Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
Pediatr Res. 2023 Aug;94(2):539-546. doi: 10.1038/s41390-023-02535-z. Epub 2023 Feb 21.
Hypoxic ischemic encephalopathy remains a significant cause of developmental disability. The standard of care for term infants is hypothermia, which has multifactorial effects. Therapeutic hypothermia upregulates the cold-inducible protein RNA binding motif 3 (RBM3) that is highly expressed in developing and proliferative regions of the brain. The neuroprotective effects of RBM3 in adults are mediated by its ability to promote the translation of mRNAs such as reticulon 3 (RTN3). METHODS: Hypoxia ischemia or control procedure was conducted in Sprague Dawley rat pups on postnatal day 10 (PND10). Pups were immediately assigned to normothermia or hypothermia at the end of the hypoxia. In adulthood, cerebellum-dependent learning was tested using the conditioned eyeblink reflex. The volume of the cerebellum and the magnitude of cerebral injury were measured. A second study quantified RBM3 and RTN3 protein levels in the cerebellum and hippocampus collected during hypothermia.
Hypothermia reduced cerebral tissue loss and protected cerebellar volume. Hypothermia also improved learning of the conditioned eyeblink response. RBM3 and RTN3 protein expression were increased in the cerebellum and hippocampus of rat pups subjected to hypothermia on PND10.
Hypothermia was neuroprotective in male and female pups and reversed subtle changes in the cerebellum after hypoxic ischemic.
Hypoxic ischemic produced tissue loss and a learning deficit in the cerebellum. Hypothermia reversed both the tissue loss and learning deficit. Hypothermia increased cold-responsive protein expression in the cerebellum and hippocampus. Our results confirm cerebellar volume loss contralateral to the carotid artery ligation and injured cerebral hemisphere, suggesting crossed-cerebellar diaschisis in this model. Understanding the endogenous response to hypothermia might improve adjuvant interventions and expand the clinical utility of this intervention.
缺氧缺血性脑病仍然是导致发育障碍的一个重要原因。对于足月婴儿的标准治疗方法是低温治疗，它具有多种作用。低温治疗会上调冷诱导蛋白 RNA 结合基序 3（RBM3）的表达，RBM3 在大脑发育和增殖区域中高度表达。RBM3 在成人中的神经保护作用是通过其促进诸如 RTN3 等 mRNA 翻译的能力来介导的。
在出生后第 10 天（PND10）对 Sprague Dawley 幼鼠进行缺氧缺血或对照处理。在缺氧结束时，幼鼠立即被分配到常温或低温治疗。在成年期，使用条件性眨眼反射测试小脑依赖性学习。测量小脑的体积和脑损伤的程度。第二项研究在低温治疗期间定量测定小脑和海马中 RBM3 和 RTN3 蛋白水平。
低温治疗减少了脑组织损失并保护了小脑体积。低温治疗还改善了条件性眨眼反应的学习。在 PND10 时接受低温治疗的幼鼠的小脑和海马中，RBM3 和 RTN3 蛋白表达增加。
低温治疗对雄性和雌性幼鼠均具有神经保护作用，并逆转了缺氧缺血后的小脑细微变化。
缺氧缺血导致小脑组织损失和学习缺陷。低温治疗逆转了这两种组织损失和学习缺陷。低温治疗增加了小脑和海马中冷反应蛋白的表达。我们的研究结果证实了与颈总动脉结扎和损伤大脑半球相对应的小脑体积损失，表明该模型中存在交叉小脑去神经支配。了解低温治疗的内源性反应可能会改善辅助干预措施，并扩大该干预措施的临床应用。
