Display options
Cite
Ostapiuk A, Urbanska EM. Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?. CNS Neurosci Ther. 2021;28(1):19-35doi: 10.1111/cns.13768.
Ostapiuk, A., & Urbanska, E. M. (2022). Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?. CNS neuroscience & therapeutics, 28(1), 19-35. https://doi.org/10.1111/cns.13768
Ostapiuk, Aleksandra, and Urbanska, Ewa M. "Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?." CNS neuroscience & therapeutics vol. 28,1 (2022): 19-35. doi: https://doi.org/10.1111/cns.13768
Ostapiuk A, Urbanska EM. Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?. CNS Neurosci Ther. 2022 Jan;28(1):19-35. doi: 10.1111/cns.13768. Epub 2021 Dec 03. PMID: 34862742; PMCID: PMC8673711.
Copy Download .nbib Format: NLM
Share it on

CNS Neurosci Ther. 2022 Jan;28(1):19-35. doi: 10.1111/cns.13768. Epub 2021 Dec 03.

Kynurenic acid in neurodegenerative disorders-unique neuroprotection or double-edged sword?.

CNS neuroscience & therapeutics

Aleksandra Ostapiuk, Ewa M Urbanska

Affiliations

  1. Laboratory of Cellular and Molecular Pharmacology, Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Lublin, Poland.

PMID: 34862742 PMCID: PMC8673711 DOI: 10.1111/cns.13768

Abstract

AIMS: The family of kynurenine pathway (KP) metabolites includes compounds produced along two arms of the path and acting in clearly opposite ways. The equilibrium between neurotoxic kynurenines, such as 3-hydroxykynurenine (3-HK) or quinolinic acid (QUIN), and neuroprotective kynurenic acid (KYNA) profoundly impacts the function and survival of neurons. This comprehensive review summarizes accumulated evidence on the role of KYNA in Alzheimer's, Parkinson's and Huntington's diseases, and discusses future directions of potential pharmacological manipulations aimed to modulate brain KYNA.

DISCUSSION: The synthesis of specific KP metabolites is tightly regulated and may considerably vary under physiological and pathological conditions. Experimental data consistently imply that shift of the KP to neurotoxic branch producing 3-HK and QUIN formation, with a relative or absolute deficiency of KYNA, is an important factor contributing to neurodegeneration. Targeting specific brain regions to maintain adequate KYNA levels seems vital; however, it requires the development of precise pharmacological tools, allowing to avoid the potential cognitive adverse effects.

CONCLUSIONS: Boosting KYNA levels, through interference with the KP enzymes or through application of prodrugs/analogs with high bioavailability and potency, is a promising clinical approach. The use of KYNA, alone or in combination with other compounds precisely influencing specific populations of neurons, is awaiting to become a significant therapy for neurodegenerative disorders.

© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Keywords: Alzheimer's disease; Huntington's disease; N-methyl-D-aspartate; Parkinson's disease; mitochondrial toxin; neurodegeneration

References

  1. Epilepsy Res. 1994 Jul;18(3):185-94 - PubMed
  2. Neuroscience. 1997 Jun;78(4):967-75 - PubMed
  3. Amino Acids. 2008 Aug;35(2):503-5 - PubMed
  4. Behav Brain Res. 2003 Mar 18;140(1-2):1-47 - PubMed
  5. Schizophr Res. 2014 Dec;160(1-3):80-7 - PubMed
  6. J Neuroimmunol. 2001 Nov 1;120(1-2):190-8 - PubMed
  7. J Huntingtons Dis. 2015;4(2):109-18 - PubMed
  8. Neuroreport. 1996 Dec 20;8(1):15-8 - PubMed
  9. J Neurol Sci. 2005 Dec 15;239(1):31-5 - PubMed
  10. Exp Neurol. 2009 Dec;220(2):230-3 - PubMed
  11. Neurosci Lett. 1989 Feb 27;97(3):271-5 - PubMed
  12. Curr Med Chem. 2017;24(23):2471-2495 - PubMed
  13. Neurosci Lett. 2008 Apr 18;435(2):169-73 - PubMed
  14. J Mol Neurosci. 2009 Jun;38(2):128-42 - PubMed
  15. J Med Chem. 1994 Mar 4;37(5):647-55 - PubMed
  16. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Apr 30;33(3):519-29 - PubMed
  17. J Neurochem. 2005 May;93(3):762-5 - PubMed
  18. Neurosignals. 2005;14(3):126-35 - PubMed
  19. Front Immunol. 2018 Jan 31;9:151 - PubMed
  20. Neuropathol Appl Neurobiol. 1982 Sep-Oct;8(5):377-93 - PubMed
  21. Prog Neuropsychopharmacol Biol Psychiatry. 1999 May;23(4):741-52 - PubMed
  22. J Neural Transm (Vienna). 2012 Feb;119(2):165-72 - PubMed
  23. Adv Exp Med Biol. 2003;527:601-8 - PubMed
  24. J Neurol Sci. 1992 Mar;108(1):80-7 - PubMed
  25. J Neurosci. 1991 Jun;11(6):1649-59 - PubMed
  26. Biochim Biophys Acta. 2009 Dec;1794(12):1802-12 - PubMed
  27. Front Immunol. 2020 Mar 05;11:388 - PubMed
  28. J Neurosci Res. 1997 Nov 1;50(3):457-65 - PubMed
  29. Anal Biochem. 1990 Mar;185(2):363-76 - PubMed
  30. Nature. 2013 Apr 18;496(7445):382-5 - PubMed
  31. Arch Biochem Biophys. 2021 Jan 15;697:108702 - PubMed
  32. Exp Neurol. 2006 Jan;197(1):31-40 - PubMed
  33. J Neurochem. 1999 May;72(5):2135-44 - PubMed
  34. Neuroreport. 1999 Jan 18;10(1):61-5 - PubMed
  35. Acta Neurobiol Exp (Wars). 2003;63(2):101-8 - PubMed
  36. Neurosci Lett. 1984 Aug 10;48(3):273-8 - PubMed
  37. ACS Chem Neurosci. 2017 Dec 20;8(12):2667-2675 - PubMed
  38. J Neurochem. 2005 May;93(3):611-23 - PubMed
  39. Ann Neurol. 1991 Nov;30(5):717-23 - PubMed
  40. Neurosci Lett. 2003 Jul 31;346(1-2):97-100 - PubMed
  41. Eur J Neurosci. 2001 May;13(9):1683-93 - PubMed
  42. J Neurochem. 2010 Jun;113(6):1416-25 - PubMed
  43. Synapse. 1991 Oct;9(2):129-35 - PubMed
  44. Pharmacol Biochem Behav. 2013 Jul;108:54-60 - PubMed
  45. Eur J Pharmacol. 2020 Sep 15;883:173363 - PubMed
  46. Ann N Y Acad Sci. 1992 May 11;648:140-53 - PubMed
  47. Neuropathol Appl Neurobiol. 2005 Aug;31(4):395-404 - PubMed
  48. J Neurosci. 2014 Aug 6;34(32):10592-602 - PubMed
  49. J Diabetes Res. 2019 Oct 13;2019:4957879 - PubMed
  50. Ann Neurol. 1990 Oct;28(4):539-46 - PubMed
  51. J Neurochem. 1992 Dec;59(6):2076-80 - PubMed
  52. Biosci Biotechnol Biochem. 2013;77(7):1517-21 - PubMed
  53. Proc Natl Acad Sci U S A. 2016 May 10;113(19):5435-40 - PubMed
  54. J Clin Neurosci. 1997 Apr;4(2):218-27 - PubMed
  55. Exp Neurol. 2016 Aug;282:99-118 - PubMed
  56. Mov Disord. 2020 Nov;35(11):2028-2037 - PubMed
  57. J Med Chem. 1997 Dec 19;40(26):4378-85 - PubMed
  58. Redox Rep. 2012;17(1):28-46 - PubMed
  59. J Neurochem. 2001 Aug;78(4):842-53 - PubMed
  60. Cell. 2011 Jun 10;145(6):863-74 - PubMed
  61. Ann Neurol. 1998 Sep;44(3 Suppl 1):S115-20 - PubMed
  62. Glia. 2007 Jan 1;55(1):78-92 - PubMed
  63. Life Sci. 1996;58(21):1891-9 - PubMed
  64. Biochem Pharmacol. 1989 Aug 1;38(15):2405-9 - PubMed
  65. Science. 1983 Jan 21;219(4582):316-8 - PubMed
  66. Physiol Rev. 2009 Jan;89(1):73-120 - PubMed
  67. Mol Neurobiol. 2018 Aug;55(8):6319-6328 - PubMed
  68. Drug Discov Today. 2016 Feb;21(2):315-24 - PubMed
  69. Mov Disord. 2005 Jul;20(7):792-802 - PubMed
  70. Neurotoxicol Teratol. 2011 Sep-Oct;33(5):538-47 - PubMed
  71. J Neurochem. 1989 Apr;52(4):1319-28 - PubMed
  72. Mol Cell Biol. 2004 Aug;24(16):6919-30 - PubMed
  73. Am J Physiol Cell Physiol. 2005 Nov;289(5):C1075-84 - PubMed
  74. J Neurochem. 1990 Oct;55(4):1327-39 - PubMed
  75. Endocrinol Diabetes Metab J. 2017 Nov;1(4): - PubMed
  76. Metabolites. 2017 Aug 11;7(3): - PubMed
  77. J Neurochem. 2001 May;77(4):1108-15 - PubMed
  78. Neuropharmacology. 2014 Jan;76 Pt A:137-45 - PubMed
  79. J Neurol Sci. 2011 Nov 15;310(1-2):256-60 - PubMed
  80. Mov Disord. 1991;6(2):133-8 - PubMed
  81. J Neurochem. 2019 Dec;151(5):656-668 - PubMed
  82. J Neurosci Res. 2005 Jun 1;80(5):677-82 - PubMed
  83. Anal Biochem. 1988 Feb 15;169(1):89-94 - PubMed
  84. Free Radic Biol Med. 2013 Sep;62:132-144 - PubMed
  85. Neurotox Res. 2009 Jul;16(1):77-86 - PubMed
  86. J Neurochem. 2005 Dec;95(6):1521-40 - PubMed
  87. Neurosci Lett. 2002 Sep 13;330(1):49-52 - PubMed
  88. Eur J Pharmacol. 2006 Jul 17;541(3):147-51 - PubMed
  89. Exp Neurol. 2002 Sep;177(1):233-41 - PubMed
  90. Eur J Neurosci. 2001 Jun;13(11):2141-7 - PubMed
  91. J Neural Transm (Vienna). 2000;107(3):343-53 - PubMed
  92. Gen Pharmacol. 1992 Mar;23(2):235-9 - PubMed
  93. J Neurochem. 2020 Mar;152(6):627-649 - PubMed
  94. Neuropharmacology. 2014 Jul;82:11-8 - PubMed
  95. World J Biol Psychiatry. 2012 Oct;13(7):482-92 - PubMed
  96. Pharmacol Res. 2012 Feb;65(2):254-60 - PubMed
  97. Br J Pharmacol. 1988 Apr;93(4):868-76 - PubMed
  98. N Engl J Med. 1998 Oct 8;339(15):1044-53 - PubMed
  99. Int J Tryptophan Res. 2013 Sep 15;6:57-66 - PubMed
  100. J Neurol Sci. 1995 May;130(1):39-47 - PubMed
  101. Bioorg Med Chem Lett. 2017 Apr 15;27(8):1705-1708 - PubMed
  102. Eur J Neurosci. 1999 Nov;11(11):3857-63 - PubMed
  103. Acta Neuropathol. 2006 Aug;112(2):127-37 - PubMed
  104. CNS Neurosci Ther. 2022 Jan;28(1):19-35 - PubMed
  105. Brain Res. 1992 Aug 14;588(1):1-5 - PubMed
  106. Neuropsychopharmacology. 2003 Aug;28(8):1454-62 - PubMed
  107. Neuroreport. 1997 Nov 10;8(16):3501-5 - PubMed
  108. J Neural Transm (Vienna). 2012 Feb;119(2):235-43 - PubMed
  109. Neurosci Lett. 1988 Nov 22;94(1-2):145-50 - PubMed
  110. J Neural Transm (Vienna). 1998;105(4-5):439-61 - PubMed
  111. FEBS J. 2011 Nov;278(22):4425-34 - PubMed
  112. J Neural Transm (Vienna). 2011 Jun;118(6):865-75 - PubMed
  113. J Neural Transm (Vienna). 1999;106(2):165-81 - PubMed
  114. Trends Pharmacol Sci. 2017 Jun;38(6):541-555 - PubMed
  115. J Neurochem. 1997 Jul;69(1):290-8 - PubMed
  116. J Neural Transm (Vienna). 2012 Feb;119(2):133-9 - PubMed
  117. J Neural Transm Suppl. 2006;(70):285-304 - PubMed
  118. Schizophr Bull. 2007 May;33(3):797-804 - PubMed
  119. J Mol Neurosci. 2010 Jan;40(1-2):204-10 - PubMed
  120. Adv Exp Med Biol. 1991;294:515-8 - PubMed
  121. J Neurochem. 1991 Aug;57(2):533-40 - PubMed
  122. Neuropharmacology. 2005 May;48(6):788-95 - PubMed
  123. Neurology. 1992 Sep;42(9):1702-6 - PubMed
  124. Cell Chem Biol. 2018 Apr 19;25(4):426-438.e4 - PubMed
  125. Brain Res. 1988 Jun 28;454(1-2):164-9 - PubMed
  126. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jan 3;48:304-13 - PubMed
  127. J Neurochem. 2009 Apr;109(2):316-25 - PubMed
  128. Brain Res. 2000 Mar 31;860(1-2):149-56 - PubMed
  129. J Neurosci Res. 2019 Nov;97(11):1455-1468 - PubMed
  130. Psychopharmacology (Berl). 2014 Jul;231(14):2799-809 - PubMed
  131. Neurology. 2005 Dec 27;65(12):1863-72 - PubMed
  132. Oxid Med Cell Longev. 2018 May 24;2018:5272741 - PubMed
  133. J Neurochem. 1978 Mar;30(3):607-13 - PubMed
  134. J Inflamm (Lond). 2011 Oct 08;8:25 - PubMed
  135. Neuropharmacology. 2011 Jun;60(7-8):1227-31 - PubMed
  136. Biochemistry. 2008 Nov 25;47(47):12420-33 - PubMed
  137. Int J Tryptophan Res. 2014 Apr 28;7:1-7 - PubMed
  138. Int J Tryptophan Res. 2009;2:1-19 - PubMed
  139. Toxicol Sci. 2010 May;115(1):89-97 - PubMed
  140. J Neurochem. 2007 Jul;102(1):103-11 - PubMed
  141. J Comp Neurol. 1992 Dec 1;326(1):82-90 - PubMed
  142. J Parkinsons Dis. 2017;7(s1):S11-S19 - PubMed
  143. Glia. 2005 Jan 1;49(1):15-23 - PubMed
  144. J Neurochem. 2010 Jan;112(1):112-22 - PubMed
  145. Eur J Pharmacol. 1996 Nov 21;315(3):263-7 - PubMed
  146. Neurochem Res. 1980 Mar;5(3):223-39 - PubMed
  147. J Neuroimmunol. 2020 Nov 15;348:577380 - PubMed
  148. J Neurosci Res. 2004 Feb 1;75(3):436-40 - PubMed
  149. Glia. 2014 Oct;62(10):1595-607 - PubMed
  150. J Biochem. 1976 Apr;79(4):13P-21P - PubMed
  151. Neurosci Biobehav Rev. 1997 May;21(3):289-93 - PubMed
  152. J Biol Chem. 2006 Aug 4;281(31):22021-22028 - PubMed
  153. Brain Res. 1993 Jul 16;617(1):76-80 - PubMed
  154. Front Immunol. 2019 Nov 06;10:2570 - PubMed
  155. Neurotox Res. 2007 Dec;12(4):247-62 - PubMed
  156. Brain Res. 1982 Sep 9;247(1):184-7 - PubMed
  157. Int J Mol Sci. 2015 Apr 29;16(5):9772-93 - PubMed
  158. Neuroscience. 2013 May 15;238:19-28 - PubMed
  159. Nature. 1991 Jan 31;349(6308):414-8 - PubMed
  160. Front Mol Biosci. 2019 Feb 08;6:3 - PubMed
  161. Int J Tryptophan Res. 2017 Mar 15;10:1178646917691938 - PubMed
  162. Neurobiol Dis. 2020 Sep;143:104963 - PubMed
  163. Brain Struct Funct. 2017 May;222(4):1663-1672 - PubMed
  164. Exp Neurol. 2010 Jul;224(1):188-96 - PubMed
  165. Neurobiol Aging. 2015 Mar;36(3):1559-68 - PubMed
  166. Neurosci Lett. 2000 Apr 14;283(3):233-5 - PubMed
  167. Biol Psychiatry. 2004 Aug 15;56(4):255-60 - PubMed
  168. Alzheimers Res Ther. 2019 Nov 28;11(1):93 - PubMed
  169. Eur J Neurosci. 2009 Feb;29(3):529-38 - PubMed
  170. Neurochem Int. 2007 Jan;50(2):308-13 - PubMed
  171. Neurosci Lett. 2013 Oct 11;553:138-41 - PubMed
  172. J Pharmacol Exp Ther. 2008 Jan;324(1):342-51 - PubMed
  173. Neuroscience. 1994 Jul;61(2):237-43 - PubMed
  174. Science. 1983 Feb 25;219(4587):979-80 - PubMed
  175. Neuropharmacology. 2017 Jan;112(Pt B):264-274 - PubMed
  176. Adv Med Sci. 2010;55(2):204-11 - PubMed
  177. Eur J Pharmacol. 2005 Jul 11;517(3):217-23 - PubMed
  178. Neurotoxicol Teratol. 2011 Mar-Apr;33(2):303-12 - PubMed
  179. Eur J Pharmacol. 2002 Jul 19;448(2-3):133-7 - PubMed
  180. Brain. 1992 Oct;115 ( Pt 5):1249-73 - PubMed
  181. Cells. 2020 Jun 26;9(6): - PubMed
  182. Schizophr Bull. 2012 Jun;38(4):769-78 - PubMed
  183. J Neurochem. 2021 Jul;158(2):539-553 - PubMed
  184. Trends Pharmacol Sci. 2013 Feb;34(2):136-43 - PubMed
  185. Pharmacol Rep. 2006 Jul-Aug;58(4):507-11 - PubMed
  186. Eur J Pharmacol. 1998 Oct 16;359(1):55-8 - PubMed
  187. Neuroscience. 2004;126(4):899-914 - PubMed
  188. Schizophr Bull. 2012 May;38(3):426-32 - PubMed
  189. Biomolecules. 2020 Apr 08;10(4): - PubMed
  190. J Cereb Blood Flow Metab. 1999 Jul;19(7):771-7 - PubMed
  191. Neurobiol Aging. 2019 Aug;80:11-20 - PubMed
  192. J Neurochem. 1991 Jun;56(6):2007-17 - PubMed
  193. FEBS J. 2012 Apr;279(8):1386-97 - PubMed
  194. PLoS One. 2013 Nov 29;8(11):e82180 - PubMed
  195. Front Cell Neurosci. 2015 May 18;9:178 - PubMed
  196. J Neurochem. 1989 Mar;52(3):985-7 - PubMed
  197. Curr Biol. 2011 Jun 7;21(11):961-6 - PubMed
  198. Alzheimers Res Ther. 2021 Jan 9;13(1):20 - PubMed
  199. Eur J Pharmacol. 2007 Jun 1;563(1-3):130-3 - PubMed
  200. Science. 2017 Jul 28;357(6349): - PubMed
  201. Front Immunol. 2018 Jan 10;8:1957 - PubMed
  202. J Neurosci Res. 2005 Feb 1;79(3):375-82 - PubMed
  203. Nat Rev Dis Primers. 2015 Apr 23;1:15005 - PubMed
  204. Sci Rep. 2020 Feb 21;10(1):3184 - PubMed
  205. Amino Acids. 2009 Jan;36(1):75-80 - PubMed
  206. Front Immunol. 2021 Sep 23;12:716980 - PubMed
  207. Behav Brain Res. 2008 Jan 25;186(2):161-7 - PubMed
  208. FEBS J. 2012 Apr;279(8):1356-65 - PubMed
  209. Neurobiol Dis. 2004 Dec;17(3):455-61 - PubMed
  210. Adv Exp Med Biol. 2003;527:621-8 - PubMed
  211. Oxid Med Cell Longev. 2013;2013:104024 - PubMed
  212. Front Neurosci. 2020 Dec 21;14:574652 - PubMed
  213. Eur J Cell Biol. 2008 Jun;87(6):389-97 - PubMed
  214. J Struct Biol. 2014 Mar;185(3):257-66 - PubMed

Publication Types