We previously found that high-dose methylprednisolone increased the incidence of critical illness-related corticosteroid insufficiency (CIRCI) and mortality in rats with traumatic brain injury (TBI), whereas low-dose hydrocortisone but not methylprednisolone exerted protective effects. However, the receptor-mediated mechanism remains unclear. This study investigated the receptor-mediated mechanism of the opposite effects of different glucocorticoids on the survival of paraventricular nucleus (PVN) cells and the incidence of CIRCI after TBI. Based on controlled cortical impact (CCI) and treatments, male SD rats (n = 300) were randomly divided into the sham, CCI, CCI + GCs (methylprednisolone 1 or 30 mg/kg/day; corticosterone 1 mg/kg/day), CCI + methylprednisolone+RU486 (RU486 50 mg/kg/day), and CCI + corticosterone+spironolactone (spironolactone 50 mg/kg/day) groups. Blood samples were collected 7 days before and after CCI. Brain tissues were collected on postinjury day 7 and processed for histology and western blot analysis. We examined the incidence of CIRCI, mortality, apoptosis in the PVN, the receptor-mediated mechanism, and downstream signaling pathways on postinjury day 7. We found that methylprednisolone and corticosterone exerted opposite effects on the survival of PVN cells and the incidence of CIRCI by activating different receptors. High-dose methylprednisolone increased the nuclear glucocorticoid receptor (GR) level and subsequently increased cell loss in the PVN and the incidence of CIRCI. In contrast, low-dose corticosterone but not methylprednisolone played a protective role by upregulating mineralocorticoid receptor (MR) activation. The possible downstream receptor signaling mechanism involved the differential effects of GR and MR on the activity of the Akt/CREB/BDNF pathway. The excessive activation of GR by high-dose methylprednisolone exacerbated apoptosis in the PVN and increased CIRCI. In contrast, refilling of MR by corticosterone protects PVN neurons and reduces the incidence of CIRCI by promoting GR/MR rebalancing after TBI.

中文翻译：

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皮质类固醇受体再平衡通过 Akt/CREB/BDNF 信号传导促进室旁核细胞存活，缓解创伤性脑损伤后与危重疾病相关的皮质类固醇不足

我们以前发现高剂量甲泼尼龙会增加创伤性脑损伤 (TBI) 大鼠的危重疾病相关皮质类固醇不足 (CIRCI) 的发生率和死亡率，而低剂量氢化可的松而不是甲泼尼龙发挥保护作用。然而，受体介导的机制仍不清楚。本研究探讨了不同糖皮质激素对室旁核 (PVN) 细胞存活和 TBI 后 CIRCI 发生率的相反作用的受体介导机制。基于受控皮质影响 (CCI) 和治疗，雄性 SD 大鼠（n = 300）随机分为假手术、CCI、CCI + GC（甲基强的松龙 1 或 30 mg/kg/天；皮质酮 1 mg/kg/天） , CCI + 甲泼尼龙 + RU486 (RU486 50 毫克/公斤/天), 和 CCI + 皮质酮 + 螺内酯（螺内酯 50 mg/kg/天）组。在 CCI 前后 7 天收集血样。在受伤后第 7 天收集脑组织并进行组织学和蛋白质印迹分析。我们在损伤后第 7 天检查了 CIRCI 的发生率、死亡率、PVN 中的细胞凋亡、受体介导的机制和下游信号通路。我们发现甲基强的松龙和皮质酮对 PVN 细胞的存活和 CIRCI 的发生率产生相反的影响激活不同的受体。高剂量甲泼尼龙增加了核糖皮质激素受体 (GR) 水平，随后增加了 PVN 中的细胞损失和 CIRCI 的发生率。相比之下，低剂量皮质酮而非甲泼尼龙通过上调盐皮质激素受体 (MR) 的激活发挥保护作用。可能的下游受体信号机制涉及 GR 和 MR 对 Akt/CREB/BDNF 通路活性的不同影响。高剂量甲基强的松龙对 GR 的过度激活加剧了 PVN 中的细胞凋亡并增加了 CIRCI。相比之下，皮质酮对 MR 的再填充保护 PVN 神经元并通过促进 TBI 后 GR/MR 再平衡来降低 CIRCI 的发生率。