPS-induced sepsis in subsequent publications, in which a much lower KYNA dose of 30 mg/kg, i.p., was used [ 99 , 100 ]. Most recently, Wang et al (2022) demonstrated that intraperitoneally administered KYNA (5 mg/kg; three times at days 3, 6, and 9) reduced the mortality of mice infected with Candida albicans [ 94 ].…”

“…Detailed data on the health-promoting effects of KYNA administration in animals regardless of the route of administration are presented in Table S7 [ 26 , 87 , 90 , 93 , 94 , 95 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ].…”

Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity

“…Norman et al ( 32 ) reported that neutrophils were significantly recruited by the brain during the acute inflammatory phase of sepsis, and the transmigration of neutrophils across the endothelial barrier was the main cause of vascular barrier breakdown. Recent studies documented that SB225002 (the antagonist of CXCR2) or kynurenic acid could protect the brain against neutrophil activation and BBB permeability changes in septic animals ( 33 , 34 ). However, neutrophil recruitment was not involved in cognitive impairment ( 35 ).…”