Insulin-like Growth Factor-1 Prevents Hypoxia/Reoxygenation-Induced White Matter Injury in Sickle Cell Mice.
Rimi HazraHolland HubertLynda Little-IhrigSamit GhoshSolomon Ofori-AcquahXiaoming HuEnrico M NovelliPublished in: Biomedicines (2023)
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.
Keyphrases
- white matter
- endothelial cells
- high glucose
- binding protein
- growth hormone
- multiple sclerosis
- cerebral ischemia
- drug induced
- pi k akt
- poor prognosis
- blood flow
- subarachnoid hemorrhage
- diabetic rats
- high fat diet induced
- brain injury
- liver failure
- early onset
- intensive care unit
- type diabetes
- mouse model
- cell proliferation
- hepatitis b virus
- red blood cell
- newly diagnosed
- insulin resistance
- single molecule
- endoplasmic reticulum stress
- skeletal muscle