Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
Int J Mol Sci. 2024 Nov 1;25(21):11765. doi: 10.3390/ijms252111765.
Ischemic stroke is a leading cause of disability and mortality worldwide. Recently, increasing evidence implicates microRNAs (miRs) in the pathophysiology of ischemic stroke. Studies have shown that miR-15a/16-1 is abnormally expressed in brains after ischemic stroke, and its upregulation may increase ischemic damage. Given that sex and age are significant modifiers of stroke outcomes, here we investigated whether inhibiting miR-15a/16-1 with antagomirs mitigates cerebral ischemia/reperfusion (I/R) injury in a sex- and age-dependent manner. Young (3 months) and aged (18 months) male and female C57/BL mice underwent 1-h middle cerebral artery occlusion and 3-7 days reperfusion (tMCAO). We administered miR-15a/16-1 antagomir (30 pmol/g) or control antagomir (NC, 30 pmol/g) via tail vein 2 h post-MCAO. Neurobehavioral testing and infarct volume assessment were performed on days 3 and 7. Compared to controls, antagomir treatment significantly improved neurobehavioral outcomes and reduced infarct volume in tMCAO mice at day 7, with the effects being more pronounced in young mice. Notably, young female mice exhibited superior survival and sensorimotor function compared to young male mice. These results were also replicated in a permanent MCAO (pMCAO) mice model. This suggests miR-15a/16-1 antagomir and estradiol may synergistically regulate genes involved in neurovascular cell death, inflammation, and oxidative stress, with sex and age-dependent expression of miR-15a/16-1 and its targets likely underlying the observed variations. Overall, our findings identify miR-15a/16-1 antagomir as a promising therapeutic for ischemic stroke and suggest that sex and age should be considered when developing miR-based therapeutic strategies.
缺血性中风是全球范围内导致残疾和死亡的主要原因。最近，越来越多的证据表明 microRNAs（miRs）在缺血性中风的病理生理学中起作用。研究表明，miR-15a/16-1 在缺血性中风后大脑中异常表达，其上调可能增加缺血性损伤。鉴于性别和年龄是中风结果的重要修饰因子，我们在这里研究了用反义寡核苷酸抑制 miR-15a/16-1 是否能以性别和年龄依赖的方式减轻脑缺血/再灌注（I/R）损伤。年轻（3 个月）和年老（18 个月）雄性和雌性 C57/BL 小鼠接受 1 小时大脑中动脉闭塞和 3-7 天再灌注（tMCAO）。我们在 MCAO 后 2 小时通过尾静脉给予 miR-15a/16-1 反义寡核苷酸（30 pmol/g）或对照反义寡核苷酸（NC，30 pmol/g）。在第 3 天和第 7 天进行神经行为测试和梗死体积评估。与对照组相比，反义寡核苷酸治疗在 tMCAO 小鼠中显著改善了神经行为结果，并在第 7 天减少了梗死体积，在年轻小鼠中效果更为明显。值得注意的是，年轻雌性小鼠的存活率和感觉运动功能优于年轻雄性小鼠。这些结果在永久性 MCAO（pMCAO）小鼠模型中得到了复制。这表明 miR-15a/16-1 反义寡核苷酸和雌二醇可能协同调节涉及神经血管细胞死亡、炎症和氧化应激的基因，miR-15a/16-1 及其靶基因的性别和年龄依赖性表达可能是观察到的变化的基础。总的来说，我们的研究结果表明 miR-15a/16-1 反义寡核苷酸是一种有前途的缺血性中风治疗方法，并表明在开发基于 miR 的治疗策略时应考虑性别和年龄。
