Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury
Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury
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DOI：
10.1016/j.expneurol.2021.113652
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发表时间：
2021-02-23
影响因子：
5.3
通讯作者：
Semple, Bridgette D.
中科院分区：
文献类型：
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作者：
Fletcher, Jessica L.;Dill, Larissa K.;Semple, Bridgette D.
幼儿有很高的风险持续创伤性脑损伤（TBI），这可能会导致终身衰弱的后果。重要的是，年轻的大脑显示出特别容易受到损伤，这可能归因于在损伤时髓鞘神经系统的持续成熟。在此，我们研究了部分原肌球蛋白受体激酶B（Trk B）激动剂LM 22 A-4急性治疗对小儿TBI后病理和神经行为结果的影响，假设靶向Trk B将使组织损伤最小化并支持功能恢复。我们专注于有髓神经束-胼胝体和外囊-基于最近的证据表明TrkB激活增强少突胶质细胞髓鞘再生。出生后第21天的雄性小鼠接受实验性TBI或假手术。急性损伤后，广泛的细胞死亡，一个强大的神经胶质反应和破坏的紧凑髓鞘是明显的受伤的大脑。然后TBI或假手术小鼠接受鼻内盐水媒介物或LM 22 A-4 14天。从损伤后4周开始进行行为测试，并在5周时收集大脑进行组织学检查。TBI小鼠表现出多动症，焦虑样行为减少和社会记忆障碍。LM 22 A-4改善了异常的抗焦虑表型，但对社会记忆缺陷没有影响。使用光谱共聚焦反射显微镜检测持续髓鞘碎片在外伤后5周的TBI小鼠的外囊，这是伴随着区域明显的缺陷少突胶质细胞祖细胞和有丝分裂后的少突胶质细胞，以及慢性反应性神经胶质增生和胼胝体和受损的外囊萎缩。LM 22 A-4治疗改善了病灶周围外囊中的髓鞘缺陷，以及组织体积损失和反应性神经胶质增生的程度。然而，在损伤后5周检测到这种TrkB激动剂对少突胶质细胞群体没有影响。总的来说，我们的结果表明，在生命早期TBI后立即靶向TrkB可提供神经保护并保持髓鞘完整性，并且随着儿科受伤大脑的成熟，这与一些改善的神经行为结果相关。
Young children have a high risk of sustaining a traumatic brain injury (TBI), which can have debilitating life-long consequences. Importantly, the young brain shows particular vulnerability to injury, likely attributed to ongoing maturation of the myelinating nervous system at the time of insult. Here, we examined the effect of acute treatment with the partial tropomyosin receptor kinase B (TrkB) agonist, LM22A-4, on pathological and neurobehavioral outcomes after pediatric TBI, with the hypothesis that targeting TrkB would minimize tissue damage and support functional recovery. We focused on myelinated tracts-the corpus callosum and external capsules-based on recent evidence that TrkB activation potentiates oligodendrocyte remyelination. Male mice at postnatal day 21 received an experimental TBI or sham surgery. Acutely post-injury, extensive cell death, a robust glial response and disruption of compact myelin were evident in the injured brain. TBI or sham mice then received intranasal saline vehicle or LM22A-4 for 14 days. Behavior testing was performed from 4 weeks post-injury, and brains were collected at 5 weeks for histology. TBI mice showed hyperactivity, reduced anxiety-like behavior, and social memory impairments. LM22A-4 ameliorated the abnormal anxiolytic phenotype but had no effect on social memory deficits. Use of spectral confocal reflectance microscopy detected persistent myelin fragmentation in the external capsule of TBI mice at 5 weeks post-injury, which was accompanied by regionally distinct deficits in oligodendrocyte progenitor cells and post-mitotic oligodendrocytes, as well as chronic reactive gliosis and atrophy of the corpus callosum and injured external capsule. LM22A-4 treatment ameliorated myelin deficits in the perilesional external capsule, as well as tissue volume loss and the extent of reactive gliosis. However, there was no effect of this TrkB agonist on oligodendroglial populations detected at 5 weeks postinjury. Collectively, our results demonstrate that targeting TrkB immediately after TBI during early life confers neuroprotection and preserves myelin integrity, and this was associated with some improved neurobehavioral outcomes as the pediatric injured brain matures.