中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (11): 1950-1960.doi: 10.4103/1673-5374.259622

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

新型鞘氨醇-1受体调节剂BAF312改善局灶性自身免疫性脑炎的大脑皮质网络功能

  

  • 出版日期:2019-11-15 发布日期:2019-11-15
  • 基金资助:

    研究得到了瑞士巴塞尔诺华生物医学研究所（SGM）的支持

The next-generation sphingosine-1 receptor modulator BAF312 (siponimod) improves cortical network functionality in focal autoimmune encephalomyelitis

Petra Hundehege 1, Manuela Cerina 1 , Susann Eichler 1 , Christian Thomas 1 , Alexander M. Herrmann 1 , Kerstin Göbel 1 , Thomas Müntefering 1 , Juncal Fernandez-Orth 1 , Stefanie Bock 1 , Venu Narayanan 1 , Thomas Budde 2 , Erwin-Josef Speckmann 2 , Heinz Wiendl 1 , Anna Schubart 3 , Tobias Ruck 1 , Sven G. Meuth 1   

  1. 1 Department of Neurology with Institute of Translational Neurology, Westfälische Wilhelms-Universität, Münster, Germany
    2 Institute of Physiology I, Westfälische Wilhelms-Universität, Münster, Germany
    3 Novartis Institutes of Biomedical Research, Basel, Switzerland
  • Online:2019-11-15 Published:2019-11-15
  • Contact: Petra Hundehege, PhD, petra.hundehege@ukmuenster.de.
  • Supported by:

     This study was supported by the Novartis Institutes of Biomedical Research, Basel, Switzerland (to SGM).

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摘要：

BAF312 （siponimod）是一种新型鞘氨醇-1-磷酸受体调节剂，可延缓进展型多发性硬化的进展。除了通过隔离淋巴组织中的淋巴细胞减少炎症，BAF312还可穿过血脑屏障与其在神经元、星形胶质细胞和少突胶质细胞上的受体进行结合。为了评估BAF312潜在的直接神经保护作用，给予实验性自身免疫性脑脊髓炎小鼠灌胃或脑内局部给予BAF312。（1）离体流式细胞术显示系统BAF312给药，而不是局部给药降低脑灰质和白质病变小鼠免疫细胞浸润；（2）脑切片的体外电压敏感染料成像显示，电刺激白质纤维束使损伤大脑皮质的时空激活模式发生改变；（3）BAF312给药使脑皮质神经元回路功能部分恢复；（4）结果表明BAF312可穿过血脑屏障发挥神经保护作用，而并非依赖于其对免疫细胞的外周作用。

orcid: 0000-0001-9562-0285(Petra Hundehege)

关键词: 多发性硬化, 局灶性实验性自身免疫性脑脊髓炎, 皮质, 灰质, 白质, BAF312, 轴突损伤, 神经保护

Abstract:

Autoimmune diseases of the central nervous system (CNS) like multiple sclerosis (MS) are characterized by inflammation and demyelinated lesions in white and grey matter regions. While inflammation is present at all stages of MS, it is more pronounced in the relapsing forms of the disease, whereas progressive MS (PMS) shows significant neuroaxonal damage and grey and white matter atrophy. Hence, disease-modifying treatments beneficial in patients with relapsing MS have limited success in PMS. BAF312 (siponimod) is a novel sphingosine-1-phosphate receptor modulator shown to delay progression in PMS. Besides reducing inflammation by sequestering lymphocytes in lymphoid tissues, BAF312 crosses the blood-brain barrier and binds its receptors on neurons, astrocytes and oligodendrocytes. To evaluate potential direct neuroprotective effects, BAF312 was systemically or locally administered in the CNS of experimental autoimmune encephalomyelitis mice with distinct grey- and white-matter lesions (focal experimental autoimmune encephalomyelitis using an osmotic mini-pump). Ex-vivo flow cytometry revealed that systemic but not local BAF312 administration lowered immune cell infiltration in animals with both grey and white matter lesions. Ex-vivo voltage-sensitive dye imaging of acute brain slices revealed an altered spatio-temporal pattern of activation in the lesioned cortex compared to controls in response to electrical stimulation of incoming white-matter fiber tracts. Here, BAF312 administration showed partial restore of cortical neuronal circuit function. The data suggest that BAF312 exerts a neuroprotective effect after crossing the blood-brain barrier independently of peripheral effects on immune cells. Experiments were carried out in accordance with German and EU animal protection law and approved by local authorities (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen; 87-51.04.2010.A331) on December 28, 2010.

Key words: multiple sclerosis, focal experimental autoimmune encephalomyelitis, cortical grey matter, white matter, BAF312, neuroaxonal damage, neuroprotection