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.
Background Multiple sclerosis (MS) is a chronic disease in the central nervous system (CNS), characterized by inflammatory cells invade into the brain and the spinal cord. Among a bulk of different MS models, the rodent model of experimental autoimmune encephalomyelitis (EAE) is the most widely used and best understood. 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.Methods Female C57BL/6 mice were expressed by an ultra-sensitive protein calcium sensor GCamp6f in somatosensory cortex neurons through stereotaxic virus injection. Then we induced EAE model in mice with myelin oligodendrocyte glycoprotein (MOG) peptide (35-55) and used two-photon calcium imaging to chronically observe cortical activity in vivo throughout the disease progression. Besides, we performed whole-cell electrophysiological recording to determine the frequency of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) in cortical brain slices of preclinical EAE mice.ResultsHere we 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 were found at the remission stage. Arctigenin treatment not only restricted inordinate individually neural spiking, calcium influx and network activity at preclinical stage, but also restored neuronal activity and communication at remission stage. In addition, we confirmed that the frequency of AMPA receptor-sEPSC was also increased at preclinical stage and can be blunted by Arctigenin. Conclusions Our findings suggest that excitotoxicity resulted from calcium influx is involved in EAE at preclinical stage. Moreover, Arctigenin exerts neuroprotective effect by limiting hyperactivity at preclinical stage and ameliorates EAE symptoms, indicating Arctigenin could be a potential therapeutic drug for neuroprotection in MS-related neuropsychological disorders.
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