Fabres Rafael Bandeira, Nunes Ricardo Ribeiro, de Medeiros de Mattos Marcel, Andrade Mirella Kielek Galvan, Martini Ana Paula Rodrigues, Tassinari Isadora D'Ávila, Sanches Eduardo Farias, de Fraga Luciano Stürmer, Netto Carlos Alexandre
Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Sarmento Leite, 500, 90050-170, Porto Alegre, Brazil.
Postgraduate Programme in Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Sarmento Leite, 500, 90050-170, Porto Alegre, Brazil.
Metab Brain Dis. 2022 Oct;37(7):2315-2329. doi: 10.1007/s11011-022-01030-4. Epub 2022 Jul 2.
Therapeutic hypothermia (TH) is the standard treatment for neonatal hypoxia-ischemia (HI) with a time window limited up to 6 h post injury. However, influence of sexual dimorphism in the therapeutic window for TH has not yet been elucidated in animal models of HI. Therefore, the aim of this study was to investigate the most effective time window to start TH in male and female rats submitted to neonatal HI. Wistar rats (P7) were divided into the following groups: NAÏVE and SHAM (control groups), HI (submitted to HI) and TH (submitted to HI and TH; 32ºC for 5 h). TH was started at 2 h (TH-2 h group), 4 h (TH-4 h group), or 6 h (TH-6 h group) after HI. At P14, animals were subjected to behavioural tests, volume of lesion and reactive astrogliosis assessments. Male and female rats from the TH-2 h group showed reduction in the latency of behavioral tests, and decrease in volume of lesion and intensity of GFAP immunofluorescence. TH-2 h females also showed reduction of degenerative cells and morphological changes in astrocytes. Interestingly, females from the TH-6 h group showed an increase in volume of lesion and in number of degenerative hippocampal cells, associated with worse behavioral performance. Together, these results indicate that TH neuroprotection is time- and sex-dependent. Moreover, TH started later (6 h) can worsen volume of brain lesion in females. These data indicate the need to develop specific therapeutic protocols for each sex and reinforce the importance of early onset of the hypothermic treatment.
治疗性低温（TH）是新生儿缺氧缺血（HI）的标准治疗方法，其时间窗限制在损伤后6小时内。然而，在HI动物模型中，尚未阐明TH治疗窗中性二态性的影响。因此，本研究的目的是调查新生HI雄性和雌性大鼠开始TH的最有效时间窗。将Wistar大鼠（P7）分为以下几组：未处理组和假手术组（对照组）、HI组（接受HI）和TH组（接受HI和TH；32℃持续5小时）。TH在HI后2小时（TH-2小时组）、4小时（TH-4小时组）或6小时（TH-6小时组）开始。在P14时，对动物进行行为测试、损伤体积和反应性星形胶质细胞增生评估。TH-2小时组的雄性和雌性大鼠行为测试潜伏期缩短，损伤体积减小，GFAP免疫荧光强度降低。TH-2小时组的雌性大鼠还显示退行性细胞减少和星形胶质细胞形态变化。有趣的是，TH-6小时组的雌性大鼠损伤体积和海马退行性细胞数量增加，行为表现更差。总之，这些结果表明TH神经保护具有时间和性别依赖性。此外，较晚开始TH（6小时）会使雌性大鼠脑损伤体积恶化。这些数据表明需要为每种性别制定特定的治疗方案，并强调低温治疗早期开始的重要性。
