Valproic Acid-Mediated Neuroprotection and Regeneration in Injured Retinal Ganglion Cells
Valproic Acid-Mediated Neuroprotection and Regeneration in Injured Retinal Ganglion Cells
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DOI：
10.1167/iovs.09-3903
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发表时间：
2010-01-01
影响因子：
4.4
通讯作者：
Lagreze, Wolf Alexander
中科院分区：
文献类型：
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作者：
Biermann, Julia;Grieshaber, Philippe;Lagreze, Wolf Alexander
目的.丙戊酸（VPA）已被证明在神经退行性疾病中具有神经保护作用。VPA抑制组蛋白去乙酰化酶（HDAC）并延迟变性神经元的凋亡。作者研究了VPA是否延迟视神经挤压（ONC）后视网膜神经节细胞（RGC）死亡并增强轴突再生。此外，还分析了VPA介导的保护作用的潜在分子靶点。对大鼠左眼进行ONC，大鼠皮下（SC; 300 mg/kg，每日两次）或玻璃体内（单次损伤后注射）接受VPA或林格氏溶液。荧光金标记的RGC的密度在5或8天后在视网膜平片中进行分析。视网膜组织也被收获和处理以定量视网膜外植体中轴突的生长;评估caspase-3活性;分析转录因子cAMP反应元件结合蛋白（CREB）;并测定乙酰化组蛋白3和4以及磷酸化细胞外信号调节激酶（pERK）1/2。ONC后5天和8天，与林格氏液（62%和37%活RGC）相比，皮下VPA治疗后RGC的存活率分别为93%和58%（P < 0.001）。同样，在损伤后立即单次玻璃体内注射VPA显著延迟了RGC的凋亡（P = 0.0016）。用VPA处理的受损RGC在培养物中显示出比接受林格氏液的压碎对照（115个轴突/外植体）更好的轴突再生（196个轴突/外植体）。VPA治疗后，右侧对照眼的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活性降低、CREB诱导、pERK 1/2激活，但不伴随组蛋白乙酰化改变。VPA提供ONC后的神经保护和轴突再生。在几种途径中观察到改变;然而，VPA介导的保护的确切机制尚未完全了解。（Invest Ophthalmol维斯科学。2010;51：526-534）DOI：10.1167/iovs.09-3903
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. (Invest Ophthalmol Vis Sci. 2010;51:526-534) DOI:10.1167/iovs.09-3903