Department of Critical Care Medicine, Safar Center for Resuscitation Research, UPMC Children's Hospital of Pittsburgh, Rangos Research Center - 6th floor, Pittsburgh, PA, 15224, USA.
USF Health Heart Institute, University of South Florida Morsani College of Medicine, MDD 0630, 560 Channelside Drive, Tampa, FL, 33602, USA.
Pediatr Res. 2023 Oct;94(4):1355-1364. doi: 10.1038/s41390-023-02652-9. Epub 2023 May 16.
Fibroblast growth factor 21 (FGF21) is a neuroprotectant with cognitive enhancing effects but with poorly characterized mechanism(s) of action, particularly in females. Prior studies suggest that FGF21 may regulate cold-shock proteins (CSPs) and CA2-marker proteins in the hippocampus but empirical evidence is lacking.
We assessed in normothermic postnatal day (PND) 10 female mice, if hypoxic-ischemic (HI) brain injury (25 min 8% O/92% N) altered endogenous levels of FGF21 in serum or in the hippocampus, or its receptor β-klotho. We also tested if systemic administration of FGF21 (1.5 mg/kg) modulated hippocampal CSPs or CA2 proteins. Finally, we measured if FGF21 therapy altered markers of acute hippocampal injury.
HI increased endogenous serum FGF21 (24 h), hippocampal tissue FGF21 (4d), and decreased hippocampal β-klotho levels (4d). Exogenous FGF21 therapy modulated hippocampal CSP levels, and dynamically altered hippocampal CA2 marker expression (24 h and 4d). Finally, FGF21 ameliorated neuronal damage markers at 24 h but did not affect GFAP (astrogliosis) or Iba1 (microgliosis) levels at 4d.
FGF21 therapy modulates CSP and CA2 protein levels in the injured hippocampus. These proteins serve different biological functions, but our findings suggest that FGF21 administration modulates them in a homeostatic manner after HI.
Hypoxic-ischemic (HI) injury in female post-natal day (PND) 10 mice decreases hippocampal RNA binding motif 3 (RBM3) levels in the normothermic newborn brain. HI injury in normothermic newborn female mice alters serum and hippocampal fibroblast growth factor 21 (FGF21) levels 24 h post-injury. HI injury in normothermic newborn female mice alters hippocampal levels of N-terminal EF-hand calcium binding protein 2 (NECAB2) in a time-dependent manner. Exogenous FGF21 therapy ameliorates the HI-mediated loss of hippocampal cold-induced RNA-binding protein (CIRBP). Exogenous FGF21 therapy modulates hippocampal levels of CA2-marker proteins after HI.
成纤维细胞生长因子 21（FGF21）是一种具有神经保护作用和认知增强作用的物质，但作用机制尚不清楚，尤其是在女性中。先前的研究表明，FGF21 可能调节海马体中的冷休克蛋白（CSPs）和 CA2 标志物蛋白，但缺乏经验证据。
我们在正常体温的出生后 10 天（PND）雌性小鼠中评估了缺氧缺血（HI）脑损伤（25 分钟 8% O/92% N）是否改变了血清或海马体中的内源性 FGF21 水平及其受体 β-klotho。我们还测试了是否全身给予 FGF21（1.5mg/kg）可以调节海马体中的 CSP 或 CA2 蛋白。最后，我们测量了 FGF21 治疗是否改变了急性海马损伤的标志物。
HI 增加了内源性血清 FGF21（24 小时）、海马组织 FGF21（4 天）和降低了海马体 β-klotho 水平（4 天）。外源性 FGF21 治疗调节了海马体 CSP 水平，并动态改变了海马体 CA2 标志物的表达（24 小时和 4 天）。最后，FGF21 在 24 小时改善了神经元损伤标志物，但在 4 天不影响 GFAP（星形胶质增生）或 Iba1（小胶质增生）水平。
FGF21 治疗调节 HI 后海马体中 CSP 和 CA2 蛋白的水平。这些蛋白具有不同的生物学功能，但我们的发现表明，在 HI 后，FGF21 的给药以一种稳态的方式调节它们。
在正常体温的新生雌性 PND 10 天小鼠中，缺氧缺血（HI）损伤降低了正常体温新生大脑中海马体 RNA 结合基序 3（RBM3）的水平。在正常体温的新生雌性小鼠中，HI 损伤在损伤后 24 小时改变了血清和海马体成纤维细胞生长因子 21（FGF21）的水平。在正常体温的新生雌性小鼠中，HI 损伤以时间依赖性方式改变了海马体 N 端 EF 手钙结合蛋白 2（NECAB2）的水平。外源性 FGF21 治疗可改善 HI 介导的海马体冷诱导 RNA 结合蛋白（CIRBP）的丢失。外源性 FGF21 治疗调节 HI 后海马体 CA2 标志物蛋白的水平。
