Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke

Abstract

IntroductionHeatstroke is defined as a form of excessive hyperthermia (>40 °C) associated with a systemic inflammatory response that leads to multi-organ dysfunction in which central nervous system (CNS) disorders such as delusion, convulsion and coma predominate [1] . Our recent results have demonstrated that heatstroke rodents display hypotension, systemic inflammatory responses, hypothalamic ischemia and neuronal damage, and multi-organ dysfunction [2][3][4] .Kynurenic acid (KYNA) or its metabolic precursor L-kynurenine may be of therapeutic value in neurodegenerative diseased models [5,6] . For example, systemically administered high doses of KYNA had a neuroprotective effect in the gerbil model of global ischemia [7] . Both the homocysteine-induced impairment of endothelial cells [8] and the motility and inflammatory activation in the early phase of acute experimental colitis in the rat [9] were significantly reduced by administration of KYNA. The aim of this study was to investigate whether the heatstroke induced hypotension, systemic inflammatory responses, hypothalamic ischemia and damage, and multiorgan dysfunction could be attenuated by KYNA preconditioning. Accordingly, the temporal profiles of the apoptotic cell numbers of spleen, kidney, liver, lung, and hypothalamus, Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke Aim: To assess whether systemic delivery of kynurenic acid improves the outcomes of heatstroke in rats. Methods: Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline 0.3 mL/kg rat weight) or kynurenic acid (30-100 mg in 0.3 mL saline/kg) 4 h before the start of thermal experiments. They were exposed to an ambient temperature of 43 ºC for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 ºC) and used as normothermic controls. Their core temperatures, mean arterial pressures, serum levels of systemic inflammatory response molecules, hypothalamic values of apoptotic cells and neuronal damage scores, and spleen, liver, kidney and lung values of apoptotic cells were determined. Results: The survival time values during heatstroke for vehicle-treated rats were decreased from the control values of 475-485 min to new values of 83-95 min. Treatment with KYNA (30-100 mg/kg, iv) 4 h before the start of heat stress significantly and dose-dependently decreased the survival time to new values of 152-356 min (P<0.05). Vehicle-treated heatstroke rats displayed hypotension, hypothalamic neuronal degeneration and apoptosis, increased serum levels of tunor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-10 (IL-10), and spleen, liver, kidney, and lung apoptosis. KYNA preconditioning protected against hypotension but not hyperthermia and attenuated hypothalamic neuronal degeneration and apoptosis during heatstroke. KYNA preconditioning attenuated spleen, kidney, liver, and lung apoptosis and up-regulated serum IL-10 levels but down-regulated serum TNF-α and ICAM-1 lev...

Corrective effects of hepatotoxicity by hepatic Dyrk1a gene delivery in mice with intermediate hyperhomocysteinemia

“…Interestingly, KYNA might exert a protective role on multiple organs during heatstroke through anti-inflammatory mechanisms [22]. Here, we found that the plasma levels of KYNA were significantly lower in Cbs +/− mice supplemented with methionine but trended higher after injection with AdDYRK1A (Fig.…”

The kynurenine pathway is involved in bacterial meningitis

“…During the course of bacterial meningitis, anti-inflammatory cytokines are produced to mitigate the induced inflammation [ 4 , 31 ]. Some studies have proposed that cells of the immune system use a bidirectional communication in which TRP catabolism through IDO activity drives the generation of IL-10-producing regulatory T-cells [ 8 , 9 , 18 , 19 ]. In BM patients, we observed a positive correlation between IDO activity and the inflammatory cytokines IFN-γ and IL-1Ra (Table 2 ).…”

“…Similar data were obtained in a study carried out by Hsieh et al ., showing that KYNA improves the outcomes of heatstroke in rats. In this model, KYNA inhibited the expression of inflammatory molecules such as TNF-α and ICAM-1 and enhanced IL-10 levels [ 19 ]. Corroborating the findings regarding neuroprotection, the reduced production of KYNA in astrocytes has been proposed to increase neurological symptoms of cerebral malaria [ 38 ].…”

“…Altogether, these findings suggest that IDO has prominent importance during bacterial meningitis due to the following: its capacity to maintain PARP-1 activity through NAD synthesis, protecting against cell death [ 6 , 16 ]; the generation of reactive oxygen species (ROS), helping the defense mechanisms in addition to maintaining IDO activity [ 8 - 10 , 26 ]; its capacity to produce some antioxidant metabolites [ 27 ]; and regulating the immune response via the known vessel-relaxing ability which KYN possess during inflammation and other immunosuppressive mechanisms [ 18 , 19 , 42 ]. We also suggest that AADAT + 401C/T patients can present a better outcome during BM disease via a reduced inflammatory response and increased capacity of the neuroprotective role of KYNA, which requires further investigation.…”

“…Important immunomodulatory properties, mainly related to the immunosuppressive effect of IDO, have also been attributed to this pathway [ 8 , 9 , 17 ]. A feedback mechanism in modulating the immune responses has been proposed because proinflammatory stimuli activate the KP and an anti-inflammatory effect mediated by KYNA has been observed [ 8 , 18 , 19 ]. IDO is preferentially induced by interferons, with IFN-γ being the main cytokine involved in its induction.…”