Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Transl Stroke Res. 2020 Oct;11(5):1117-1136. doi: 10.1007/s12975-020-00792-2. Epub 2020 Mar 5.
In perinatal stroke, the initial injury results in a chronic inflammatory response caused by the release of proinflammatory cytokines, gliosis and microglia activation. This chronic and ongoing inflammatory response exacerbates the brain injury, often resulting in encephalopathy and cerebral palsy (CP). Using a neonatal rat model of hypoxia-ischemia (HI) at postnatal day (P)7, we demonstrated that chronic inflammation is persistent and continues into the tertiary phase of perinatal stroke and can be attenuated by the administration of methylprednisolone sodium-succinate (MPSS, 30 mg/kg), a US Food and Drug Administration (FDA) approved anti-inflammatory agent. The inflammatory response was assessed by real-time quantitative PCR and ELISA for markers of inflammation (CCL3, CCL5, IL18 and TNFα). Structural changes were evaluated by histology (LFB/H&E), while cellular changes were assessed by Iba-1, ED1, GFAP, NeuN, Olig2 and CC1 immunostaining. Functional deficits were assessed with the Cylinder test and Ladder Rung Walking test. MPSS was injected 14 days after HI insult to attenuate chronic inflammation. In neonatal conditions such as CP, P21 is a clinically relevant time-point in rodents, corresponding developmentally to a 2-year-old human. Administration of MPSS resulted in reduced structural damage (corpus callosum, cortex, hippocampus, striatum), gliosis and reactive microglia and partial restoration of the oligodendrocyte population. Furthermore, significant behavioural recovery was observed. In conclusion, we demonstrated that administration of MPSS during the tertiary phase of perinatal stroke results in attenuation of the chronic inflammatory response, leading to pathophysiological and functional recovery. This work validates the high clinical impact of MPSS to treat neonatal conditions linked to chronic inflammation.
在围产期脑卒中，初始损伤导致促炎细胞因子的释放、神经胶质增生和小胶质细胞激活引起的慢性炎症反应。这种慢性和持续的炎症反应加剧了脑损伤，通常导致脑病和脑瘫 (CP)。我们使用新生大鼠缺氧缺血 (HI) 模型在出生后第 7 天 (P) 证明，慢性炎症是持续的，并持续到围产期脑卒中的三级阶段，可以通过给予甲泼尼龙琥珀酸钠 (MPSS，30mg/kg) 来减轻，MPSS 是一种美国食品和药物管理局 (FDA) 批准的抗炎药。通过实时定量 PCR 和 ELISA 评估炎症标志物 (CCL3、CCL5、IL18 和 TNFα) 来评估炎症反应。通过组织学 (LFB/H&E) 评估结构变化，通过 Iba-1、ED1、GFAP、NeuN、Olig2 和 CC1 免疫染色评估细胞变化。通过圆筒试验和阶梯走梯试验评估功能缺陷。在 HI 损伤后 14 天注射 MPSS 以减轻慢性炎症。在 CP 等新生儿情况下，P21 是啮齿动物的一个临床相关时间点，在发育上相当于 2 岁的人类。MPSS 的给药导致结构损伤减少（胼胝体、皮层、海马、纹状体）、神经胶质增生和反应性小胶质细胞，并部分恢复少突胶质细胞群体。此外，观察到显著的行为恢复。总之，我们证明在围产期脑卒中的三级阶段给予 MPSS 可减轻慢性炎症反应，从而导致病理生理和功能恢复。这项工作验证了 MPSS 治疗与慢性炎症相关的新生儿疾病的高临床影响。
