Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of medicine, Seoul, Republic of Korea.
J Neurol Sci. 2012 Sep 15;320(1-2):1-5. doi: 10.1016/j.jns.2012.05.038. Epub 2012 Jun 12.
Glycogen synthase kinase-3β (GSK-3β) activity plays a central role in motor neuron degeneration. We hypothesized that GSK-3β inhibitor would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS).
A total of 40 transgenic mice harboring the human G93A mutated SOD1 gene and 14 wild type mice were used following confirmation of their genotype. The 40 transgenic mice were divided into 2 groups; ALS transgenic mice_control and ALS transgenic mice_GSK-3β inhibitor treatment. The clinical status, rotarod test and survival of the transgenic ALS mice and wild-type mice were evaluated. Additionally, motor neuron counting, GSK-3β activity and extrinsic apoptotic signals in spinal cord were also investigated.
The treatment with GSK-3β inhibitor showed excellent motor ability and delay of the symptom onset and survival in the ALS transgenic mice. However, after clinical symptoms developed, the neuroprotective effect of GSK-3β inhibitor was not significant. And the biochemical results revealed the weakly increased extrinsic apoptotic signals in the ALS transgenic mice by GSK-3β inhibitor treatment.
The present study suggests that GSK-3β inhibitor would be a novel promising therapeutic strategy in ALS; however neuroprotective effect of GSK-3β inhibitor may be reduced via extrinsic apoptosis or non-neuronal patho-mechanism in late-stage of disease.
糖原合酶激酶-3β（GSK-3β）的活性在运动神经元变性中起着核心作用。我们假设 GSK-3β 抑制剂将延长运动神经元的存活并抑制肌萎缩侧索硬化症（ALS）的疾病进展。
共使用了 40 只携带人类 G93A 突变 SOD1 基因的转基因小鼠和 14 只野生型小鼠，在确认其基因型后进行了研究。将 40 只转基因小鼠分为 2 组；ALS 转基因小鼠对照组和 ALS 转基因小鼠 GSK-3β 抑制剂治疗组。评估了转基因 ALS 小鼠和野生型小鼠的临床状况、转棒试验和生存情况。此外，还研究了脊髓中运动神经元计数、GSK-3β 活性和外在凋亡信号。
GSK-3β 抑制剂的治疗显示出优异的运动能力，并且延迟了 ALS 转基因小鼠的症状发作和存活时间。然而，在出现临床症状后，GSK-3β 抑制剂的神经保护作用并不显著。生化结果表明，GSK-3β 抑制剂治疗后 ALS 转基因小鼠中外在凋亡信号略有增加。
本研究表明 GSK-3β 抑制剂可能是 ALS 的一种有前途的新型治疗策略；然而，GSK-3β 抑制剂的神经保护作用可能通过疾病晚期的外在凋亡或非神经元病理机制而降低。
