Manivannan, Susruta, Harari, Balkis, Muzaffar, Maryam, Elalfy, Omar, Hettipathirannahelage, Sameera, James, Zoe, Sharouf, Feras ![]() ![]() ![]() ![]() |
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Abstract
Despite medical advances, neurological recovery after severe traumatic brain injury (TBI) remains poor. Elevated levels of high mobility group box protein-1 (HMGB1) are associated with poor outcomes; likely via interaction with receptors for advanced-glycation-end-products (RAGE). We examined the hypothesis that HMGB1 post-TBI is anti-neurogenic and whether this is pharmacologically reversible. Post-natal rat cortical mixed neuro-glial cell cultures were subjected to needle-scratch injury and examined for HMGB1-activation/neuroinflammation. HMGB1-related genes/networks were examined using genome-wide RNA-seq studies in cortical perilesional tissue samples from adult mice. Post-natal rat cortical neural stem/progenitor cell cultures were generated to quantify effects of injury-condition medium (ICM) on neurogenesis with/without RAGE antagonist glycyrrhizin. Needle-injury upregulated TNF-α/NOS-2 mRNA-expressions at 6 h, increased proportions of activated microglia, and caused neuronal loss at 24 h. Transcriptome analysis revealed activation of HMGB1 pathway genes/canonical pathways in vivo at 24 h. A 50% increase in HMGB1 protein expression, and nuclear-to-cytoplasmic translocation of HMGB1 in neurons and microglia at 24 h post-injury was demonstrated in vitro. ICM reduced total numbers/proportions of neuronal cells, but reversed by 0.5 μM glycyrrhizin. HMGB1 is activated following in vivo post mechanical injury, and glycyrrhizin alleviates detrimental effects of ICM on cortical neurogenesis. Our findings highlight glycyrrhizin as a potential therapeutic agent post-TBI. View Full-Text Keywords: traumatic brain injury; neurogenesis; HMGB1; neuroinflammation
Item Type: | Article |
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Date Type: | Published Online |
Status: | Published |
Schools: | Biosciences Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) |
Additional Information: | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
Publisher: | MDPI |
ISSN: | 2076-3425 |
Date of First Compliant Deposit: | 26 October 2020 |
Date of Acceptance: | 19 October 2020 |
Last Modified: | 25 Jun 2024 19:24 |
URI: | https://orca.cardiff.ac.uk/id/eprint/135947 |
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