Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice

Neurotox Res. 2018 Apr;33(3):593-606. doi: 10.1007/s12640-017-9848-0. Epub 2017 Dec 12.

Abstract

Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH) activity. Patients usually present progressive cortical leukodystrophy and commonly develop acute bilateral striatal degeneration mainly during infections that markedly worse their prognosis. A role for quinolinic acid (QA), a key metabolite of the kynurenine pathway, which is activated during inflammatory processes, on the pathogenesis of the acute striatum degeneration occurring in GA I was proposed but so far has not yet been evaluated. Therefore, we investigated whether an acute intrastriatal administration of quinolinic acid (QA) could induce histopathological alterations in the striatum of 30-day-old wild-type (WT) and GCDH knockout (Gcdh-/-) mice. Striatum morphology was evaluated by hematoxylin and eosin, T lymphocyte presence (CD3), and glial activation (GFAP and S100β) by immunohistochemistry and 3-nitrotyrosine (YNO2) by immunofluorescence. QA provoked extensive vacuolation, edema, and especially lymphocyte infiltration in the striatum of Gcdh-/-. QA also enhanced CD3 staining and the number of YNO2 positive cells in Gcdh-/- mice, relatively to WT, indicating T lymphocyte infiltration and nitrosative stress, respectively. QA-treated WT mice also showed an increase of GFAP and S100β staining, which is indicative of reactive astrogliosis, whereas the levels of these astrocytic proteins were not changed in Gcdh-/- QA-injected mice. The present data indicate that QA significantly contributes to the histopathological changes observed in the striatum of Gcdh-/- mice.

Keywords: Acute striatum degeneration; Glutaric acidemia type I; Histopathology; Neuroinflammation; Nitrosative stress; Quinolinic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / diet therapy
  • Amino Acid Metabolism, Inborn Errors / genetics
  • Amino Acid Metabolism, Inborn Errors / pathology*
  • Animals
  • Brain Diseases, Metabolic / diet therapy
  • Brain Diseases, Metabolic / genetics
  • Brain Diseases, Metabolic / pathology*
  • CD3 Complex / metabolism
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Glutaryl-CoA Dehydrogenase / deficiency*
  • Glutaryl-CoA Dehydrogenase / genetics
  • Inflammation / chemically induced*
  • Inflammation / genetics*
  • Lysine / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidation-Reduction / drug effects
  • Quinolinic Acid / toxicity*
  • S100 Calcium Binding Protein beta Subunit / metabolism
  • Statistics, Nonparametric
  • Time Factors
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • CD3 Complex
  • Glial Fibrillary Acidic Protein
  • S100 Calcium Binding Protein beta Subunit
  • S100b protein, mouse
  • 3-nitrotyrosine
  • Tyrosine
  • Glutaryl-CoA Dehydrogenase
  • Quinolinic Acid
  • Lysine

Supplementary concepts

  • Glutaric Acidemia I