Turan Nefize, Miller Brandon A, Huie J Russell, Heider Robert A, Wang Jun, Wali Bushra, Yousuf Seema, Ferguson Adam R, Sayeed Iqbal, Stein Donald G, Pradilla Gustavo
Cerebrovascular Research Laboratory, Emory University School of Medicine, Atlanta, Georgia; Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia.
Department of Neurosurgery, University of California, San Francisco, San Francisco, California, USA.
World Neurosurg. 2018 Feb;110:e150-e159. doi: 10.1016/j.wneu.2017.10.118. Epub 2017 Oct 31.
Subarachnoid hemorrhage (SAH) induces widespread inflammation leading to cellular injury, vasospasm, and ischemia. Evidence suggests that progesterone (PROG) can improve functional recovery in acute brain injury owing to its anti-inflammatory and neuroprotective properties, which could also be beneficial in SAH. We hypothesized that PROG treatment attenuates inflammation-mediated cerebral vasospasm and microglial activation, improves synaptic connectivity, and ameliorates functional recovery after SAH.
We investigated the effect of PROG in a cisternal SAH model in adult male C57BL/6 mice. Neurobehavioral outcomes were evaluated using rotarod latency and grip strength tests. Basilar artery perimeter, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor 1 (GluR1)/synaptophysin colocalization, and Iba-1 immunoreactivity were quantified histologically.
PROG (8 mg/kg) significantly improved rotarod latency at day 6 and grip strength at day 9. PROG-treated mice had significantly reduced basilar artery vasospasm at 24 hours. GluR1/synaptophysin colocalization, indicative of synaptic GluR1, was significantly reduced in the SAH+Vehicle group at 24 hours, and PROG treatment significantly attenuated this reduction. PROG treatment significantly reduced microglial cell activation and proliferation in cerebellum and cortex but not in the brainstem at 10 days.
PROG treatment ameliorated cerebral vasospasm, reduced microglial activation, restored synaptic GluR1 localization, and improved neurobehavioral performance in a murine model of SAH. These results provide a rationale for further translational testing of PROG therapy in SAH.
蛛网膜下腔出血（SAH）会引发广泛的炎症反应，导致细胞损伤、血管痉挛和缺血。有证据表明，孕酮（PROG）因其抗炎和神经保护特性，可改善急性脑损伤后的功能恢复，这对SAH可能也有益处。我们假设PROG治疗可减轻炎症介导的脑血管痉挛和小胶质细胞激活，改善突触连接，并改善SAH后的功能恢复。
我们在成年雄性C57BL/6小鼠的脑池SAH模型中研究了PROG的作用。使用转棒潜伏期和握力测试评估神经行为结果。通过组织学方法对基底动脉周长、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸谷氨酸受体1（GluR1）/突触素共定位以及Iba-1免疫反应性进行定量分析。
PROG（8mg/kg）在第6天显著改善了转棒潜伏期，在第9天提高了握力。PROG治疗的小鼠在24小时时基底动脉痉挛明显减轻。在24小时时，SAH+溶媒组中指示突触GluR1的GluR1/突触素共定位显著降低，而PROG治疗显著减轻了这种降低。在第10天时，PROG治疗显著减少了小脑和皮质中小胶质细胞的激活和增殖，但在脑干中未减少。
在SAH小鼠模型中，PROG治疗减轻了脑血管痉挛，减少了小胶质细胞激活，恢复了突触GluR1定位，并改善了神经行为表现。这些结果为进一步对SAH进行PROG治疗的转化试验提供了理论依据。
