Haque Azizul, Das Arabinda, Samantaray Supriti, Matzelle Denise, Capone Mollie, Wallace Gerald, Husarik Aarti N, Taheri Saied, Reiter Russel J, Varma Abhay, Ray Swapan K, Banik Naren L
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Neurosurgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Int J Mol Sci. 2022 Feb 21;23(4):2384. doi: 10.3390/ijms23042384.
Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17β-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side effects makes advocating its therapeutic use difficult. Therefore, this study aimed at investigating the therapeutic efficacy of Premarin (PRM) in SCI. PRM is an FDA-approved E2 (10%) formulation, which is used for hormone replacement therapy with minimal risk of serious side effects. The effects of PRM on SCI were examined by magnetic resonance imaging, immunofluorescent staining, and western blot analysis in a rat model. SCI animals treated with vehicle alone, PRM, E2 receptor antagonist (ICI), or PRM + ICI were graded in a blinded way for locomotor function by using the Basso-Beattie-Bresnahan (BBB) locomotor scale. PRM treatment for 7 days decreased post-SCI lesion volume and attenuated neuronal cell death, inflammation, and axonal damage. PRM also altered the balance of pro- and anti-apoptotic proteins in favor of cell survival and improved angiogenesis and microvascular growth. Increased expression of estrogen receptors (ERs) ERα and ERβ following PRM treatment and their inhibition by ER inhibitor indicated that the neuroprotection associated with PRM treatment might be E2-receptor mediated. The attenuation of glial activation with decreased inflammation and cell death, and increased angiogenesis by PRM led to improved functional outcome as determined by the BBB locomotor scale. These results suggest that PRM treatment has significant therapeutic implications for the improvement of post-SCI outcome.
脊髓损伤（SCI）会导致严重的死亡率和发病率。目前，美国食品药品监督管理局（FDA）尚未批准任何用于治疗SCI的药物疗法。此前，低剂量的雌激素（17β-雌二醇，E2）已被证明可改善大鼠SCI模型的损伤后结果。然而，相关副作用的范围使得提倡其治疗用途变得困难。因此，本研究旨在调查普瑞马林（PRM）对SCI的治疗效果。PRM是一种经FDA批准的E2（10%）制剂，用于激素替代疗法，严重副作用风险极小。通过磁共振成像、免疫荧光染色和蛋白质印迹分析，在大鼠模型中检测了PRM对SCI的影响。使用Basso-Beattie-Bresnahan（BBB）运动评分量表，对单独接受赋形剂、PRM、E2受体拮抗剂（ICI）或PRM + ICI治疗的SCI动物的运动功能进行盲法分级。PRM治疗7天可减少SCI后损伤体积，并减轻神经元细胞死亡、炎症和轴突损伤。PRM还改变了促凋亡蛋白和抗凋亡蛋白的平衡，有利于细胞存活，并改善了血管生成和微血管生长。PRM治疗后雌激素受体（ERs）ERα和ERβ的表达增加，而ER抑制剂对其有抑制作用，这表明与PRM治疗相关的神经保护作用可能是由E2受体介导的。PRM减轻了胶质细胞活化，减少了炎症和细胞死亡，并增加了血管生成，从而改善了BBB运动评分量表所确定的功能结果。这些结果表明，PRM治疗对改善SCI后的结果具有重要的治疗意义。
