Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution,Brain Research

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Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution
Brain Research ( IF 2.7 ) Pub Date : 2024-05-08 , DOI: 10.1016/j.brainres.2024.148988
Yiwei Fu ₁ , Rongrong Liu ₁ , Yuexin Zhao ₁ , Yuhan Xie ₂ , Honglei Ren ₁ , Yu Wu ₃ , Bohao Zhang ₄ , Xiuju Chen ₃ , Ying Guo ₅ , Yang Yao ₁ , Wei Jiang ₁ , Ranran Han ₁

Affiliation

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood–brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood–brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.

中文翻译：

Veliparib 通过抑制炎症反应和加速血肿消退对脑出血小鼠发挥保护作用

聚（ADP-核糖）聚合酶（PARP）抑制剂具有有效的抗炎作用，包括抑制脑小胶质细胞的活化。 Veliparib 是一种著名的 PARP1/2 抑制剂，具有特别高的脑渗透性，但其对中风结果的影响尚不清楚。在此，研究了 veliparib 对脑出血（ICH）（最致命的中风类型）短期结果的影响。应用胶原酶诱导的小鼠ICH模型，并进行T2加权磁共振成像评估病变体积。还测量了运动功能和血肿体积。我们进一步进行了免疫荧光、酶联免疫吸附测定、流式细胞术和血脑屏障评估，以探索潜在的机制。我们的结果表明，veliparib 剂量依赖性地减少了 ICH 病变体积，并且在剂量为 5 mg/kg 时，veliparib 显着改善了小鼠运动功能，并促进了 ICH 后第 3 天和第 7 天的血肿消退。 Veliparib 抑制神经胶质细胞活化并下调促炎细胞因子的产生。 ICH 后第 3 天，Veliparib 显着减少小胶质细胞计数并抑制外周免疫细胞浸润到大脑中。 Veliparib 在 ICH 后第 3 天改善了血脑屏障的完整性。这些发现表明，veliparib 通过抑制炎症反应来改善 ICH 结局，可能代表一种有前途的 ICH 新型疗法。

更新日期：2024-05-08

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