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

Jinhao Huang,Haiyan Lyu,Qifeng Li,Julia Wong,Zhanqiang Wang,Chaoliang Tang,Leandro B Do Prado,Hua Su,Kang Huo

doi:10.3390/ijms21228481

Jinhao Huang, Haiyan Lyu + Show 7 more

Open Access

https://doi.org/10.3390/ijms21228481

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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.

Highlights

Stroke is one of the major causes of death in the US
We found that young mice developed long-lasting (≥ 8 weeks) spatial memory dysfunction when bone fracture preceded ischemic stroke by 6 h, which was associated with an accumulation of CX3C chemokine receptor 1+ (Cx3cr1+) cells in the hippocampal stratum lacunosum moleculare (SLM), stratum oriens and alveus [32]
We showed that accumulation of microglia/macrophages correlated with an exacerbation of blood brain barrier (BBB) leakage in the hippocampus and white matter (WM) damage in basal ganglia in mice subjected to tibia fracture (BF) 6 h before ischemic stroke (BF+stroke)

Summary

Introduction

Stroke is one of the major causes of death in the US (www.strokecenter.org/patients/about-stroke/ stroke-statistics/). Compared to the general population, the risk of bone fracture in stroke patients is about two- to four-fold higher. We showed in animal models that bone fracture before or after ischemic stroke caused more neuronal damage and sensorimotor dysfunction [13,14,15,16]. 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 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

Methods

Results

Conclusion