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

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.

RETRACTED ARTICLE: Lycium barbarum polysaccharide alleviates oxygen glucose deprivation-induced PC-12 cells damage by up-regulating miR-24

“…It is reported LBPs can induce cell autophagy to protect against peripheral neuropathy in streptozotocininduced diabetic rats [22]. Shi et al displayed LBPs enhanced cell viability in OGD-treated primary cultured cortical neurons [23]. In addition, Yu et al have detected the functions of LBPs in OGD/reperfusion-treated primary hippocampal neuron cells and the results revealed the pretreatment of LBPs obviously enhanced cell viability, reduced cell apoptosis, cell autophagy and ROS [24].…”

Bungeanum Improves Cognitive Dysfunction and Neurological Deficits in D-Galactose-Induced Aging Mice via Activating PI3K/Akt/Nrf2 Signaling Pathway

“…The stained slices were observed and photographed under an optical microscope for examining the pathological changes and comparing number of Nissl bodies in the hippocampus. The damage score of neurons was assessed accordance to the scoring criteria by Shi et al (2017). The Nissl body counts in hippocampus CA1 and the CA3 regions from each animal were calculated using ImageJ software (Liang et al, 2019).…”

Beneficial Effect of Intestinal Fermentation of Natural Polysaccharides

“…An increase in phospho-Drp1 and a decrease in Opa1 that negatively correlated with LBP dosage were observed [ 186 ]. In addition, according to Shi et al [ 187 ], Lycium barbarum polysaccharides protected against ischemic injury via modulating NR2B and NR2A signaling pathways.…”