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The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis.


  • 影响因子:3.21
  • DOI:10.1007/s00415-020-09993-z
  • 作者列表:"Lunetta C","Moglia C","Lizio A","Caponnetto C","Dubbioso R","Giannini F","Matà S","Mazzini L","Sabatelli M","Siciliano G","Simone IL","Sorarù G","Toriello A","Trojsi F","Vedovello M","D'Ovidio F","Filippi M","Calvo A","and EDARAVALS Study Group.
  • 发表时间:2020-06-17

OBJECTIVES:The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy. METHODS:We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers. Taking into account ALS patients with at least 12 months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches. RESULTS:A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study. No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses. The EVN treatment was overall well tolerated. CONCLUSIONS:The study showed that EVN treatment was well tolerated. No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function. These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease.


目的: 本研究的目的是分析接受依达拉奉 (EVN) 治疗的意大利患者的 ALS 疾病进展和呼吸功能,以及坚持,疗法。 方法: 我们对 2017 年 5 月至 2019 年 5 月在 39 个意大利 ALS 中心接受 EVN 治疗的患者进行了一项观察性研究。考虑到至少 12 个月 EVN 治疗的 ALS 患者,我们将 ALSFRS-R 和 FVC 的下降与来自合并资源开放存取 ALS 临床试验 (PRO-ACT) 数据库的一组匹配的历史对照进行了比较,同时使用描述性和生存分析方法。 结果: 本研究共招募了 331 例接受 EVN 治疗的意大利 ALS 患者和 290 例匹配的历史对照。在描述性和生存分析中比较两个队列,未发现疾病进展或呼吸功能有显著差异。EVN 治疗总体耐受性良好。 结论: 研究表明 EVN 治疗耐受性良好。在接受 EVN 治疗和未接受 EVN 治疗的 ALS 患者中,在疾病进展和呼吸功能方面均无显著差异。这些发现证明需要进一步的研究来更好地阐明 EVN 是否可以被认为是 ALS 疾病的有效治疗方法。



作者列表:["Aimé P","Karuppagounder SS","Rao A","Chen Y","Burke RE","Ratan RR","Greene LA"]

METHODS::Identifying disease-causing pathways and drugs that target them in Parkinson's disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.

翻译标题与摘要 下载文献
作者列表:["Sebastián-Serrano Á","Simón-García A","Belmonte-Alfaro A","Pose-Utrilla J","Santos-Galindo M","Del Puerto A","García-Guerra L","Hernández IH","Schiavo G","Campanero MR","Lucas JJ","Iglesias T"]

METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

翻译标题与摘要 下载文献
作者列表:["Mendes FR","Leclerc JL","Liu L","Kamat PK","Naziripour A","Hernandez D","Li C","Ahmad AS","Doré S"]

METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.