Administration of all-trans retinoic acid after experimental traumatic brain injury is brain protective.

BACKGROUND AND PURPOSE: All-trans retinoic acid (ATRA) is a vitamin A metabolite, important in the developing and mature brain. Pre-injury ATRA administration ameliorates ischaemic brain insults in rodents. This study examined the effects of post-traumatic ATRA treatment in experimental traumatic brain injury (TBI). EXPERIMENTAL APPROACH: Male adult mice were subjected to the controlled cortical impact model of TBI or sham procedure and killed at 7 or 30 days post-injury (dpi). ATRA (10 mg kg-1, i.p.) was given immediately after the injury and 1, 2 and 3 dpi. Neurological function and sensorimotor coordination were evaluated. Brains were processed for (immuno-) histological, mRNA and protein analyses (qPCR and western blot). KEY RESULTS: ATRA treatment reduced brain lesion size, reactive astrogliosis and axonal injury at 7 dpi, and hippocampal granule cell layer (GCL) integrity was protected at 7 and 30 dpi, independent of cell proliferation in neurogenic niches and blood-brain barrier damage. Neurological and motor deficits over time and the brain tissue loss at 30 dpi were not affected by ATRA treatment. ATRA decreased gene expression of markers for damage-associated molecular pattern (HMGB1), apoptosis (caspase-3 and Bax), activated microglia (TSPO), and reactive astrogliosis (GFAP, SerpinA3N) at 7 dpi and a subset of markers at 30 dpi (TSPO, GFAP). CONCLUSION AND IMPLICATIONS: In experimental TBI, post-traumatic ATRA administration exerted brain protective effects, including long-term protection of GCL integrity, but did not affect neurological and motor deficits. Further investigations are required to optimize treatment regimens to enhance ATRA's brain protective effects and improve outcomes.

Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-kappaB activation and downstream events.

Streptolysin O (SLO), archetype of a cholesterol-binding bacterial cytolysin, forms large pores in the plasma membrane of mammalian cells. We have recently reported that when a limited number of pores are generated in a cell, they can be sealed in a Ca++-dependent process. Here, we show that resealing is followed by the release of IL-6 and IL-8 from keratinocytes and from endothelial cells, both relevant targets for SLO attack. Production of cytokines by these cells was preceded by activation of transcription factor nuclear factor kappaB, which thus emerges as a common denominator of stress responses to various pore-forming agents, including alpha-toxin of Staphylococcus aureus and complement. Furthermore, we show that activation and cytokine release in response to an agent that forms a pore in the plasma membrane do not depend on paracrine effects, because supernatants of cells perforated by SLO did not activate bystander cells. The study provides definitive evidence that a transient transmembrane pore suffices to trigger productive transcriptional activation in a target cell.