Hermine Olivier, Gros Laurent, Tran Truong-An, Loussaief Lamya, Flosseau Kathleen, Moussy Alain, Mansfield Colin D, Vermersch Patrick
Imagine Institute, INSERM UMR 1163, University of Paris, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France.
Department of Hematology, Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
PLoS One. 2025 May 14;20(5):e0322199. doi: 10.1371/journal.pone.0322199. eCollection 2025.
Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the innate neuroimmune system. We have studied the neuroprotective action of masitinib on the manifestations of experimental autoimmune encephalitis (EAE) induced axonal and neuronal damage. EAE is a model of neuroimmune-driven chronic neuroinflammation and therefore highly relevant to masitinib's mechanism of action in neurodegenerative diseases. Importantly, neuronal damage, or prevention thereof, can be rapidly assessed by measuring serum neurofilament light chain (NfL) concentration in EAE-induced mice.
EAE induction was performed in healthy female C57BL/6 mice via active MOG 35-55 peptide immunization. Treatments were initiated 14 days post EAE induction. On day-0, 39 mice with established EAE symptoms were randomly assigned to 3 treatment groups (n = 13): EAE control, masitinib 50 mg/kg/day (M50), and masitinib 100 mg/kg/day (M100). The treatment started on day-1 and ended on day-15. Blood samples were collected on day-1 and day-8, via tail vein sampling, and on day-15, via intracardiac puncture. Assessments included quantification of serum NfL levels along the disease duration, cytokine quantification at day-15, and clinical assessments.
Masitinib treatment significantly (p < 0.0001) limited NfL production with respect to control; specifically, relative change in serum NfL concentration at day-8 was 43% and 60% lower for the M50 and M100 groups, respectively. Likewise, for the assessment of absolute serum NfL at day-8 and day-15, there was a significantly lower NfL concentration for masitinib treatment as compared with control. Furthermore, EAE mice treated with masitinib showed significantly lower concentrations of several well-established pro-inflammatory cytokines relative to control at day-15. A beneficial effect of masitinib on functional performance was also observed, with both M50 and M100 groups showing significantly less relative deterioration in grip strength at day-15 as compared with control (p < 0.001).
This study is the first demonstration that masitinib, a drug that targets the innate as opposed to the adaptive neuroimmune system, can lower serum NfL levels, and by extension therefore, neuronal damage, in a neuroimmune-driven neurodegenerative disease model. Overall, findings indicate that masitinib has a neuroprotective effect under conditions of chronic neuroinflammation and therefore plausible disease-modifying activity across a broad range of neurodegenerative diseases.
马西替尼是一种口服酪氨酸激酶抑制剂，作用于先天性神经免疫系统的活化细胞。我们研究了马西替尼对实验性自身免疫性脑脊髓炎（EAE）所致轴突和神经元损伤表现的神经保护作用。EAE是一种神经免疫驱动的慢性神经炎症模型，因此与马西替尼在神经退行性疾病中的作用机制高度相关。重要的是，通过测量EAE诱导小鼠的血清神经丝轻链（NfL）浓度，可以快速评估神经元损伤或其预防情况。
通过主动免疫MOG 35-55肽在健康雌性C57BL/6小鼠中诱导EAE。在EAE诱导后14天开始治疗。在第0天，将39只出现EAE症状的小鼠随机分为3个治疗组（n = 13）：EAE对照组、马西替尼50 mg/kg/天（M50）组和马西替尼100 mg/kg/天（M100）组。治疗从第1天开始，至第15天结束。在第1天和第8天通过尾静脉采血，在第15天通过心脏穿刺采集血样。评估包括疾病持续期间血清NfL水平的定量、第15天细胞因子的定量以及临床评估。
与对照组相比，马西替尼治疗显著（p < 0.0001）限制了NfL的产生；具体而言，M50组和M100组在第8天血清NfL浓度的相对变化分别降低了43%和60%。同样，在评估第8天和第15天的血清NfL绝对值时，与对照组相比，马西替尼治疗组的NfL浓度显著降低。此外，在第15天，用马西替尼治疗的EAE小鼠与对照组相比，几种公认的促炎细胞因子浓度显著降低。还观察到马西替尼对功能表现有有益作用，M50组和M100组在第15天的握力相对恶化程度均显著低于对照组（p < 0.001）。
本研究首次证明，与适应性神经免疫系统相反，作用于先天性神经免疫系统的药物马西替尼可降低神经免疫驱动的神经退行性疾病模型中的血清NfL水平，进而减少神经元损伤。总体而言，研究结果表明马西替尼在慢性神经炎症条件下具有神经保护作用，因此在广泛的神经退行性疾病中可能具有疾病修饰活性。
