Bone Fracture Enhanced Blood-Brain Barrier Breakdown in the Hippocampus and White Matter Damage of Stroke Mice

Abstract

Background: Tibia fracture (BF) before stroke shortly causes long-term post-stroke memory dysfunction in mice. The mechanism is unclear. We hypothesize that BF enhances neuroinflammation and blood brain barrier (BBB) breakdown in the hippocampus and white matter (WM) damage. Methods: Mice were assigned to groups: BF, stroke, BF+stroke (BF 6 h before stroke) and sham. BBB integrity was analyzed 3 days after the surgeries and WM injury was analyzed 3 days and 8 weeks after the surgeries. Results: Stroke and BF+stroke groups had more activated microglia/macrophages and lower levels of claudin-5 in the ipsilateral hippocampi than the BF group. BF+stroke group had the highest number microglia/macrophages and the lowest level of claudin-5 among all groups and had fewer pericytes than BF group. Stroke and BF+stroke groups had smaller WM areas in the ipsilateral basal ganglia than the sham group 8 weeks after the injuries. The BF+stroke group also had smaller WM areas in the ipsilateral than sham and BF groups 3 days after the injuries and in the contralateral basal ganglia than stroke and BF groups 8 weeks after the injuries. Conclusions: BF exacerbates neuroinflammation and BBB leakage in the hippocampus and WM damage in basal ganglia, which could contribute to the long-lasting memory dysfunction in BF+stroke mice.

Reduction of neuroinflammation alleviated mouse post bone fracture and stroke memory dysfunction

“…It has been reported that WM damage 42 and ipsilateral hippocampal atrophy is associated with long-term memory dysfunction after ischemic stroke. 43 Our previous studies showed WM 44 and GCL atrophy 9 in mice 8 weeks after BF and stroke. In this study, we showed that inhibition of inflammation through PHA treatment reduced WM and GCL atrophy and increased neurogenesis in DG at the subacute stage of the injuries.…”

Perioperative stroke: A perspective on challenges and opportunities for experimental treatment and diagnostic strategies

“…23,24 Moreover, there was a pronounced blood-brain barrier (BBB) breakdown. 25 Detrimental effects were also seen when bone fracture was induced after pMCAO. 26 Poststroke bone fractures are further associated with larger brain edema volumes in subacute stroke stages, 27 potentially due to mentioned BBB breakdown.…”

“…120 Biomaterials and scaffolds may help to provide such cues in larger lesions, 152 whereas smaller lesions or those predominantly situated in the white matter may be attractive targets for restorative therapies. 25,153 However, a profound preclinical proof of concept of restorative approaches is not available so far, and any clinical application is unlikely to happen in the near future.…”