Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, Philadelphia, PA 19140, United States of America; Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, Philadelphia, PA 19140, United States of America.
Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, Philadelphia, PA 19140, United States of America.
Exp Neurol. 2022 Mar;349:113961. doi: 10.1016/j.expneurol.2021.113961. Epub 2021 Dec 23.
Increasing the intrinsic growth potential of neurons after injury has repeatedly been shown to promote some level of axonal regeneration in rodent models. One of the most studied pathways involves the activation of the PI3K/AKT/mTOR pathways, primarily by reducing the levels of PTEN, a negative regulator of PI3K. Likewise, activation of signal transducer and activator of transcription 3 (STAT3) has previously been shown to boost axonal regeneration and sprouting within the injured nervous system. Here, we examined the regeneration of the corticospinal tract (CST) after cortical expression of constitutively active (ca) Akt3 and STAT3, both separately and in combination. Overexpression of caAkt3 induced regeneration of CST axons past the injury site independent of caSTAT3 overexpression. STAT3 demonstrated improved axon sprouting compared to controls and contributed to a synergistic improvement in effects when combined with Akt3 but failed to promote axonal regeneration as an individual therapy. Despite showing impressive axonal regeneration, animals expressing Akt3 failed to show any functional improvement and deteriorated with time. During this period, we observed progressive Akt3 dose-dependent increase in behavioral seizures. Histology revealed increased phosphorylation of ribosomal S6 protein within the unilateral cortex, increased neuronal size, microglia activation and hemispheric enlargement (hemimegalencephaly).
在损伤后提高神经元的内在生长潜力已被反复证明可以促进啮齿动物模型中某些程度的轴突再生。最受研究的途径之一涉及 PI3K/AKT/mTOR 途径的激活，主要是通过降低 PI3K 的负调节剂 PTEN 的水平来实现。同样，先前已经表明激活信号转导子和转录激活子 3 (STAT3) 可以促进损伤神经系统内的轴突再生和发芽。在这里，我们研究了皮质表达组成型激活 (ca) Akt3 和 STAT3 后皮质脊髓束 (CST) 的再生，分别单独和联合表达。caAkt3 的过表达诱导 CST 轴突在损伤部位以外的再生，而不依赖于 caSTAT3 的过表达。STAT3 显示出与对照相比，轴突发芽得到改善，并与 Akt3 结合时协同改善，但作为单独治疗未能促进轴突再生。尽管表现出令人印象深刻的轴突再生，但表达 Akt3 的动物没有显示出任何功能改善，并且随着时间的推移而恶化。在此期间，我们观察到 Akt3 的剂量依赖性行为性癫痫发作逐渐增加。组织学显示单侧皮质中核糖体 S6 蛋白的磷酸化增加，神经元大小增加，小胶质细胞激活和半球增大（半球肥大）。
