ILB®, a low molecular weight dextran sulphate, restores glutamate homeostasis, amino acid metabolism and neurocognitive functions in a rat model of severe traumatic brain injury

Giacomo Lazzarino, Valentina Di Pietro, Marco Rinaudo, Zsuzsanna Nagy, Nicholas Barnes, Lars Bruce, Stefano Signoretti*, Renata Mangione, Miriam Wissam Saab, Barbara Tavazzi*, Tony Belli, Giuseppe Lazzarino, Angela Maria Amorini, Ann Logan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

In a previous study, we found that administration of ILB®, a new low molecular weight dextran sulphate, significantly improved mitochondrial functions and energy metabolism, as well as decreased oxidative/nitrosative stress, of brain tissue of rats exposed to severe traumatic brain injury (sTBI), induced by the closed-head weight-drop model of diffused TBI. Using aliquots of deproteinized brain tissue of the same animals of this former study, we here determined the concentrations of 24 amino acids of control rats, untreated sTBI rats (sacrificed at 2 and 7 days post-injury) and sTBI rats receiving a subcutaneous ILB® administration (at the dose levels of 1, 5 and 15 mg/kg b.w.) 30 min post-impact (sacrificed at 2 and 7 days post-injury). Additionally, in a different set of experiments, new groups of control rats, untreated sTBI rats and ILB®-treated rats (administered 30 min after sTBI at the dose levels of 1 or 5 mg/kg b.w.) were studied for their neurocognitive functions (anxiety, locomotor capacities, short- and long-term memory) at 7 days after the induction of sTBI. Compared to untreated sTBI animals, ILB® significantly decreased whole brain glutamate (normalizing the glutamate/glutamine ratio), glycine, serine and γ-aminobutyric acid. Furthermore, ILB® administration restored arginine metabolism (preventing nitrosative stress), levels of amino acids involved in methylation reactions (methionine, L-cystathionine, S-adenosylhomocysteine), and N-acetylaspartate homeostasis. The macroscopic evidences of the beneficial effects on brain metabolism induced by ILB® were the relevant improvement in neurocognitive functions of the group of animals treated with ILB® 5 mg/kg b.w., compared to the marked cognitive decline measured in untreated sTBI animals. These results demonstrate that ILB® administration 30 min after sTBI prevents glutamate excitotoxicity and normalizes levels of amino acids involved in crucial brain metabolic functions. The ameliorations of amino acid metabolism, mitochondrial functions and energy metabolism in ILB®-treated rats exposed to sTBI produced significant improvement in neurocognitive functions, reinforcing the concept that ILB® is a new effective therapeutic tool for the treatment of sTBI, worth being tested in the clinical setting.
Original languageEnglish
Article number8460
Number of pages19
JournalInternational Journal of Molecular Sciences
Volume23
Issue number15
DOIs
Publication statusPublished - 30 Jul 2022

Bibliographical note

Funding Information:
This research was funded by Tikomed AB, who had no influence on the conduct of the trial and was not involved in data collection or analysis.

Publisher Copyright:
© 2022 by the authors.

Keywords

  • HPLC
  • amino acids
  • glutamate excitotoxicity
  • low molecular weight dextran sulphate
  • methyl cycle
  • neurocognitive functions
  • oxidative/nitrosative stress
  • severe traumatic brain injury

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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