Differential effects of FK506 on structural and functional axonal deficits after diffuse brain injury in the immature rat.
Differential effects of FK506 on structural and functional axonal deficits after diffuse brain injury in the immature rat.
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DOI：
10.1097/nen.0b013e31826f5876
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发表时间：
2012-11
影响因子：
3.2
通讯作者：
Raghupathi R
中科院分区：
文献类型：
--
作者：
Dileonardi AM;Huh JW;Raghupathi R
弥漫性轴索损伤是儿童创伤性脑损伤的主要组成部分，并与长期认知障碍相关。成年啮齿类动物的创伤性脑损伤与胼胝体复合动作电位（CAP）降低有关，但未成年啮齿类动物创伤相关弥漫性轴索损伤的信息有限。我们研究了闭合性颅脑损伤对17日龄大鼠胼胝体CAP的影响。损伤后1 - 14天（dpi），胼胝体中有髓和无髓纤维的CAP缺陷。这些缺陷伴随着轴突内的200 kDa的神经丝亚基（NF 200）在1和3 dpi的去磷酸化，减少总NF 200在3 dpi和轴突变性在3和7 dpi。虽然总磷酸酶活性下降，在1 dpi，钙调磷酸酶活性不变。钙调神经磷酸酶抑制剂FK 506显著减弱了损伤诱导的NF 200去磷酸化和3 dpi和7 dpi的轴突变性，但不影响NF 200蛋白水平的降低或受损的轴突运输。FK 506在3 dpi时对CAP缺陷没有影响，但在7 dpi时仅加剧了有髓纤维的缺陷。因此，与成年动物相比，FK 506治疗并未改善脑损伤未成熟动物的轴突功能，这表明钙调神经磷酸酶可能不会导致轴突功能受损。
Diffuse axonal injury is a major component of traumatic brain injury in children and correlates with long-term cognitive impairment. Traumatic brain injury in adult rodents has been linked to a decrease in compound action potential (CAP) in the corpus callosum but information on trauma-associated diffuse axonal injury in immature rodents is limited. We investigated the effects of closed head injury on CAP in the corpus callosum of 17-day-old rats. The injury resulted in CAP deficits of both myelinated and unmyelinated fibers in the corpus callosum between 1 and 14 days post-injury (dpi). These deficits were accompanied by intra-axonal dephosphorylation of the 200-kDa neurofilament subunit (NF200) at 1 and 3 dpi, a decrease in total NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi. Although total phosphatase activity decreased at 1 dpi, calcineurin activity was unchanged. The calcineurin inhibitor, FK506, significantly attenuated the injury-induced NF200 dephosphorylation of NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi, but did not affect the decrease in NF200 protein levels or impaired axonal transport. FK506 had no effect on CAP deficits at 3 dpi, but exacerbated the deficit in only the myelinated fibers at 7 dpi. Thus, in contrast to adult animals, FK506 treatment did not improve axonal function in brain-injured immature animals, suggesting that calcineurin may not contribute to impaired axonal function.