Arctigenin Exerts Neuroprotective Effect by Ameliorating Cortical Activities in Experimental Autoimmune Encephalomyelitis In Vivo.

Liangpeng Wei,Rongxin Zhang,Hui Shen,Yuanyuan Li,Ran Ding,Baihui Lan,Cunle Guo,Shiyang Yuan,Zhenyi Xue

doi:10.3389/fimmu.2021.691590

Abstract

Multiple sclerosis (MS) is a chronic disease in the central nervous system (CNS), characterized by inflammatory cells that invade into the brain and the spinal cord. Among a bulk of different MS models, the most widely used and best understood rodent model is experimental autoimmune encephalomyelitis (EAE). Arctigenin, a botanical extract from Arctium lappa, is reported to exhibit pharmacological properties, including anti-inflammation and neuroprotection. However, the effects of arctigenin on neural activity attacked by inflammation in MS are still unclear. Here, we use two-photon calcium imaging to observe the activity of somatosensory cortex neurons in awake EAE mice in vivo and found added hyperactive cells, calcium influx, network connectivity, and synchronization, mainly at preclinical stage of EAE model. Besides, more silent cells and decreased calcium influx and reduced network synchronization accompanied by a compensatory rise in functional connectivity are found at the remission stage. Arctigenin treatment not only restricts inordinate individually neural spiking, calcium influx, and network activity at preclinical stage but also restores neuronal activity and communication at remission stage. In addition, we confirm that the frequency of AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) is also increased at preclinical stage and can be blunted by arctigenin. These findings suggest that excitotoxicity characterized by calcium influx is involved in EAE at preclinical stage. What is more, arctigenin exerts neuroprotective effect by limiting hyperactivity at preclinical stage and ameliorates EAE symptoms, indicating that arctigenin could be a potential therapeutic drug for neuroprotection in MS-related neuropsychological disorders.

Highlights

Multiple sclerosis (MS) is a chronic disease in which inflammatory processes attack the central nervous system (CNS) characterized by widespread inflammation, demyelination, gliosis, and neuropsychological disorders, resulting a huge healthcare burden [1, 2]
With chronic real-time two-photon Ca2+ imaging in somatosensory cortex, we discovered engagement of cortical hyperactivity at preclinical stage of EAE, including increase in fraction of hyperactive cells, calcium influx into cells, cortical functional connectivity, and network synchronization
The amplitude of calcium transient in EAE mice was very low in remission stage, which means defective neuronal activity

Summary

Introduction

Multiple sclerosis (MS) is a chronic disease in which inflammatory processes attack the central nervous system (CNS) characterized by widespread inflammation, demyelination, gliosis, and neuropsychological disorders, resulting a huge healthcare burden [1, 2]. MS has been hallmarked by demyelinating lesions in the focal white matter till [3]. With more investigation of MS, it is clear that detectable pathological changes have occurred in normally appearing white matter, as well as in the CNS grey matter because of the presence of focal grey matter lesions and gray matter atrophy [4]. As the most widely used model in MS research, experimental autoimmune encephalomyelitis (EAE) is usually accompanied by perivascular infiltration of leukocytes, demyelination, and axonal damage in cerebral cortex and white matter [11]. It is reported that EAE leads cortical layer five neuron loss and atrophy of the whole cerebral cortex, which strongly correlates with axonal damage [13,14,15]. Neural apoptosis and abnormal activity are found in layer 2/3 cortex [11, 16]

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