Cyclin D1 Gene Ablation Confers Neuroprotection in Traumatic Brain Injury
Cyclin D1 Gene Ablation Confers Neuroprotection in Traumatic Brain Injury
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DOI：
10.1089/neu.2011.1980
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发表时间：
2012-03-01
影响因子：
4.2
通讯作者：
Faden, Alan I.
中科院分区：
文献类型：
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作者：
Kabadi, Shruti V.;Stoica, Bogdan A.;Faden, Alan I.
细胞周期激活(CCA)是脑创伤后继发性损伤的主要机制之一，可导致神经细胞死亡、小胶质细胞激活和神经功能障碍。细胞周期蛋白D1(CD1)是CCA的关键调节因子，在创伤性脑损伤后神经元和小胶质细胞中表达上调。在这项研究中，我们对CD1野生型(CD1(+/+))和基因敲除(CD1(-/-))小鼠进行了受控皮质撞击(CCI)损伤，以评估CD1在创伤后神经变性和神经炎症中的作用。早在伤后24小时，CD1(+/+)小鼠在损伤侧大脑半球就显示出CCA标记，包括CD1、E2F1和增殖细胞核抗原(PCNA)的增加，以及荧光Jade B染色的增加，表明神经元变性。这些小鼠在损伤后21天观察到海马神经元的进行性丢失，这与认知功能的下降有关。损伤侧脑内小胶质细胞活化在伤后7d达高峰，21d持续增加。相比之下，CD1(-/-)小鼠在伤后24小时显示出CCA和神经变性的减少，并在伤后21天改善了认知功能，减轻了海马神经细胞的丢失，减少了损伤体积，并激活了皮质小胶质细胞。这些发现表明，依赖CD1的CCA在颅脑损伤引起的神经炎症、进行性神经退行性变和相关的神经功能障碍中起着重要作用。我们的结果进一步证实了CCA在创伤后继发性损伤中的作用，并提示抑制CD1可能是脑外伤的关键治疗靶点。
Cell cycle activation (CCA) is one of the principal secondary injury mechanisms following brain trauma, and it leads to neuronal cell death, microglial activation, and neurological dysfunction. Cyclin D1 (CD1) is a key modulator of CCA and is upregulated in neurons and microglia following traumatic brain injury (TBI). In this study we subjected CD1-wild-type (CD1(+/+)) and knockout (CD1(-/-)) mice to controlled cortical impact (CCI) injury to evaluate the role of CD1 in post-traumatic neurodegeneration and neuroinflammation. As early as 24 h post-injury, CD1(+/+) mice showed markers of CCA in the injured hemisphere, including increased CD1, E2F1, and proliferating cell nuclear antigen (PCNA), as well as increased Fluoro-Jade B staining, indicating neuronal degeneration. Progressive neuronal loss in the hippocampus was observed through 21 days post-injury in these mice, which correlated with a decline in cognitive function. Microglial activation in the injured hemisphere peaked at 7 days post-injury, with sustained increases at 21 days. In contrast, CD1(-/-) mice showed reduced CCA and neurodegeneration at 24 h, as well as improved cognitive function, attenuated hippocampal neuronal cell loss, decreased lesion volume, and cortical microglial activation at 21 days post-injury. These findings indicate that CD1-dependent CCA plays a significant role in the neuroinflammation, progressive neurodegeneration, and related neurological dysfunction resulting from TBI. Our results further substantiate the proposed role of CCA in post-traumatic secondary injury, and suggest that inhibition of CD1 may be a key therapeutic target for TBI.