Neurogenesis after traumatic brain injury - The complex role of HMGB1 and neuroinflammation

• Published in: Neuropharmacology Vol. 183; p. 108400
• Main Authors: Manivannan, S., Marei, O., Elalfy, O., Zaben, M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-02-2021
• Subjects: HMGB1; Neurogenesis; Neuroinflammation; Traumatic brain injury; Neuroinflammation; Traumatic brain injury; HMGB1; Neurogenesis
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.108400

Traumatic brain injury (TBI) is amongst the leading causes of morbidity and mortality worldwide. Despite evidence of neurogenesis post-TBI, survival and integration of newborn neurons remains impaired. High Mobility Group Box protein 1 (HMGB1) is an ‘alarmin’ released hyper-acutely following TBI and implicated in hosting the neuro-inflammatory response to injury. It is also instrumental in mediating neurogenesis under physiological conditions. Given its dual role in mediating neuro-inflammation and neurogenesis, it serves as a promising putative target for therapeutic modulation. In this review, we discuss neurogenesis post-TBI, neuro-pharmacological aspects of HMGB1, and its potential as a therapeutic target.
PubMed database was searched with varying combinations of the following search terms: HMGB1, isoforms, neurogenesis, traumatic brain injury, Toll-like receptor (TLR), receptor for advanced glycation end-products (RAGE).
Several in vitro and in vivo studies demonstrate evidence of neurogenesis post-injury. The HMGB1-RAGE axis mediates neurogenesis throughout development, whilst interaction with TLR-4 promotes the innate immune response. Studies in the context of injury demonstrate that these receptor effects are not mutually exclusive. Despite recognition of different HMGB1 isoforms based on redox/acetylation status, effects on neurogenesis post-injury remain unexplored. Recent animal in vivo studies examining HMGB1 antagonism post-TBI demonstrate predominantly positive results, but specific effects on neurogenesis and longer-term outcomes remain unclear.
HMGB1 is a promising therapeutic target but its effects on neurogenesis post-TBI remains unclear. Given the failure of several pharmacological strategies to improve outcomes following TBI, accurate delineation of HMGB1 signalling pathways and effects on post-injury neurogenesis are vital.
•Hippocampal and cortical neurogenesis occurs post-traumatic brain injury.•Dual role of HMGB1 in neuro-inflammation and neurogenesis.•Interaction with RAGE mediates neurogenesis; TLR4 mediates immune response.•Differential roles of HMGB1 isoforms/receptors post-injury are unclear.•Promising therapeutic strategies targeting HMGB1 post-traumatic brain injury.