Neuroprotective effects of Sonic hedgehog agonist SAG in a rat model of neonatal stroke.
Neuroprotective effects of Sonic hedgehog agonist SAG in a rat model of neonatal stroke.
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DOI：
10.1038/s41390-021-01408-7
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发表时间：
2021-12
影响因子：
3.6
通讯作者：
Gonzalez F
中科院分区：
文献类型：
--
作者：
Nguyen V;Chavali M;Larpthaveesarp A;Kodali S;Gonzalez G;Franklin RJM;Rowitch DH;Gonzalez F
新生儿中风影响1/2800活产婴儿，是神经损伤的主要原因。Sonic hedgehog（Shh）信号通路对中枢神经系统（CNS）发育至关重要，并且在不同的CNS损伤模型中具有神经保护和修复作用。先前的研究已经证明了小分子Shh-Smoothened激动剂（SAG）对新生儿小脑损伤的有益作用，并且它改善了小鼠中与唐氏综合征相关的脑结构缺陷。在这里，我们研究了SAG在新生儿缺血再灌注（中风）和成年局灶性白色损伤大鼠模型中的神经保护作用。本研究采用大鼠P10大脑中动脉短暂闭塞和溴化乙锭（EB）注射造成脑损伤。在手术和SAG或载体治疗后，我们分析了组织损失、细胞增殖和命运以及行为结果。我们报告说，单剂量的SAG新生儿中风后管理保存脑容量，减少胶质细胞增生，增强少突胶质细胞祖细胞（OPC）和EC增殖，并导致长期的认知改善。单剂量SAG也促进了成年大鼠局灶性脱髓鞘后OPCs的增殖。这些发现表明，在实验性新生儿中风后，在减少脑损伤和改善行为结果方面，创伤后一次性SAG治疗是有益的。一次性剂量的小分子Sonic hedgehog激动剂在大鼠模型中预防新生儿中风并改善长期行为结果。这项研究扩展了Sonic hedgehog在治疗发展中脑损伤中的应用，以前在唐氏综合征和小脑损伤的动物模型中显示。Sonic hedgehog激动剂因其安全性和低剂量而成为治疗新生儿脑卒中最有前途的药物之一。
Neonatal stroke affects 1 in 2800 live births and is a major cause of neurological injury. The Sonic hedgehog (Shh) signaling pathway is critical for central nervous system (CNS) development and has neuroprotective and reparative effects in different CNS injury models. Previous studies have demonstrated beneficial effects of small molecule Shh-Smoothened agonist (SAG) against neonatal cerebellar injury and it improves Down syndrome-related brain structural deficits in mice. Here we investigated SAG neuroprotection in rat models of neonatal ischemia–reperfusion (stroke) and adult focal white matter injury. We used transient middle cerebral artery occlusion at P10 and ethidium bromide (EB) injection in adult rats to induce damage. Following surgery and SAG or vehicle treatment, we analyzed tissue loss, cell proliferation and fate, and behavioral outcome. We report that a single dose of SAG administered following neonatal stroke preserved brain volume, reduced gliosis, enhanced oligodendrocyte progenitor cell (OPC) and EC proliferation, and resulted in long-term cognitive improvement. Single-dose SAG also promoted proliferation of OPCs following focal demyelination in the adult rat. These findings indicate benefit of one-time SAG treatment post insult in reducing brain injury and improving behavioral outcome after experimental neonatal stroke. A one-time dose of small molecule Sonic hedgehog agonist protected against neonatal stroke and improved long-term behavioral outcomes in a rat model. This study extends the use of Sonic hedgehog in treating developing brain injury, previously shown in animal models of Down syndrome and cerebellar injury. Sonic hedgehog agonist is one of the most promising therapies in treating neonatal stroke thanks to its safety profile and low dosage.
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