Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury.
Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury.
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DOI：
10.1159/000477490
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发表时间：
2017
影响因子：
2.9
通讯作者：
Levison SW
中科院分区：
文献类型：
--
作者：
Kim BH;Guardia Clausi M;Frondelli M;Nnah IC;Saqcena C;Dobrowolski R;Levison SW
缺氧缺血性（HI）脑损伤引起的新生儿脑病引发了一波神经炎性事件，导致最初损伤后数周出现进行性变性和功能缺陷。在最近的一组研究中，我们评估了一种小分子拮抗剂对激活素样激酶5（ALK 5）、TGFβ受体在中度围产期HI大鼠模型中的治疗效果，发现神经系统结局显著改善。在此，我们扩展了这些研究，以评价延迟TGFβ受体拮抗剂在出生后第6天（P6）和出生后第9天（P9）HI大鼠幼仔（有和无低温）中的疗效。在HI后3天开始通过渗透泵全身给予ALK 5受体拮抗剂SB 505124。扩展我们早期的数据集，其显示用SB 505124处理的P6幼仔中海马的保护，当在P60测试时，这些动物对它们的海马的损伤较小，并且在Morris水迷宫上的表现比溶媒处理的HI动物有所改善。相比之下，SB 505124在HI后3天给予P9幼仔时，没有改善感觉运动缺陷并加剧海马和丘脑体积损失。SB 505124处理的大鼠在P9损伤后，在Morris水迷宫中的表现往往比溶剂处理的大鼠更差，SB 505124处理与低温结合时，不能保护P9幼崽的海马或丘脑神经元。为了阐明ALK 5抑制减少P6 HI模型中神经元死亡的机制，我们评估了新皮质、海马和丘脑以及皮质下白色物质神经元中的自噬标志物水平，发现SB 505124增加了自噬体数量和脂化LC 3水平，脂化LC 3是已知介导自噬的关键蛋白LC 3。总之，我们的研究结果表明，在大鼠中，在P9周围发生的CNS对TGF-β1的反应中存在动态转换，其中TGFβ信号传导抑制功能结果。这种反应类似于在成人中风和其他CNS疾病模型中拮抗TGFβ信号传导的结果。我们的结论是，减弱TGF-β1信号传导可能是中度早产儿HI相关脑病的有效治疗方法，通过增强脑自噬作用保护新皮质、海马和丘脑，有助于降低进行性神经元细胞死亡的程度。
Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the initial insult. In a recent set of studies, we evaluated the therapeutic efficacy of a small molecule antagonist for the activin-like kinase 5 (ALK5), TGFβ receptor in a rat model of moderate perinatal HI and found significant improvements in neurologic outcomes. Here we have extended those studies to evaluate the efficacy of delayed TGFβ receptor antagonism in postnatal day 6 (P6) and postnatal day 9 (P9) HI rat pups with and without hypothermia. The ALK5 receptor antagonist SB505124 was administered systemically by osmotic pump beginning 3 days following HI. Extending our earlier dataset that showed protection of the hippocampus in P6 pups treated with SB505124, these animals sustained less damage to their hippocampi and had improved performance on the Morris water maze when tested at P60 versus vehicle-treated HI animals. By contrast, SB505124 did not improve sensorimotor deficits and exacerbated hippocampal and thalamic volume loss when administered 3 days after HI to P9 pups. SB505124-treated rats injured on P9 tended to perform worse than their vehicle-treated counterparts on Morris water maze, and SB505124 treatment did not preserve hippocampal or thalamic neurons for P9 pups when combined with hypothermia. To elucidate the mechanism whereby ALK5 inhibition reduced neuronal death in the P6 HI model, we assessed levels of autophagy markers in neurons of the neocortex, hippocampus and thalamus, and in the subcortical white matter, and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3, a key protein known to mediate autophagy, LC3. Altogether, our results demonstrate that there is a dynamic switch in the CNS response to TGF-β1 that occurs around P9 in rats where TGFβ signaling inhibition worsens functional outcomes. This response is similar to the outcome of antagonizing TGFβ signaling in adult stroke and other CNS disease models. We conclude that attenuating TGF-β1 signaling will likely be an effective treatment for HI-related encephalopathy in moderately pre-term infants, offering protection of the neocortex, hippocampus and thalamus with enhanced cerebral autophagy contributing to the decrease in extent of progressive neuronal cell death.
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影响因子：
16.2
作者：
Fanselow, Michael S.;Dong, Hong-Wei
通讯作者：
Dong, Hong-Wei
影响因子：
11.2
作者：
Nobuta, Hiroko;Ghiani, Cristina A.;Waschek, James A.
通讯作者：
Waschek, James A.
影响因子：
4.5
作者：
Hamilton, Nicholas
通讯作者：
Hamilton, Nicholas
影响因子：
168.9
作者：
Gluckman, PD;Wyatt, JS;Gunn, AJ
通讯作者：
Gunn, AJ
DOI：
10.1523/jneurosci.1256-12.2012
发表时间：
2012-10-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hamby ME;Coppola G;Ao Y;Geschwind DH;Khakh BS;Sofroniew MV
通讯作者：
Sofroniew MV