Institute of Basic Science and Experimental Medicine (ICBME), University Institute, Italian Hospital, Buenos Aires, Argentina; Leloir Institute Foundation, Institute for Biochemical Investigations of Buenos Aires, (IIBBA, CONICET), Buenos Aires, Argentina.
Leloir Institute Foundation, Institute for Biochemical Investigations of Buenos Aires, (IIBBA, CONICET), Buenos Aires, Argentina.
Brain Behav Immun. 2018 Mar;69:515-531. doi: 10.1016/j.bbi.2018.01.010. Epub 2018 Jan 31.
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of unknown aetiology that causes neurological disabilities in young adults. MS displays different clinical patterns, including recurrent episodes with remission periods ("relapsing-remitting MS" (RRMS)), which can progress over several years to a secondary progressive form (SPMS). However, 10% of patients display persistent progression at the onset of disease ("primary progressive MS" (PPMS)). Currently, no specific therapeutic agents are available for the progressive forms, mainly because the underlying pathogenic mechanisms are not clear and because no animal models have been specifically developed for these forms. The development of MS animal models is required to clarify the pathological mechanisms and to test novel therapeutic agents. In the present work, we overexpressed interleukin 1 beta (IL-1β) in the cortex to develop an animal model reflecting the main pathological hallmarks of MS. The treated animals presented with neuroinflammation, demyelination, glial activation, and neurodegeneration along with cognitive symptoms and MRI images consistent with MS pathology. We also demonstrated the presence of meningeal inflammation close to cortical lesions, with characteristics similar to those described in MS patients. Systemic pro-inflammatory stimulation caused a flare-up of the cortical lesions and behavioural symptoms, including impairment of working memory and the appearance of anxiety-like symptoms. Our work demonstrated induced cortical lesions, reflecting the main histopathological hallmarks and cognitive impairments characterizing the cortical pathology described in MS patients with progressive forms of the disease.
多发性硬化症（MS）是一种病因不明的炎症性脱髓鞘疾病，可导致年轻人出现神经功能障碍。MS 表现出不同的临床模式，包括有缓解期的复发发作（“复发缓解型多发性硬化症”（RRMS）），这些发作可在数年内进展为继发性进行性形式（SPMS）。然而，10%的患者在疾病发作时表现出持续进展（“原发性进行性多发性硬化症”（PPMS））。目前，尚无针对进行性形式的特定治疗药物，主要是因为潜在的发病机制尚不清楚，并且没有专门为这些形式开发的动物模型。需要开发 MS 动物模型来阐明病理机制并测试新的治疗药物。在本工作中，我们在大脑皮层中过表达白细胞介素 1β（IL-1β），以开发一种反映 MS 主要病理特征的动物模型。治疗后的动物表现出神经炎症、脱髓鞘、神经胶质细胞激活和神经退行性变，以及与 MS 病理学一致的认知症状和 MRI 图像。我们还证明了脑膜炎症与皮质病变接近，其特征与在 MS 患者中描述的特征相似。全身促炎刺激会导致皮质病变和行为症状加剧，包括工作记忆受损和出现焦虑样症状。我们的工作证明了诱导性皮质病变的存在，反映了 MS 患者具有进行性形式的疾病的皮质病变所描述的主要组织病理学特征和认知障碍。
