Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Ann Neurol. 2014 Mar;75(3):395-410. doi: 10.1002/ana.24087. Epub 2014 Mar 7.
There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury; therefore, the neuroprotective therapeutic potential of innate defense regulator peptides (IDRs) was investigated.
The anti-inflammatory effects of 3 IDRs was measured in lipopolysaccharide (LPS)-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3 hours after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 hours before LPS or 3 hours after LPS+HI.
IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3 hours after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for, eg, Fadd and Tnfsf9) and inflammatory (for, eg, interleukin 1, tumor necrosis factor α, chemokines, and cell adhesion molecules) pathways and showed marked protection of both white and gray brain matter.
IDR-1018 suppresses proinflammatory mediators and cell injurious mechanisms in the developing brain, and postinsult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both gray and white matter, and lacks significant effects on the brain under normal conditions. Thus, this peptide provides the features of a promising neuroprotective agent in newborns with brain injury.
目前尚无针对新生儿脑损伤的药物治疗方法。已知先天免疫反应的激活是围产期脑损伤的一个关键致病因素；因此，研究了先天防御调节肽（IDR）的神经保护治疗潜力。
在脂多糖（LPS）激活的小鼠小神经胶质细胞中测量了 3 种 IDR 的抗炎作用。然后，在一种将炎症挑战（LPS）与缺氧缺血（HI）相结合的临床相关模型中，在新生儿脑损伤后 3 小时给予 IDR，评估 IDR 赋予体内神经保护的能力。为了深入了解肽对 LPS 诱导的炎症和神经保护机制的影响，用 IDR-1018 处理的幼鼠在 LPS 前 4 小时或 LPS+HI 后 3 小时进行了大脑全局基因表达谱分析。
IDR-1018 减少了体外 LPS 刺激的小神经胶质细胞产生的炎症介质，并调节了体内 LPS 诱导的神经炎症。当在 LPS+HI 后 3 小时给予时，IDR-1018 对凋亡（例如 Fadd 和 Tnfsf9）和炎症（例如白细胞介素 1、肿瘤坏死因子α、趋化因子和细胞粘附分子）途径的调节分子发挥作用，并显示出对白色和灰色脑组织的明显保护作用。
IDR-1018 抑制发育中大脑中的促炎介质和细胞损伤机制，而损伤后治疗可有效减轻 LPS 诱导的缺氧缺血性脑损伤。IDR-1018 全身给药时在大脑中有效，对灰质和白质均具有神经保护作用，并且在正常情况下对大脑无明显影响。因此，这种肽为脑损伤新生儿提供了一种有希望的神经保护剂的特征。
