Brain damage caused by neonatal hypoxia-ischemia and the effects of hypothermia in severe combined immunodeficient (SCID) mice
Brain damage caused by neonatal hypoxia-ischemia and the effects of hypothermia in severe combined immunodeficient (SCID) mice
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DOI：
10.1016/j.expneurol.2020.113577
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发表时间：
2021-01-05
影响因子：
5.3
通讯作者：
Tsuji, Masahiro
中科院分区：
文献类型：
--
作者：
Ogawa, Yuko;Tanaka, Emi;Tsuji, Masahiro
新生儿缺氧缺血性脑病（HIE）是新生儿脑损伤的主要原因。虽然临床试验显示低温治疗对新生儿缺氧缺血性脑病具有神经保护作用，但其效果并不令人满意。基于细胞的治疗作为新生儿缺氧缺血性脑病的新疗法引起了广泛关注。已经在免疫缺陷/免疫抑制动物中进行了各种人细胞移植方法的临床前研究，例如严重联合免疫缺陷（SCID）小鼠，其缺乏功能性T和B淋巴细胞。然而，SCID小鼠新生儿HIE的详细特征尚未被描述。在临床前研究中，新生儿HIE的新疗法应与低温联合评估，低温已成为新生儿HIE的标准治疗方法。然而，低温在SCID小鼠中的作用尚未被描述。在本研究中，我们比较了新生儿缺氧缺血性（HI）脑损伤的SCID小鼠和野生型小鼠治疗或不低温。雄性和雌性小鼠幼崽出生后第12天进行HI损伤诱导的单侧颈总动脉结扎结合全身缺氧。在HI损伤后的第一个4小时内，体温维持在36 ℃（对于正常体温组）或32 ℃（对于低温组）。根据大多数评估，SCID小鼠脑损伤的严重程度与野生型小鼠没有差异，即，脑血流量、轻偏瘫、肌力、自发活动、大脑半球体积、脑病理损伤和血清细胞因子水平，尽管脾重、脑重、外周血白细胞计数和某些细胞因子水平在基因型之间存在差异。根据大多数评估，在SCID小鼠中低温的效果与野生型小鼠中的效果相当。总而言之，这些研究结果表明，SCID小鼠可用作新生儿缺氧缺血性脑病细胞治疗的适当临床前模型。
Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of brain damage in newborns. Although therapeutic hypothermia has been shown to be neuroprotective against neonatal HIE in clinical trials, its effect is not satisfactory. Cell-based therapies have attracted much attention as novel treatments for HIE. Preclinical studies on a variety of human cell transplantation methods have been performed in immunodeficient/immunosuppressed animals, such as severe combined immunodeficient (SCID) mice, which lack functional T and B lymphocytes. The detailed characteristics of neonatal HIE in SCID mice, however, have not been delineated. In preclinical studies, novel therapies for neonatal HIE should be evaluated in combination with hypothermia, which has become a standard treatment for neonatal HIE. However, the effects of hypothermia in SCID mice have not been delineated. In the present study, we compared neonatal hypoxic-ischemic (HI) brain damage in SCID mice and wild-type mice treated with or without hypothermia. Male and female mouse pups were subjected to HI insult induced by unilateral common carotid artery ligation combined with systemic hypoxia on postnatal day 12. In the first 4 h after HI insult, body temperature was maintained at 36 degrees C for the normothermia groups or 32 degrees C for the hypothermia groups. The severity of brain damage in SCID mice did not differ from that in wild-type mice based on most evaluations, i.e., cerebral blood flow, hemiparesis, muscle strength, spontaneous activity, cerebral hemispheric volume, neumpathological injury, and serum cytokine levels, although spleen weight, brain weight, leukocyte counts and the levels of some cytokines in the peripheral blood were different between genotypes. The effects of hypothermia in SCID mice were comparable to those in wild-type mice based on most evaluations. Taken together, these findings indicate that SCID mice can be used as an appropriate preclinical model for cell therapies for neonatal HIE.