Hazra Rimi, Hubert Holland, Little-Ihrig Lynda, Ghosh Samit, Ofori-Acquah Solomon, Hu Xiaoming, Novelli Enrico M
Pittsburgh Heart Lung and Blood Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Biomedicines. 2023 Feb 24;11(3):692. doi: 10.3390/biomedicines11030692.
Occlusion of cerebral blood vessels causes acute cerebral hypoxia-an important trigger of ischemic white matter injury and stroke in sickle cell disease (SCD). While chronic hypoxia triggers compensatory neuroprotection via insulin-like growth factor-1 (IGF-1) and hypoxia inducible factor-1α (HIF-1α), severe bouts of acute hypoxia and subsequent restoration of blood flow (hypoxia/reoxygenation, H/R) overwhelm compensatory mechanisms and cause neuroaxonal damage-identified as white matter lesions-in the brain. The neuroprotective role of IGF-1 in the pathogenesis of white matter injury in SCD has not been investigated; however, it is known that systemic IGF-1 is reduced in individuals with SCD. We hypothesized that IGF-1 supplementation may prevent H/R-induced white matter injury in SCD. Transgenic sickle mice homozygous for human hemoglobin S and exposed to H/R developed white matter injury identified by elevated expression of non-phosphorylated neurofilament H (SMI32) with a concomitant decrease in myelin basic protein (MBP) resulting in an increased SMI32/MBP ratio. H/R-challenge also lowered plasma and brain IGF-1 expression. Human recombinant IGF-1 prophylaxis significantly induced HIF-1α and averted H/R-induced white matter injury in the sickle mice compared to vehicle-treated mice. The expression of the IGF-1 binding proteins IGFBP-1 and IGFBP-3 was elevated in the IGF-1-treated brain tissue indicating their potential role in mediating neuroprotective HIF-1α signaling. This study provides proof-of-concept for IGF-1-mediated neuroprotection in SCD.
脑血管闭塞会导致急性脑缺氧，这是镰状细胞病（SCD）中缺血性白质损伤和中风的重要触发因素。虽然慢性缺氧通过胰岛素样生长因子-1（IGF-1）和缺氧诱导因子-1α（HIF-1α）触发代偿性神经保护作用，但严重的急性缺氧发作以及随后的血流恢复（缺氧/复氧，H/R）会使代偿机制不堪重负，并导致神经轴突损伤，即大脑中的白质病变。IGF-1在SCD白质损伤发病机制中的神经保护作用尚未得到研究；然而，已知SCD患者的全身IGF-1水平会降低。我们假设补充IGF-1可能预防SCD中H/R诱导的白质损伤。纯合人类血红蛋白S并暴露于H/R的转基因镰状小鼠出现了白质损伤，表现为非磷酸化神经丝H（SMI32）表达升高，同时髓鞘碱性蛋白（MBP）减少，导致SMI32/MBP比值增加。H/R刺激还降低了血浆和大脑中IGF-1的表达。与载体处理的小鼠相比，人重组IGF-1预防显著诱导了HIF-1α，并避免了镰状小鼠中H/R诱导的白质损伤。在IGF-1处理的脑组织中，IGF-1结合蛋白IGFBP-1和IGFBP-3的表达升高，表明它们在介导神经保护性HIF-1α信号传导中可能发挥作用。这项研究为IGF-1介导的SCD神经保护作用提供了概念验证。
