Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke.

Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 100956087 Publication Model: Print Cited Medium: Internet ISSN: 1745-7254 (Electronic) Linking ISSN: 16714083 NLM ISO Abbreviation: Acta Pharmacol Sin Subsets: MEDLINE

Publication: 2009- : New York : Nature Publishing Group
Original Publication: Beijing, China : Science Press, c2000-

Excitatory Amino Acid Antagonists/*pharmacology ; Heat Stroke/*drug therapy ; Kynurenic Acid/*pharmacology ; Multiple Organ Failure/*prevention & control; Animals ; Apoptosis/drug effects ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/administration & dosage ; Fever/etiology ; Fever/prevention & control ; Heat Stroke/complications ; Hypotension/etiology ; Hypotension/prevention & control ; Kynurenic Acid/administration & dosage ; Male ; Multiple Organ Failure/etiology ; Rats ; Rats, Sprague-Dawley ; Survival Rate ; Time Factors ; Treatment Outcome

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 °C for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 °C) 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 tumor 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 levels during heatstroke.
Conclusion: Our results suggest that systemic delivery of kynurenic acid may attenuate multiorgan dysfunction in rats after heatstroke.

N Engl J Med. 2002 Jun 20;346(25):1978-88. (PMID: 12075060)
Acta Neurochir Suppl. 1997;70:269-74. (PMID: 9416344)
Shock. 2003 Apr;19(4):388-93. (PMID: 12688553)
Pharmacol Rep. 2009 Jul-Aug;61(4):751-6. (PMID: 19815960)
J Biol Chem. 1998 Jan 16;273(3):1647-53. (PMID: 9430708)
Chem Immunol. 1991;50:98-115. (PMID: 1686177)
Neurosci Lett. 1988 Jul 19;90(1-2):208-12. (PMID: 3412643)
Shock. 2007 Jun;27(6):663-71. (PMID: 17505307)
J Surg Res. 1996 Jun;63(1):333-8. (PMID: 8661221)
Eur J Pharmacol. 1988 Sep 1;154(1):85-7. (PMID: 2846328)
Nitric Oxide. 2006 Dec;15(4):408-16. (PMID: 16765619)
Exp Neurol. 2006 May;199(1):67-76. (PMID: 16405889)
Neurosci Lett. 1986 Nov 21;71(3):361-4. (PMID: 2879266)
Prog Neuropsychopharmacol Biol Psychiatry. 1999 May;23(4):741-52. (PMID: 10390731)
J Trauma. 2010 Oct;69(4):805-12. (PMID: 20400921)
Toxicol Pathol. 2000 Mar-Apr;28(2):277-84. (PMID: 10805145)
Science. 1993 Oct 29;262(5134):689-95. (PMID: 7901908)
Brain Res. 2005 Mar 10;1037(1-2):43-51. (PMID: 15777751)
Curr Med Chem. 2006;13(26):3145-54. (PMID: 17168703)
Am J Physiol. 1978 Nov;235(5):R228-36. (PMID: 727284)
Neurogastroenterol Motil. 2010 Feb;22(2):217-25, e68. (PMID: 19735360)
Shock. 2002 Jul;18(1):86-92. (PMID: 12095141)
J Neurosci. 2001 Oct 1;21(19):7463-73. (PMID: 11567036)
J Neurosci. 1990 Sep;10(9):2965-73. (PMID: 2168940)
J Exp Med. 1993 Feb 1;177(2):547-50. (PMID: 8426124)
Br J Surg. 1974 Sep;61(9):727-30. (PMID: 4412451)
Br J Surg. 1996 May;83(5):588-601. (PMID: 8689199)
J Biol Chem. 2006 Aug 4;281(31):22021-22028. (PMID: 16754668)
Pediatr Neonatol. 2009 Oct;50(5):208-16. (PMID: 19856864)
Neuropharmacology. 1995 Jan;34(1):1-26. (PMID: 7623957)
J Clin Invest. 1995 Nov;96(5):2339-47. (PMID: 7593621)
Nat Med. 2003 May;9(5):575-81. (PMID: 12692538)
Am J Surg. 2002 Jan;183(1):70-4. (PMID: 11869707)
J Neurochem. 1991 Jun;56(6):2007-17. (PMID: 1827495)
Neuron. 1988 Oct;1(8):623-34. (PMID: 2908446)
Int Rev Cytol. 2002;221:93-148. (PMID: 12455747)
Shock. 2008 Dec;30(6):668-74. (PMID: 18496235)
Ann Intern Med. 1998 Aug 1;129(3):173-81. (PMID: 9696724)
Ann Neurol. 1987 Dec;22(6):730-4. (PMID: 3435082)
Restor Neurol Neurosci. 1998;13(1-2):3-10. (PMID: 12671283)
Crit Care Med. 2005 Jun;33(6):1377-83. (PMID: 15942359)
Ann Neurol. 1982 May;11(5):499-502. (PMID: 7103426)
Am J Physiol Heart Circ Physiol. 2001 Feb;280(2):H509-21. (PMID: 11158946)

0 (Excitatory Amino Acid Antagonists)
H030S2S85J (Kynurenic Acid)

Date Created: 20110205 Date Completed: 20110607 Latest Revision: 20211020

20231215

PMC4009940

10.1038/aps.2010.191

21293468