Department of Neurology, Changhai Hospital Affiliated to the Second Military Medical University, Shanghai, China.
Neuroscience. 2013 Feb 12;231:272-81. doi: 10.1016/j.neuroscience.2012.11.050. Epub 2012 Dec 7.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitors administered prior to or immediately after experimental stroke confer acute neuroprotection. However, it remains unclear if delayed treatment with a PTEN inhibitor improves long-term functional recovery after stroke. We addressed the issue in this study. Adult male mice were subjected to 1h of middle cerebral artery occlusion (MCAO) followed by treatment with a well-established PTEN inhibitor BPV or saline daily for 14 days, starting at 24h after MCAO. Functional recovery was assessed with behavioral tests and acute infarct volumes were analyzed histologically. Delayed BPV treatment did not reduce infarction during the acute phase, but significantly improved long-term functional recovery after MCAO. Since PTEN is a critical intrinsic inhibitory factor in axonal regeneration, we further examined BPV effects on axonal densities following MCAO using bielschowsky silver staining and immunohistochemistry with antibodies against myelin basic protein. Delayed BPV treatment significantly increased axon densities in the ischemic brain at 14 days after MCAO. Moreover, PTEN expression persistently remained high in the ischemic brain over 14 days after MCAO, and BPV treatment increased post-ischemic activation of Akt and mTOR in the ischemic brain. Akt and mTOR activation are the well-established cascades downstream to PTEN inhibition and have been shown to contribute to post-injury axonal regrowth in response to PTEN inhibition. Consistently, in an in vitro neuronal ischemia model, BPV enhanced axonal outgrowth of primary cortical neurons after oxygen-glucose deprivation and the enhancing effects were abolished by Akt/mTOR inhibition. In conclusion, delayed BPV treatment improved functional recovery from experimental stroke possibly via enhancing axonal growth and Akt/mTOR activation contributed to BPV-enhanced post-stroke axon growth.
磷酸酶和张力蛋白同源物缺失于染色体 10（PTEN）抑制剂在实验性中风之前或之后立即给药可提供急性神经保护。然而，尚不清楚延迟给予 PTEN 抑制剂是否会改善中风后的长期功能恢复。我们在这项研究中解决了这个问题。成年雄性小鼠接受 1 小时大脑中动脉闭塞（MCAO）后，立即用一种成熟的 PTEN 抑制剂 BPV 或生理盐水治疗，每天一次，共 14 天，从 MCAO 后 24 小时开始。使用行为测试评估功能恢复，并用组织学分析急性梗死体积。延迟 BPV 治疗不会减少急性期的梗死，但显著改善 MCAO 后的长期功能恢复。由于 PTEN 是轴突再生的关键内在抑制因子，我们进一步使用 Bielschowsky 银染色和髓鞘碱性蛋白抗体的免疫组织化学检测，研究了 MCAO 后 BPV 对轴突密度的影响。延迟 BPV 治疗显著增加了 MCAO 后 14 天缺血性大脑中的轴突密度。此外，PTEN 表达在 MCAO 后 14 天内持续在缺血性大脑中保持较高水平，BPV 治疗增加了缺血性大脑中 Akt 和 mTOR 的缺血后激活。Akt 和 mTOR 的激活是 PTEN 抑制的下游的成熟级联，并且已经表明它们有助于对 PTEN 抑制的损伤后轴突再生。一致地，在体外神经元缺血模型中，BPV 增强了氧葡萄糖剥夺后原代皮质神经元的轴突生长，并且 Akt/mTOR 抑制消除了增强作用。总之，延迟 BPV 治疗改善了实验性中风的功能恢复，可能是通过增强轴突生长和 Akt/mTOR 激活，从而促进了 BPV 增强的中风后轴突生长。
