Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Neuroscience. 2011 Oct 27;194:195-207. doi: 10.1016/j.neuroscience.2011.08.003. Epub 2011 Aug 5.
Our previous studies show that insulin-like growth factor-1 (IGF-1) can either protect against or increase lipopolysaccharide (LPS)-induced damage in the developing brain, depending on the dose, when it is co-administered with LPS through intracerebral injection. To further explore effects of IGF-1 on central inflammation associated brain injury, IGF-1 was administered through intranasal infusion in the current study. Postnatal day 5 (P5) rats were exposed to LPS at a dose of 1 μg/g body weight or sterile saline through intracerebral injection. Recombinant human insulin-like growth factor-1 (rhIGF-1) at a dose of 50 μg/pup or vehicle was administered intranasally 1 or 2 h after the LPS injection. Neonatal LPS exposure resulted in oligodendrocyte (OL) and white matter injury in the P6 or P21 rat brain. The damages include dilatation of lateral ventricles, pyknotic cell death, loss of OL progenitor cells and mature OLs in the cingulum area, and impairment of myelination at the corpus callosum area. Neurological dysfunctions were observed in juvenile rats with neonatal LPS exposure. Intranasal IGF-1 treatment at either 1 or 2 h after LPS exposure significantly attenuated LPS-induced brain injury and improved some behavioral deficits. Intranasal IGF-1 treatment also reduced infiltration of polymorphonuclear (PMN) leukocytes and activation of microglia in the rat brain 24 h after LPS exposure, but it did not prevent the elevation in concentrations of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα) in the LPS-exposed rat brain during the first 24 h. This is an indication that direct anti-inflammation might not be the primary mechanism for the protection of IGF-1, and other mechanisms, such as anti-apoptotic effects, are likely involved in its protective effects.
我们之前的研究表明，胰岛素样生长因子-1（IGF-1）与脂多糖（LPS）通过脑内注射共同给药时，其剂量取决于剂量，既可保护发育中的大脑免受 LPS 诱导的损伤，也可增加 LPS 诱导的损伤。为了进一步探讨 IGF-1 对中枢炎症相关脑损伤的影响，本研究通过鼻腔内滴注给予 IGF-1。在出生后第 5 天（P5），将大鼠用 1μg/g 体重 LPS 或无菌盐水通过脑内注射暴露。在 LPS 注射后 1 或 2 小时，用 50μg/只幼鼠的重组人胰岛素样生长因子-1（rhIGF-1）或载体通过鼻腔内给予。新生期 LPS 暴露导致 P6 或 P21 大鼠脑的少突胶质细胞（OL）和白质损伤。损伤包括侧脑室扩张、固缩性细胞死亡、扣带回区 OL 祖细胞和成熟 OL 的丢失，以及胼胝体区髓鞘形成受损。新生期 LPS 暴露的幼年大鼠出现神经功能障碍。在 LPS 暴露后 1 或 2 小时通过鼻腔内给予 IGF-1 治疗，可显著减轻 LPS 诱导的脑损伤并改善一些行为缺陷。鼻腔内 IGF-1 治疗还可减少 LPS 暴露后 24 小时大鼠大脑中多形核（PMN）白细胞的浸润和小胶质细胞的激活，但不能防止 LPS 暴露大鼠脑在最初 24 小时内白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNFα）浓度的升高。这表明直接抗炎可能不是 IGF-1 保护作用的主要机制，其他机制，如抗细胞凋亡作用，可能参与其保护作用。
