单次脑室内注射颗粒蛋白前体对实验性脑损伤的血脑屏障产生不利影响,Journal of Neurochemistry

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单次脑室内注射颗粒蛋白前体对实验性脑损伤的血脑屏障产生不利影响
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2021-04-26 , DOI: 10.1111/jnc.15375
Regina Hummel ₁ , Manuel Lang ₁ , Simona Walderbach ₁ , Yong Wang ₁ , Irmgard Tegeder ₂ , Christina Gölz ₁ , Michael K E Schäfer _{1,

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Affiliation

颗粒蛋白前体 (PGRN) 是一种神经营养和抗炎因子，在缺血性中风、蛛网膜下腔出血和创伤性脑损伤 (TBI) 的动物模型中具有保护作用。重组 (r) PGRN 的施用可防止Grn 中TBI 后过度的脑病理-缺陷小鼠，表明局部注射重组颗粒蛋白前体 (rPGRN) 在 TBI 急性期提供治疗益处。为了验证这一假设，我们将成年雄性 C57Bl/6N 小鼠置于 TBI 的受控皮层撞击模型中，在受伤前不久在脑室内 (ICV) 注射单剂量的 rPGRN，并检查受伤后长达 5 天的行为和生物学效应。 dpi）。rPGRN 的抗炎生物活性通过其在体外抑制炎症诱导的小鼠原代小胶质细胞和星形胶质细胞肥大的能力得到证实。然而，在 C57Bl/6N 小鼠中，rPGRN 的 ICV 给药未能在 5 天的观察期内减轻行为缺陷。5 dpi 时的（免疫）组织学基因和蛋白质表达分析没有揭示在脑损伤大小、脑炎症、神经胶质激活、神经源性壁龛中的细胞数量和神经元损伤方面的治疗益处。相反，我们观察到 TBI 诱导的紧密连接蛋白 occludin 的 mRNA 上调失败，并且在 5 dpi 时血清免疫球蛋白 G 外渗到脑实质中增加。总之，rPGRN 的单次 ICV 给药在小鼠 TBI 急性期没有预期的保护作用，但似乎会导致血脑屏障破坏的加剧。这些数据对其他类型的脑损伤和疾病中推定的 PGRN 增强方法提出了质疑。我们观察到 TBI 诱导的紧密连接蛋白 occludin mRNA 上调失败，并且在 5 dpi 时血清免疫球蛋白 G 外渗到脑实质中增加。总之，rPGRN 的单次 ICV 给药在小鼠 TBI 急性期没有预期的保护作用，但似乎会导致血脑屏障破坏的加剧。这些数据对其他类型的脑损伤和疾病中推定的 PGRN 增强方法提出了质疑。我们观察到 TBI 诱导的紧密连接蛋白 occludin mRNA 上调失败，并且在 5 dpi 时血清免疫球蛋白 G 外渗到脑实质中增加。总之，rPGRN 的单次 ICV 给药在小鼠 TBI 的急性期没有预期的保护作用，但似乎会导致血脑屏障破坏的加剧。这些数据对其他类型的脑损伤和疾病中推定的 PGRN 增强方法提出了质疑。

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Single intracerebroventricular progranulin injection adversely affects the blood–brain barrier in experimental traumatic brain injury

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor with protective effects in animal models of ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury (TBI). Administration of recombinant (r) PGRN prevents exaggerated brain pathology after TBI in Grn-deficient mice, suggesting that local injection of recombinant progranulin (rPGRN) provides therapeutic benefit in the acute phase of TBI. To test this hypothesis, we subjected adult male C57Bl/6N mice to the controlled cortical impact model of TBI, administered a single dose of rPGRN intracerebroventricularly (ICV) shortly before the injury, and examined behavioral and biological effects up to 5 days post injury (dpi). The anti-inflammatory bioactivity of rPGRN was confirmed by its capability to inhibit the inflammation-induced hypertrophy of murine primary microglia and astrocytes in vitro. In C57Bl/6N mice, however, ICV administration of rPGRN failed to attenuate behavioral deficits over the 5-day observation period. (Immuno)histological gene and protein expression analyses at 5 dpi did not reveal a therapeutic benefit in terms of brain injury size, brain inflammation, glia activation, cell numbers in neurogenic niches, and neuronal damage. Instead, we observed a failure of TBI-induced mRNA upregulation of the tight junction protein occludin and increased extravasation of serum immunoglobulin G into the brain parenchyma at 5 dpi. In conclusion, single ICV administration of rPGRN had not the expected protective effects in the acute phase of murine TBI, but appeared to cause an aggravation of blood–brain barrier disruption. The data raise questions about putative PGRN-boosting approaches in other types of brain injuries and disease.

更新日期：2021-04-26

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