Takata M, Tanaka H, Kimura M, Nagahara Y, Tanaka K, Kawasaki K, Seto M, Tsuruma K, Shimazawa M, Hara H
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Br J Pharmacol. 2013 Sep;170(2):341-51. doi: 10.1111/bph.12277.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no effective treatment. Fasudil hydrochloride (fasudil), a potent rho kinase (ROCK) inhibitor, is useful for the treatment of ischaemic diseases. In previous reports, fasudil improved pathology in mouse models of Alzheimer's disease and spinal muscular atrophy, but there is no evidence in that it can affect ALS. We therefore investigated its effects on experimental models of ALS.
In mice motor neuron (NSC34) cells, the neuroprotective effect of hydroxyfasudil (M3), an active metabolite of fasudil, and its mechanism were evaluated. Moreover, the effects of fasudil, 30 and 100 mg·kg(-1), administered via drinking water to mutant superoxide dismutase 1 (SOD1(G93A)) mice were tested by measuring motor performance, survival time and histological changes, and its mechanism investigated.
M3 prevented motor neuron cell death induced by SOD1(G93A). Furthermore, M3 suppressed both the increase in ROCK activity and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and the reduction in phosphorylated Akt induced by SOD1(G93A). These effects of M3 were attenuated by treatment with a PI3K inhibitor (LY294002). Moreover, fasudil slowed disease progression, increased survival time and reduced motor neuron loss, in SOD1(G93A) mice. Fasudil also attenuated the increase in ROCK activity and PTEN, and the reduction in Akt in SOD1(G93A) mice.
These findings indicate that fasudil may be effective at suppressing motor neuron degeneration and symptom progression in ALS. Hence, fasudil may have potential as a therapeutic agent for ALS treatment.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，目前尚无有效治疗方法。盐酸法舒地尔（法舒地尔）是一种有效的Rho激酶（ROCK）抑制剂，可用于治疗缺血性疾病。在先前的报道中，法舒地尔改善了阿尔茨海默病和脊髓性肌萎缩症小鼠模型的病理状况，但尚无证据表明其对ALS有影响。因此，我们研究了其对ALS实验模型的作用。
在小鼠运动神经元（NSC34）细胞中，评估法舒地尔的活性代谢产物羟基法舒地尔（M3）的神经保护作用及其机制。此外，通过测量运动性能、存活时间和组织学变化，测试了经饮用水给予突变型超氧化物歧化酶1（SOD1(G93A)）小鼠30和100mg·kg(-1)法舒地尔的效果，并研究其机制。
M3可预防SOD1(G93A)诱导的运动神经元细胞死亡。此外，M3可抑制ROCK活性增加以及10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）的磷酸化，以及SOD1(G93A)诱导的磷酸化Akt的减少。用PI3K抑制剂（LY294002）处理可减弱M3的这些作用。此外，法舒地尔可减缓SOD1(G93A)小鼠的疾病进展，延长存活时间并减少运动神经元损失。法舒地尔还可减弱SOD1(G93A)小鼠中ROCK活性和PTEN的增加以及Akt的减少。
这些发现表明，法舒地尔可能有效抑制ALS中的运动神经元变性和症状进展。因此，法舒地尔可能具有作为ALS治疗药物的潜力。
