Kukoamine A Protects against NMDA-Induced Neurotoxicity Accompanied with Down-Regulation of GluN2B-Containing NMDA Recep
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ORIGINAL PAPER
Kukoamine A Protects against NMDA‑Induced Neurotoxicity Accompanied with Down‑Regulation of GluN2B‑Containing NMDA Receptors and Phosphorylation of PI3K/Akt/GSK‑3β Signaling Pathway in Cultured Primary Cortical Neurons Yue Yang1,2 · Lingyue Gao1 · Yixuan Niu1 · Xiang Li1,2 · Wenwu Liu1,2 · Xiaowen Jiang1,2 · Yaqian Liu1,2 · Qingchun Zhao1,2 Received: 6 April 2020 / Revised: 7 August 2020 / Accepted: 14 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Kukoamine (KuA) is a spermine alkaloid present in traditional Chinese medicine Cortex Lycii radices, which possesses various pharmacological properties. Our previous studies have demonstrated that KuA exerts neuroprotective effects against H2O2-induced oxidative stress, radiation-induced neuroinflammation, oxidative stress and neuronal apoptosis, as well as neurotoxin-induced Parkinson’s disease through apoptosis inhibition and autophagy enhancement. The present study aimed to investigate the neuroprotective effects of KuA against NMDA-induced neuronal injury in cultured primary cortical neurons and explore the underlying mechanism. Incubation with 200 μM NMDA for 30 min induced excitotoxicity in primary cultured cortical neurons. The results demonstrated that pretreatment with KuA attenuated NMDA induced cell injury, LDH leakage and neuronal apoptosis. KuA also regulated apoptosis-related proteins. Thus, incubation with the alkaloid decreased the ratio of Bax/Bcl-2, and inhibited the release of cytochrome C, the expression of p53 and the cleavage of caspase-3. Moreover, KuA prevented the upregulation of GluN2B-containing NMDA receptors (NMDAR). Additionally, pretreatment with KuA reversed NMDA-induced dephosphorylation of Akt and GSK-3β and the protective effect of KuA on NMDA-induced cytotoxicity was abolished by wortmannin, a PI3K inhibitor. Taken together, these results indicated that KuA exerted neuroprotective effects against NMDA-induced neurotoxicity in cultural primary cortical neurons and caused the down-regulation of GluN2B-containing NMDARs as well as the phosphorylation of proteins belonging to the PI3K/ Akt/GSK-3β signaling pathway. Keywords Kukoamine A · NMDA · Neuroprotective effect · GluN2B-containing NMDARs · Apoptosis · PI3K/Akt/ GSK-3β signaling pathway Abbreviations KuA Kukoamine A NMDA N-methyl-Daspartate NMDARs NMDA receptors GSK-3β Glycogen synthase kinase-3β
* Qingchun Zhao [email protected] 1
School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People’s Republic of China
Department of Pharmacy, General Hospital of Northern Military Area, 83 Wenhua Road, Shenyang, Liaoning 110016, People’s Republic of China
2
Introduction Glutamate, as an excitatory neurotransmitter, plays essential roles in synaptic transmission, brain development and memory formation [1–3]. However, excessive extracellular glutamate could cause excitotoxicity, which plays a key role in the pathophysiology of stroke, trauma
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