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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
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Lazzarino, Giacomo, Di Pietro, Valentina Di, Rinaudo, Marco, Nagy, Zsuzsanna, Barnes, Nicholas M., Bruce, Lars, Signoretti, Stefano, Mangione, Renata, Saab, Miriam Wissam, Tavazzi, Barbara, Belli, Antonio, Lazzarino, Giuseppe, Amorini, Angela Maria and Logan, Ann (2022) 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. International Journal of Molecular Sciences, 23 (15). e8460. doi:10.3390/ijms23158460 ISSN 1422-0067.
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Official URL: https://doi.org/10.3390/ijms23158460
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 g-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.
| Item Type: | Journal Article | ||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RB Pathology R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||||
| SWORD Depositor: | Library Publications Router | ||||||
| Library of Congress Subject Headings (LCSH): | Brain -- Wounds and injuries , Brain -- Wounds and injuries -- Treatment, Dextran , Amino acids in human nutrition, Cognition disorders , Oxidative stress , High performance liquid chromatography, Brain -- Pathophysiology -- Animal models | ||||||
| Journal or Publication Title: | International Journal of Molecular Sciences | ||||||
| Publisher: | MDPI | ||||||
| ISSN: | 1422-0067 | ||||||
| Official Date: | 30 July 2022 | ||||||
| Dates: |
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| Volume: | 23 | ||||||
| Number: | 15 | ||||||
| Article Number: | e8460 | ||||||
| DOI: | 10.3390/ijms23158460 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Reuse Statement (publisher, data, author rights): | ** From MDPI via Jisc Publications Router ** History: accepted 27-07-2022; pub-electronic 30-07-2022. ** Licence for this article: https://creativecommons.org/licenses/by/4.0/ | ||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||
| Date of first compliant deposit: | 8 September 2022 | ||||||
| Date of first compliant Open Access: | 8 September 2022 | ||||||
| RIOXX Funder/Project Grant: |
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