Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis.
Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis.
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DOI：
10.1016/j.expneurol.2009.08.028
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发表时间：
2009-11
影响因子：
5.3
通讯作者：
Kiaei, Mahmoud
中科院分区：
文献类型：
--
作者：
Neymotin, Arie;Petri, Susanne;Calingasan, Noel Y.;Wille, Elizabeth;Schafer, Peter;Stewart, Charles;Hensley, Kenneth;Beal, M. Flint;Kiaei, Mahmoud
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，目前无法治疗。炎症在ALS运动神经元死亡的发病机制中起主要作用。促炎细胞因子如肿瘤坏死因子-α（TNF-α）和Fas配体（FasL）是神经炎症的最重要介质。我们以前已经证明，这些促炎细胞因子的升高发生在ALS转基因小鼠和人ALS死后脊髓组织。来那度胺是一种有效的免疫调节剂，具有下调促炎细胞因子和上调抗炎细胞因子的能力。我们先前报道了在ALS的G93 A SOD 1转基因小鼠模型中，在疾病发作前2个月开始治疗时，来那度胺的神经保护作用。由于在ALS患者中，治疗只能在症状出现后开始，我们试图确定在G93 A SOD 1小鼠中症状发作时开始来那度胺给药的疗效。我们发现，来那度胺治疗使患者的生存期从发病年龄延长了18.3天（约45%）。此外，来那度胺治疗改善了旋转棒性能，减轻了体重减轻，并减弱了腰髓中的神经元细胞死亡。定性组织学分析显示，来那度胺治疗适度降低了促炎细胞因子Fas配体、IL-1β、TNF-α和CD 40配体的表达。对预先选择的细胞因子组的RNA保护测定（RPA）显示，促炎细胞因子减少，抗炎细胞因子上调。这些数据鼓励进一步临床评价来那度胺作为阻断或减缓人类ALS患者疾病进展的治疗策略。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which is currently untreatable. Inflammation plays a major role in the pathogenesis of motor neuron death in ALS. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and Fas ligand (FasL) are amongst the most important mediators of neuro-inflammation. We have previously demonstrated that elevation of these proinflammatory cytokines occurs in both ALS transgenic mice and in human ALS postmortem spinal cord tissues. Lenalidomide is a potent immunomodulatory agent, with the ability to down-regulate proinflammatory cytokines and up-regulate anti-inflammatory cytokines. We previously reported the neuroprotective effects of lenalidomide, when treatment was started 2 months prior to onset of disease in the G93A SOD1 transgenic mouse model of ALS. Since in ALS patients, treatment can only begin after the appearance of symptoms, we sought to determine the efficacy of lenalidomide administration starting at symptom onset in the G93A SOD1 mice. We found that lenalidomide treatment extended the survival interval from the age of onset by 18.3 days (~45%). Additionally, lenalidomide treatment improved rotarod performance, reduced weight loss, and attenuated neuronal cell death in the lumbar spinal cord. Qualitative histological analysis showed that lenalidomide treatment modestly reduced the expression of the proinflammatory cytokines Fas Ligand, IL-1β, TNF-α and CD40 ligand. RNA protection Assay (RPA) on a pre-selected panel of cytokines showed that proinflammatory cytokines were reduced and anti-inflammatory cytokines were up-regulated. These data encourage further clinical evaluation of lenalidomide as therapeutic strategy to block or slow disease progression in human ALS patients.
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影响因子：
25
作者：
Nagai, Makiko;Re, Diane B.;Przedborski, Serge
通讯作者：
Przedborski, Serge
影响因子：
78.5
作者：
Bartlett, JB;Dredge, K;Dalgleish, AG
通讯作者：
Dalgleish, AG
影响因子：
4.7
作者：
Kiaei, M;Kipiani, K;Beal, MF
通讯作者：
Beal, MF
影响因子：
64.8
作者：
ROSEN, DR;SIDDIQUE, T;BROWN, RH
通讯作者：
BROWN, RH
DOI：
10.1073/pnas.0603670103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Wu, Du-Chu;Berangere Re, Diane;Przedborski, Serge
通讯作者：
Przedborski, Serge