Neuroprotective Mechanisms of Lycium barbarum Polysaccharides Against Ischemic Insults by Regulating NR2B and NR2A Containing NMDA Receptor Signaling Pathways

• Published in: Frontiers in cellular neuroscience Vol. 11; p. 288
• Main Authors: Shi, Zhongshan, Zhu, Lihui, Li, Tingting, Tang, Xiaoya, Xiang, Yonghui, Han, Xinjia, Xia, Luoxing, Zeng, Ling, Nie, Junhua, Huang, Yongxia, Tsang, Chi Kwan, Wang, Ying, Lei, Zhigang, Xu, Zaocheng, So, Kwok-Fai, Ruan, Yiwen
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 27.09.2017; Frontiers Media S.A
• Subjects: Apoptosis; Calcium (mitochondrial); Calcium influx; Calcium permeability; Caspase; Caspase-3; Cell survival; Clinical trials; Cytochrome c; Excitotoxicity; Glucose; Glutamic acid receptors (ionotropic); Ischemia; Kinases; Laboratory animals; Lycium barbarum; Lycium barbarum polysaccharides; Medical research; Medicine; Mitochondria; N-Methyl-D-aspartic acid receptors; Neuroprotection; Neuroscience; NR2A; NR2B; Peptides; Phosphorylation; Physiology; Polysaccharides; Reactive oxygen species; Signal transduction; Stroke; China; NR2B; Lycium barbarum polysaccharides; apoptosis; excitotoxicity; NR2A; ischemia
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2017.00288

Glutamate excitotoxicity plays an important role in neuronal death after ischemia. However, all clinical trials using glutamate receptor inhibitors have failed. This may be related to the evidence that activation of different subunit of NMDA receptor will induce different effects. Many studies have shown that activation of the intrasynaptic NR2A subunit will stimulate survival signaling pathways, whereas upregulation of extrasynaptic NR2B will trigger apoptotic pathways. A polysaccharide (LBP) is a mixed compound extracted from fruit. Recent studies have shown that LBP protects neurons against ischemic injury by anti-oxidative effects. Here we first reported that the effect of LBP against ischemic injury can be achieved by regulating NR2B and NR2A signaling pathways. By study, we found LBP substantially reduced CA1 neurons from death after transient global ischemia and ameliorated memory deficit in ischemic rats. By study, we further confirmed that LBP increased the viability of primary cultured cortical neurons when exposed to oxygen-glucose deprivation (OGD) for 4 h. Importantly, we found that LBP antagonized increase in expression of major proteins in the NR2B signal pathway including NR2B, nNOS, Bcl-2-associated death promoter (BAD), cytochrome C (cytC) and cleaved caspase-3, and also reduced ROS level, calcium influx and mitochondrial permeability after 4 h OGD. In addition, LBP prevented the downregulation in the expression of NR2A, pAkt and pCREB, which are important cell survival pathway components. Furthermore, LBP attenuated the effects of a NR2B co-agonist and NR2A inhibitor on cell mortality under OGD conditions. Taken together, our results demonstrated that LBP is neuroprotective against ischemic injury by its dual roles in activation of NR2A and inhibition of NR2B signaling pathways, which suggests that LBP may be a superior therapeutic candidate for targeting glutamate excitotoxicity for the treatment of ischemic stroke.