Treatment of Cerebral Ischemia Through NMDA Receptors: Metabotropic Signaling and Future Directions

Yuanyuan Li; Xiaokun Cheng; Xinying Liu; Le Wang; Jing Ha; Zibin Gao; Xiaoliang He; Zhuo Wu; Aibing Chen; Linda L Jewell; Yongjun Sun

doi:10.3389/fphar.2022.831181

Treatment of Cerebral Ischemia Through NMDA Receptors: Metabotropic Signaling and Future Directions

Front Pharmacol. 2022 Feb 21:13:831181. doi: 10.3389/fphar.2022.831181. eCollection 2022.

Authors

Yuanyuan Li¹, Xiaokun Cheng^{2

3

4

5}, Xinying Liu², Le Wang^{4

6}, Jing Ha^{1

7

8}, Zibin Gao^{1

7

8}, Xiaoliang He⁹, Zhuo Wu¹⁰, Aibing Chen¹¹, Linda L Jewell¹², Yongjun Sun^{1

7

8}

Affiliations

¹ Department of Pharmacy, Hebei University of Science and Technology, Shijiazhuang, China.
² Institute for the Development of Energy for African Sustainability, University of South Africa, Pretoria, South Africa.
³ Department of Chemical Engineering, University of South Africa, Florida, South Africa.
⁴ Department of Pharmaceutical Engineering, Hebei Chemical & Pharmaceutical College, Shijiazhuang, China.
⁵ New Drug Research & Development Co., Ltd., North China Pharmaceutical Group Corporation, Shijiazhuang, China.
⁶ Hebei Technological Innovation Center of Chiral Medicine, Shijiazhuang, China.
⁷ Hebei Research Center of Pharmaceutical and Chemical Engineering, Hebei University of Science and Technology, Shijiazhuang, China.
⁸ State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Shijiazhuang, China.
⁹ College of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang, China.
¹⁰ Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
¹¹ College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shanghai, China.
¹² Department of Chemical Engineering, University of South Africa, Pretoria, South Africa.

Abstract

Excessive activation of N-methyl-d-aspartic acid (NMDA) receptors after cerebral ischemia is a key cause of ischemic injury. For a long time, it was generally accepted that calcium influx is a necessary condition for ischemic injury mediated by NMDA receptors. However, recent studies have shown that NMDA receptor signaling, independent of ion flow, plays an important role in the regulation of ischemic brain injury. The purpose of this review is to better understand the roles of metabotropic NMDA receptor signaling in cerebral ischemia and to discuss the research and development directions of NMDA receptor antagonists against cerebral ischemia. This mini review provides a discussion on how metabotropic transduction is mediated by the NMDA receptor, related signaling molecules, and roles of metabotropic NMDA receptor signaling in cerebral ischemia. In view of the important roles of metabotropic signaling in cerebral ischemia, NMDA receptor antagonists, such as GluN2B-selective antagonists, which can effectively block both pro-death metabotropic and pro-death ionotropic signaling, may have better application prospects.

Keywords: NMDA receptor; NMDA receptor antagonists; cerebral ischemia; ion-flow independent; metabotropic signaling.

Publication types

Review