College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, 250014, Jinan, Shandong Province, China.
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510405, Guangdong Province, China.
Neurosci Lett. 2019 Apr 23;699:177-183. doi: 10.1016/j.neulet.2019.02.016. Epub 2019 Feb 10.
Axon regeneration after cerebral ischemia in mammals is inadequate to restore function, illustrating the need to design better strategies for improving outcomes. Improvement of axon regeneration has been achieved through fastigial nucleus electrostimulation (FNS) in animal researches. However, the mechanisms underlying this neuroprotection remain poorly understood. Increasing the levels of the second messenger cyclic AMP (cAMP) enhances axon regeneration, making it an excellent candidate molecule that has therapeutic potential. In the present study, we examined the expression of cAMP signaling in ischemic brain tissues following focal cerebral ischemia. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). A dipolar electrode was placed into the cerebellum to stimulate the cerebellar fastigial nucleus for 1 h after ischemia. Neurological deficits and the expressions of cAMP, PKA (protein kinase A) and ROCK (Rho-kinase) were determined. Axonal regeneration was measured by upregulation of growth-associated protein 43 (GAP43). The data indicated that FNS significantly enhanced axonal regeneration and motor function recovery after cerebral ischemia. FNS also significantly increased cAMP and PKA levels after ischemic brain injury. All the beneficial effects of FNS were blocked by Rp-cAMP, an antagonist of PKA. Our research suggested that the axonal regeneration conferred by FNS was likely achieved via the regulation of cAMP/PKA pathway.
哺乳动物脑缺血后的轴突再生不足以恢复功能,这表明需要设计更好的策略来改善预后。在动物研究中,通过小脑顶核电刺激(FNS)可以实现轴突再生的改善。然而,这种神经保护的机制仍知之甚少。增加第二信使环腺苷酸(cAMP)的水平可以增强轴突再生,使其成为具有治疗潜力的理想候选分子。在本研究中,我们研究了局灶性脑缺血后缺血脑组织中 cAMP 信号的表达。成年大鼠通过大脑中动脉闭塞(MCAO)诱导缺血。在缺血后将双极电极放置到小脑以刺激小脑顶核 1 小时。测定 cAMP、PKA(蛋白激酶 A)和 ROCK(Rho-激酶)的表达以及神经功能缺损。通过上调生长相关蛋白 43(GAP43)来测量轴突再生。数据表明,FNS 可显著促进脑缺血后轴突再生和运动功能恢复。FNS 还可显著增加缺血性脑损伤后的 cAMP 和 PKA 水平。PKA 的拮抗剂 Rp-cAMP 阻断了 FNS 的所有有益作用。我们的研究表明,FNS 诱导的轴突再生可能是通过调节 cAMP/PKA 通路实现的。