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Published on: October 27, 2020
Association between Cold-Inducible RNA-Binding Motif 3 and Hypothermia Effect in Murine Hypoxia-Ischemia Model
Xiaodan Liu1, Xiangning Jiang2, Alkisti Mikrogeorgiou Capper3
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
Introduction:
The efficacy of therapeutic hypothermia (TH) for neonatal hypoxic-ischemic encephalopathy (HIE) is inconsistent, and the cause remains unclear. This study aimed to explore the role of cold stress protein in the TH-induced neuroprotection following hypoxia-ischemia (HI) using hyperpolarized carbon-13 MRI (HP-13C MRI).
Methods:
Postnatal day 10 (P10) mice underwent unilateral HI followed by treatments with TH or normothermia (NT). HI and sham mice were scanned at 4 h and 22 h following TH after injection of hyperpolarized 13C-1 labeled pyruvate. The dynamic HP [1-13C] MR spectroscopic images (MRSI) were acquired to examine the cerebral metabolic profile, i.e., the conversion rate from pyruvate to lactate (kPL) and the ratio of lactate to pyruvate (Lac/Pyr) in the injured hemisphere. T2-weighted images and diffusion MR images were acquired to identify the anatomical structures and assess the injury. Mice brains were collected during and at 0 h, 4 h, 12 h, 18 h, and 22 h after treatments for Western Blot to investigate the time course of the levels of the cold stress protein (RNA-binding motif 3 [RBM3]) and cell death markers (spectrin 145/150 and spectrin 120) changes. The cerebral metabolic profile, RBM3 and spectrin levels, and injury size were compared across groups and between specific timepoints. The relationship between the cerebral metabolic profile and RBM3 levels in HI+TH group was also evaluated.
Results:
We observed the upregulation of RBM3 during TH at 4 h and 22 h after TH. The spectrin 145/150 and spectrin 120 were unchanged over time in HI+TH group, whereas they significantly increased at 18 h and 22 h in HI+NT group. Additionally, the injury size was noticeably larger at 22 h in HI+NT group. Lower kPL and Lac/Pyr were observed at 4 h and 22 h after TH, with a negative correlation to RBM3 levels in HI+TH group.
Conclusion:
This study demonstrates that RBM3 may be one of the key factors associated with TH-induced neuroprotection by reducing the anaerobic glycolysis process in HI mice, suggesting RBM3 upregulation may enhance the efficacy of TH for neonatal HIE.
