Minocycline Preserves the Integrity and Permeability of BBB by Altering the Activity of DKK1-Wnt Signaling in ICH Model.

Disruption of the blood-brain barrier (BBB) and subsequent neurological deficits are the most severe consequence of intracerebral hemorrhage (ICH). Minocycline has been wildly used clinically as a neurological protective agent in clinical practice. However, the underlying mechanisms by which minocycline functions remain unclear. Therefore, we assessed the influence of minocycline on BBB structure, neurological function, and inflammatory responses in a collagenase-induced ICH model, and elucidated underlying molecular mechanisms as well. Following a single injection of collagenase VII-S into the basal ganglia, BBB integrity was assessed by Evans blue extravasation while neurological function was assessed using an established neurologic function scoring system. Minocycline treatment significantly alleviated the severity of BBB disruption, brain edema, and neurological deficits in ICH model. Moreover, minocycline decreased the production of inflammatory mediators including TNF, IL-6, and MMP-9, by microglia. Minocycline treatment decreased DKK1 expression but increased Wnt1, β-catenin and Occludin, a phenomenon mimicked by DKK1 silencing. These data suggest that minocycline improves the consequences of ICH by preserving BBB integrity and attenuating neurologic deficits in a DKK1-related manner that involves enhancement of the Wnt1-β-catenin activity.

Wang G ，Li Z ，Li S ，Ren J ，Suresh V ，Xu D ，Zang W ，Liu X ，Li W ，Wang H ，Guo F ... -  《-》

Neuroprotection of minocycline by inhibition of extracellular matrix metalloproteinase inducer expression following intracerebral hemorrhage in mice.

Intracerebral hemorrhage (ICH) is a severe neurological dysfunction and a medical emergency with a high mortality rate. Minocycline ameliorates deficits in rodent models of acute and chronic neurological diseases. However, the role of minocycline in ICH remains unclear. The extracellular matrix metalloproteinase inducer (EMMPRIN) is a key inflammatory mediator in some neurological diseases, triggering matrix metalloproteinases (MMPs) production. In this study, we aimed to use minocycline to inhibit EMMPRIN and thus the activity of MMPs. Male adult C57BL/6 mice were injected with collagenase type VII or saline into the right basal ganglia and euthanized at different time points. The minocycline was intraperitoneally injected once every 12 h for three days to block the expression of EMMPRIN from two hours after ICH. We found that breakdown of the BBB was most severe 3 days after ICH. The minocycline treatment significantly decreased EMMPRIN and MMP-9 expression, reduced zonula occludens-1 and occludin, and alleviated BBB disruption. Moreover, minocycline treatment displayed a lower brain water content, lesser neurological dysfunction, and smaller injury volume on day 3 than those of the vehicle-treated group. Minocycline also inhibited the activation of microglia/macrophages, infiltration of neutrophils, and production of inflammatory mediators, including tumor necrosis factor alpha and interleukin-1beta. The current study shows that minocycline exhibits protective roles in ICH by decreasing EMMPRIN and MMP-9 expression, alleviating BBB disruption, inhibiting neuroinflammation, areducing neuronal degeneration and death.

Liu Y ，Li Z ，Khan S ，Zhang R ，Wei R ，Zhang Y ，Xue M ，Yong VW ... -  《-》

Lithium attenuates blood-brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β-catenin signaling-dependent mechanism in mice.

Vasogenic cerebral edema resulting from blood-brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/β-catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/β-catenin signaling. We evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV-induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/β-catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124. Lithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm3 vs. 19.97 ± 3.20 mm3 in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/β-catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin-5 and ZO-1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124-mediated endothelial Wnt/β-catenin signaling. Our findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.

Song D ，Ji YB ，Huang XW ，Ma YZ ，Fang C ，Qiu LH ，Tan XX ，Chen YM ，Wang SN ，Chang J ，Guo F ... -  《-》

Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat.

Wasserman JK ，Schlichter LC 《EXPERIMENTAL NEUROLOGY》

Small Interfering RNA Targeting Dickkopf-1 Contributes to Neuroprotection After Intracerebral Hemorrhage in Rats.

Li Z ，Chen X ，Zhang X ，Ren X ，Chen X ，Cao J ，Zang W ，Liu X ，Guo F ... -  《-》