HMGB1 and brain injury: Under normal conditions, HMGB1 exists as a ubiquitous nuclear DNA binding protein, but during periods of cellular stress such as excitotoxicity, necrotic conditions, or traumatic brain injury, HMGB1 is released from neurons and astrocytes into the extracellular space and binds to the TLR complex of microglia, activating the transcription factor NF-κB.