• Xuejing Hou, Shanshan Xiao, Xiaohong Xu, Mingze Qin, Xuebing Cheng, and Xiangping Xu.
• Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Department of Pediatrics, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
• Neuroscience. 2024 Jul 23; 551: 166176166-176.

AbstractEpilepsy is a progressive neurodegenerative disease highlighted by recurrent seizures, neuroinflammation, and the loss of neurons. Microglial dysfunction is commonly found in epileptic foci and contributes to neuroinflammation in the initiation and progression of epilepsy. Glycoprotein non-metastatic melanoma protein B (GPNMB), a transmembrane glycoprotein, has been involved in the microglial activation and neuroinflammation response. The present study investigated the functional significance of GPNMB in epilepsy. A proven model of epilepsy was established by intraperitoneal injection of pilocarpine to male Sprague Dawley rats. Lentivirus vectors carrying GPNMB or GPNMB short hairpin RNA (shGPNMB) were injected into the hippocampus to induce overexpression or knockdown of GPNMB. GPNMB expression was significantly upregulated and overexpression of GPNMB in the hippocampus reduced seizure activity and neuronal loss after status epilepticus (SE). We here focused on the effects of GPNMB deficiency on neuronal injury and microglia polarization 28 days after SE. GPNMB knockdown accelerated neuronal damage in the hippocampus, evidenced by increased neuron loss and neuronal cell apoptosis. Following GPNMB knockdown, M1 polarization (iNOS) and secretion of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α were increased, and M2 polarization (Arg1) and secretion of anti-inflammatory cytokines IL-4, IL-10, and TGF-β were decreased. BV2 cells were used to further confirm the regulatory role of GPNMB in modulating phenotypic transformations and inflammatory cytokine expressions in microglia. In conclusion, these results indicated that GPNMB suppressed epilepsy through repression of hippocampal neuroinflammation, suggesting that GPNMB might be considered the potential neurotherapeutic target for epilepsy management and play a protective role against epilepsy by modulating the polarization of microglia.Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.

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