MCC950 Reduces Neuronal Apoptosis in Spinal Cord Injury in Mice

Title:MCC950 Reduces Neuronal Apoptosis in Spinal Cord Injury in Mice

Volume: 20 Issue: 3

Author(s): Ning He, Xiaohe Zheng, Teng He, Gerong Shen, Kunyu Wang, Jue Hu, Mingzhi Zheng, Yueming Ding, Xinghui Song, Jinjie Zhong, Ying-Yung Chen, Lin-Lin Wang*Shen Yueliang*

Affiliation:

• Department of Basic Medicine Sciences and Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China

• Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China

Keywords: NLRP3, inflammasome, MCC950, apoptosis, Spinal Cord Injury (SCI), Oxygen-Glucose Deprivation (OGD).

Abstract:

Background: Traumatic Spinal Cord Injury (SCI) is a severe condition usually accompanied by an inflammatory process that gives rise to uncontrolled local apoptosis and a subsequent unfavorable prognosis. One reason for this unfavorable outcome could be the activation of the NLRP3 inflammasome.

Objective: MCC950 is a specific inhibitor of NLRP3 that further inhibits the formation of the NLRP3 inflammasome. The purpose of this study was to determine whether the NLRP3 inflammasome was associated with the severity of local apoptosis and whether MCC950 could prevent neuronal apoptosis following SCI.

Methods: In this study, primary cortical neurons were cultured in vitro. With or without pretreatment/ posttreatment with MCC950, neurons were subjected to Oxygen-Glucose Deprivation (OGD) for 2 h and then reperfusion for 20 h. Immunofluorescence was used to determine the expression of NLRP3, ASC, and cleaved caspase-1 in neurons. In vivo, SCI model mice were established with a 5 g weight-drop method. MCC950 was intraperitoneally injected at 0, 2, 4, 6, 8, 10, and 12 days after SCI. Basso Mouse Scale (BMS) scores and footprint assays were used to assess motor function. Paw withdrawal threshold and tail-flick latency were used to assess somatosensory function. H&E, Nissl, and TUNEL staining were used to measure histological changes and apoptosis at 3 days after SCI, and scar formation was observed by Masson staining and GFAP immunohistochemical analysis at 28 days after SCI.

Results: Immunofluorescence analysis confirmed that MCC950 inhibited OGD-induced activation of the NLRP3 inflammasome in neurons. Behavioral tests, Masson staining, and GFAP immunohistochemical analysis showed that MCC950-treated mice had improved neuronal functional recovery and reduced scar formation at 28 days after SCI. H&E, Nissl, and TUNEL staining confirmed that there were more living neurons and fewer apoptotic neurons in MCC950-treated mice than control mice at 3 days after SCI.

Conclusion: These results reveal that MCC950 exerts neuroprotective effects by reducing neuronal apoptosis, preserving the survival of the remaining neurons, attenuating the severity of the damage, and promoting the recovery of motor function after SCI.

Cite this article as:

He Ning , Zheng Xiaohe , He Teng , Shen Gerong , Wang Kunyu , Hu Jue, Zheng Mingzhi , Ding Yueming , Song Xinghui , Zhong Jinjie , Chen Ying-Yung, Wang Lin-Lin *, Yueliang Shen*, MCC950 Reduces Neuronal Apoptosis in Spinal Cord Injury in Mice, CNS & Neurological Disorders - Drug Targets 2021; 20 (3) . https://dx.doi.org/10.2174/1871527319666201005170659