丙戊酸介导的损伤视网膜神经节细胞的神经保护和再生。
Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells.
机构信息
University Eye Hospital Freiburg, Freiburg im Breisgau, Germany.
出版信息
Invest Ophthalmol Vis Sci. 2010 Jan;51(1):526-34. doi: 10.1167/iovs.09-3903. Epub 2009 Jul 23.
PURPOSE
Valproic acid (VPA) has been demonstrated to have neuroprotective effects in neurodegenerative conditions. VPA inhibits histone-deacetylases (HDAC) and delays apoptosis in degenerating neurons. The authors investigated whether VPA delays retinal ganglion cell (RGC) death and enhances axonal regeneration after optic nerve crush (ONC). Furthermore, potential molecular targets involved in VPA-mediated protection were analyzed.
METHODS
ONC was performed on the left eye of rats, which received VPA or Ringer's solution subcutaneously (SC; 300 mg/kg twice daily) or intravitreally (single postlesional injection). Densities of fluorogold-labeled RGC were analyzed in retinal flatmounts after 5 or 8 days. Retinal tissue was also harvested and processed to quantify axon growth in retinal explants; evaluate caspase-3 activity; analyze transcription factor cAMP response element binding protein (CREB); and determine acetylated histone 3 and 4, as well as phosphorylated extracellular signal-regulated kinase (pERK) 1/2.
RESULTS
Five and 8 days after ONC, 93% and 58% RGC survived after subcutaneous VPA treatment in comparison to Ringer's solution (62% and 37% viable RGC), respectively (P < 0.001). Likewise, a single intravitreal injection of VPA immediately after injury significantly delayed apoptosis in RGC (P = 0.0016). Injured RGC treated with VPA showed better regeneration of their axons in culture (196 axons/explant) than the crushed controls receiving Ringer (115 axons/explant). RGC axons of the right control eyes regenerated more after VPA treatment. VPA-mediated neuroprotection and neuroregeneration were accompanied by decreased caspase-3 activity, CREB induction, pERK1/2 activation, but not by altered histone-acetylation.
CONCLUSIONS
VPA provided neuroprotection and axonal regrowth after ONC. Alterations were observed in several pathways; however, the precise mechanism of VPA-mediated protection is not yet fully understood.
目的
已证实丙戊酸（VPA）在神经退行性疾病中有神经保护作用。VPA 抑制组蛋白去乙酰化酶（HDAC）并延迟变性神经元中的细胞凋亡。作者研究了 VPA 是否能延迟视神经挤压（ONC）后视网膜神经节细胞（RGC）的死亡并增强轴突再生。此外，还分析了参与 VPA 介导保护的潜在分子靶点。
方法
对大鼠左眼进行 ONC，大鼠接受皮下（SC；每日两次，300mg/kg）或玻璃体内（单次损伤后注射）VPA 或林格氏液治疗。在 5 或 8 天后，在视网膜平铺物上分析荧光金标记的 RGC 密度。还收获视网膜组织并处理以定量视网膜外植体中的轴突生长；评估半胱天冬酶-3 活性；分析转录因子 cAMP 反应元件结合蛋白（CREB）；并确定乙酰化组蛋白 3 和 4 以及磷酸化细胞外信号调节激酶（pERK）1/2。
结果
与林格氏液（分别为 62%和 37%存活的 RGC）相比，SC 中 VPA 治疗后第 5 和第 8 天，分别有 93%和 58%的 RGC 存活（P<0.001）。同样，损伤后立即玻璃体腔内注射 VPA 可显著延迟 RGC 凋亡（P=0.0016）。与接受林格氏液的损伤对照相比，用 VPA 处理的受损 RGC 在培养中显示出更好的轴突再生（每个外植体 196 个轴突）。用 VPA 治疗的右眼对照 RGC 轴突再生更多。VPA 介导的神经保护和神经再生伴随着 caspase-3 活性、CREB 诱导、pERK1/2 激活的降低，但组蛋白乙酰化没有改变。
结论
VPA 在 ONC 后提供神经保护和轴突再生。观察到了几个途径的改变；然而，VPA 介导保护的确切机制尚未完全清楚。
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