Abstract
Ischemic stroke can induce rapid disruption of blood-brain barrier (BBB). It has been suggested that increased BBB permeability can affect the pathological progression of ischemic tissue. However, the impact of increased BBB permeability on microglial activation and synaptic structures following reperfusion after ischemia remains unclear. In this study, we investigated microglial activation, dendritic damage and plasticity of dendritic spines after increasing BBB permeability following transient global cerebral ischemia in the somatosensory cortices in mice. Bilateral common carotid artery ligation (BCAL) was used to induce transient global cerebral ischemia. Mannitol was used to increase the BBB permeability. Intravital two-photon imaging was performed to image the dendritic structures and BBB extravasation. Microglial morphology was quantitated using a skeletonization analysis method. To evaluate inflammation of cerebral cortex, the mRNA expression levels of integrin alpha M (CD11b), CD68, chemokine (C-X-C motif) ligand 10 (IP10) and tumor necrosis factor alpha (TNF-α) were measured by fluorescent quantitative PCR. Intravital two-photon imaging revealed that mannitol caused a drastic increase in BBB extravasation during reperfusion after transient global ischemia. Increased BBB permeability induced by mannitol had no significant effect on inflammation and dendritic spines in healthy mice but triggered a marked de-ramification of microglia; importantly, in ischemic animals, mannitol accelerated de-ramification of microglia and aggravated inflammation at 3 h but not at 3 days following reperfusion after ischemia. Although mannitol did not cause significant change in the percentage of blebbed dendrites and did not affect the reversible recovery of the dendritic structures, excessive extravasation was accompanied with significant decrease in spine formation and increase in spine elimination during reperfusion in ischemic mice. These findings suggest that increased BBB permeability induced by mannitol can lead to acute activation of microglia and cause excessive loss of dendritic spines after transient global cerebral ischemia.
Highlights
Under normal physiological conditions, only specific substances from the bloodstream are allowed to enter the brain parenchyma due to a highly specialized blood-brain barrier (BBB; Betsholtz, 2014; Zhao et al, 2015)
We evaluated the recovery of dendritic structures and BBB leakage at different time points after reperfusion in Bilateral common carotid artery ligation (BCAL)-control mice
The extravasation of the BCAL-mannitol mice did not significantly increase at 120 min and 180 min compared to that at 60 min after reperfusion but was significantly higher than that in BCAL-control mice during reperfusion (Figures 1B,C extravasation (%): 120 min, BCAL-control 19.25 ± 2.24% vs. BCAL-mannitol 42.09 ± 3.57%; ∗∗p < 0.01; 180 min, BCAL-control 18.11 ± 1.80% vs. BCAL-mannitol 44.55 ± 5.76%; ∗∗p < 0.01). These results demonstrated that mannitol enhanced BBB permeability and caused excessive extravasation during reperfusion in ischemic mice
Summary
Only specific substances from the bloodstream are allowed to enter the brain parenchyma due to a highly specialized blood-brain barrier (BBB; Betsholtz, 2014; Zhao et al, 2015). The integrity of BBB is vulnerable to pathological insults and can be altered in many CNS diseases, including stroke, Alzheimer’s disease (AD), Parkinson’s disease and acute traumatic brain injury (Hawkins and Davis, 2005; Ulrich et al, 2015; Nahirney et al, 2016; Olmedo-Diaz et al, 2017; Zhang et al, 2017). Among these diseases, stroke can rapidly cause disruption of BBB. The disrupted BBB induced by transient ischemia can be restored within hours (Zhu et al, 2017b), but the prolonged increase in vascular permeability can still be detected from day 3 to day 21 after middle cerebral artery occlusion (MCAO; Lin et al, 2008)
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