Department of Pharmacology, College of Pharmacy of Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin, 150086, China.
Department of Pathophysiology, Harbin Medical University, Harbin, 150086, China.
Acta Pharmacol Sin. 2021 Mar;42(3):361-369. doi: 10.1038/s41401-020-0437-z. Epub 2020 Jul 21.
Intrauterine hypoxia (IUH) affects the growth and development of offspring. It remains unclear that how long the impact of IUH on cognitive function lasts and whether sexual differences exist. Spermidine (SPD) has shown to improve cognition, but its effect on the cognitive function of IUH offspring remains unknown. In the present study we investigated the influence of IUH on body weight and neurological, motor and cognitive function and the expression of APP, BACE1 and Tau5 proteins in brain tissues in 2- and 4-month-old IUH rat offspring, as well as the effects of SPD intervention on these parameters. IUH rat model was established by treating pregnant rats with intermittent hypoxia on gestational days 15-21, meanwhile pregnant rats were administered SPD (5 mg·kg·d;ip) for 7 days. Neurological deficits were assessed in the Longa scoring test; motor and cognitive functions were evaluated in coat hanger test and active avoidance test, respectively. We found that IUH decreased the body weight of rats in both sexes but merely impaired motor and cognitive function in female rats without changing neurological function in the rat offspring of either sex at 2 months of age. For 4-month-old offspring, IUH decreased body weight in males and impaired neurological function and increased cognitive function in both sexes. IUH did not affect APP, BACE1 or Tau5 protein expression in either the hippocampus or cortex of all offspring; however, it increased the cortical Tau5 level in 2-month-old female offspring. Surprisingly, SPD intervention prevented weight loss. SPD intervention reversed the motor and cognitive decline caused by IUH in 2-month-old female rat offspring. Taken together, IUH-induced cognitive decline in rat offspring is sex-dependent during puberty and can be recovered in adult rats. SPD intervention improves IUH-induced cognitive and neural function decline.
宫内缺氧 (IUH) 会影响后代的生长发育。目前尚不清楚 IUH 对认知功能的影响会持续多久，以及是否存在性别差异。 spermidine (SPD) 已被证明可以改善认知功能，但它对 IUH 后代认知功能的影响尚不清楚。在本研究中，我们研究了 IUH 对 2 月龄和 4 月龄 IUH 大鼠后代体重以及神经、运动和认知功能的影响，以及脑组织中 APP、BACE1 和 Tau5 蛋白的表达，并探讨了 SPD 干预对这些参数的影响。通过在妊娠第 15-21 天对孕鼠进行间歇性缺氧处理，建立 IUH 大鼠模型，同时对孕鼠进行 SPD（5mg·kg·d；ip）处理 7 天。Longa 评分试验评估神经功能缺损；通过衣架试验和主动回避试验分别评估运动和认知功能。结果发现，IUH 降低了雌雄大鼠的体重，但仅损害了雌性大鼠的运动和认知功能，而对雌雄大鼠后代的神经功能没有影响。对于 4 月龄的后代，IUH 降低了雄性大鼠的体重，损害了雌雄大鼠的神经功能，提高了雌雄大鼠的认知功能。IUH 没有影响各组后代海马和皮质中 APP、BACE1 或 Tau5 蛋白的表达，但增加了 2 月龄雌性后代皮质 Tau5 水平。令人惊讶的是，SPD 干预阻止了体重减轻。SPD 干预逆转了 2 月龄雌性大鼠后代 IUH 引起的运动和认知下降。综上所述，青春期 IUH 诱导的大鼠后代认知下降具有性别依赖性，并可在成年大鼠中恢复。SPD 干预可改善 IUH 诱导的认知和神经功能下降。
