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Front Cell Neurosci. 2017 Sep 27;11:288. doi: 10.3389/fncel.2017.00288. eCollection 2017.

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

Shi Z1,2,3,4, Zhu L1,2,3,4, Li T1, Tang X1, Xiang Y1, Han X1, Xia L1, Zeng L1, Nie J1, Huang Y1,5, Tsang CK6, Wang Y7, Lei Z8, Xu Z8, So KF1,2,4,5, Ruan Y1,2,3,4.

Author information

1
GHM Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou, China.
2
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
3
Department of Anatomy, Jinan University School of Medicine, Guangzhou, China.
4
Ministry of Education CNS Regeneration International Collaborative Laboratory, Jinan University, Guangzhou, China.
5
Department of Ophthalmology and State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
6
Clinical Neuroscience Institute, The First Affiliated Hospital, Jinan University, Guangzhou, China.
7
Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China.
8
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States.

Abstract

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 Lycium barbarum polysaccharide (LBP) is a mixed compound extracted from Lycium barbarum 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 in vivo study, we found LBP substantially reduced CA1 neurons from death after transient global ischemia and ameliorated memory deficit in ischemic rats. By in vitro 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.

KEYWORDS:

Lycium barbarum polysaccharides; NR2A; NR2B; apoptosis; excitotoxicity; ischemia

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