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Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system.

ABSTRACT: Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKC?. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ER?, ER?, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models.

SUBMITTER: Gonzalez GA

PROVIDER: S-EPMC4995517 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system.

Gonzalez Ginez A GA Hofer Matthias P MP Syed Yasir A YA Amaral Ana I AI Rundle Jon J Rahman Saifur S Zhao Chao C Kotter Mark R N MRN

Scientific reports 20160824

Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation bl ...[more]

PMID: 27554391

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Project description:Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases.

Project description:ObjectiveTo track the clinical outcomes in patients who initially presented with tumefactive demyelinating lesions (TDLs), we summarized the clinical characteristics of various etiologies, and identified possible relapse risk factors for TDLs.MethodsBetween 2001 and 2021, 116 patients initially presented with TDLs in our hospital were retrospectively evaluated. Patients were followed for relapse and clinical outcomes, and grouped according to various etiologies. Demographic information, clinical data, imaging data, and laboratory results of patients were obtained and analyzed. The risk factors of relapse were analyzed by the Log-Rank test and the Cox proportional hazard model in multivariate analysis.ResultDuring a median follow-up period of 72 months, 33 patients were diagnosed with multiple sclerosis (MS), 6 patients with Balo, 6 patients with neuromyelitis optica spectrum disorders (NMOSD), 10 patients with myelin oligodendrocyte glycoprotein antibody-associated demyelination (MOGAD), 1 patient with acute disseminated encephalomyelitis (ADEM), and the remaining 60 patients still have no clear etiology. These individuals with an unknown etiology were categorized independently and placed to the other etiology group. In the other etiology group, 13 patients had recurrent demyelinating phases, while 47 patients did not suffer any more clinical events. Approximately 46.6% of TDLs had relapses which were associated with multiple functional system involvement, first-phase Expanded Disability Status Scale score, lesions morphology, number of lesions, and lesions location (P<0.05). And diffuse infiltrative lesions (P=0.003, HR=6.045, 95%CI:1.860-19.652), multiple lesions (P=0.001, HR=3.262, 95%CI:1.654-6.435) and infratentorial involvement (P=0.006, HR=2.289, 95%CI:1.064-3.853) may be independent risk factors for recurrence. Relapse free survival was assessed to be 36 months.ConclusionsIn clinical practice, around 46.6% of TDLs relapsed, with the MS group showing the highest recurrence rate, and lesions location, diffuse infiltrative lesions, and multiple lesions might be independent risk factors for relapse. Nevertheless, despite extensive diagnostic work and long-term follow-up, the etiology of TDLs in some patients was still unclear. And these patients tend to have monophase course and a low rate of relapse.

Dataset Information

Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system.

Publications

Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system.

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