title: Prolonged Subdural Infusion of Kynurenic Acid Is Associated with Dose-Dependent Myelin Damage in the Rat Spinal Cord.
abstract: BACKGROUND
  Kynurenic acid (KYNA) is the end stage metabolite of tryptophan produced mainly by astrocytes in the central nervous system (CNS). It has neuroprotective activities but can be elevated in the neuropsychiatric disorders. Toxic effects of KYNA in the CNS are unknown. The aim of this study was to assess the effect of the subdural KYNA infusion on the spinal cord in adult rats.
  
  
  METHODS
  A total of 42 healthy adult rats were randomly assigned into six groups and were infused for 7 days with PBS (control) or 0.0002 pmol/min, 0.01 nmol/min, 0.1 nmol/min, 1 nmol/min, and 10 nmol/min of KYNA per 7 days. The effect of KYNA on spinal cord was determined using histological and electron microscopy examination. Myelin oligodendrocyte glycoprotein (MOG) was measured in the blood serum to assess a degree of myelin damage.
  
  
  RESULTS
  In all rats continuous long-lasting subdural KYNA infusion was associated with myelin damage and myelin loss that was increasingly widespread in a dose-depended fashion in peripheral, sub-pial areas. Damage to myelin sheaths was uniquely related to the separation of lamellae at the intraperiod line. The damaged myelin sheaths and areas with complete loss of myelin were associated with limited loss of scattered axons while vast majority of axons in affected areas were morphologically intact. The myelin loss-causing effect of KYNA occurred with no necrosis of oligodendrocytes, with locally severe astrogliosis and no cellular inflammatory response. Additionally, subdural KYNA infusion increased blood MOG concentration. Moreover, the rats infused with the highest doses of KYNA (1 and 10 nmol/min) demonstrated adverse neurological signs including weakness and quadriplegia.
  
  
  CONCLUSIONS
  We suggest, that subdural infusion of high dose of KYNA can be used as an experimental tool for the study of mechanisms of myelin damage and regeneration. On the other hand, the administration of low, physiologically relevant doses of KYNA may help to discover the role of KYNA in control of physiological myelination process.
authors.affiliation: Department of Anaesthesiology and Intensive Therapy Medical University, Lublin, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Dabrowski
authors.affiliation: Department of Pathology and Molecular Medicine, M. deGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jacek M
authors.initials: JM
authors.lastname: Kwiecien
authors.affiliation: Department of Neurosurgery and Paediatric Neurosurgery Medical University, Lublin, Poland.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Rola
authors.affiliation: Department of Orthopaedic and Traumatology Medical University, Lublin, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Klapec
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario, Canada.|Physical Sciences Platform, Sunnybrook Research Institute, Ontario, Canada.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Stanisz
authors.affiliation: Department of Anaesthesiology and Intensive Therapy Medical University, Lublin, Poland.
authors.forename: Edyta
authors.initials: E
authors.lastname: Kotlinska-Hasiec
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Oakden
authors.affiliation: Department of Medical Biophysics, University of Toronto, Ontario, Canada.
authors.forename: Rafal
authors.initials: R
authors.lastname: Janik
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, M. deGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Margaret
authors.initials: M
authors.lastname: Coote
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, M. deGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Benicio N
authors.initials: BN
authors.lastname: Frey
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University, Lublin, Poland.
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Turski
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D007260:Infusion Pumps; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000097:blood; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D020318:Rats, Long-Evans; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D013355:Subdural Space; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D063308:Myelin-Oligodendrocyte Glycoprotein; D007736:Kynurenic Acid