PMID- 32892226 OWN - NLM STAT- MEDLINE DCOM- 20210602 LR - 20220119 IS - 1573-6903 (Electronic) IS - 0364-3190 (Linking) VI - 45 IP - 11 DP - 2020 Nov TI - Kukoamine A Protects against NMDA-Induced Neurotoxicity Accompanied with Down-Regulation of GluN2B-Containing NMDA Receptors and Phosphorylation of PI3K/Akt/GSK-3beta Signaling Pathway in Cultured Primary Cortical Neurons. PG - 2703-2711 LID - 10.1007/s11064-020-03114-y [doi] AB - 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 H(2)O(2)-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 muM 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-3beta 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-3beta signaling pathway. FAU - Yang, Yue AU - Yang Y AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. AD - Department of Pharmacy, General Hospital of Northern Military Area, 83 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. FAU - Gao, Lingyue AU - Gao L AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. FAU - Niu, Yixuan AU - Niu Y AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. FAU - Li, Xiang AU - Li X AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. AD - Department of Pharmacy, General Hospital of Northern Military Area, 83 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. FAU - Liu, Wenwu AU - Liu W AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. AD - Department of Pharmacy, General Hospital of Northern Military Area, 83 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. FAU - Jiang, Xiaowen AU - Jiang X AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. AD - Department of Pharmacy, General Hospital of Northern Military Area, 83 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. FAU - Liu, Yaqian AU - Liu Y AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. AD - Department of Pharmacy, General Hospital of Northern Military Area, 83 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. FAU - Zhao, Qingchun AU - Zhao Q AUID- ORCID: 0000-0001-9256-9971 AD - School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. zhaoqingchun1967@163.com. AD - Department of Pharmacy, General Hospital of Northern Military Area, 83 Wenhua Road, Shenyang, Liaoning, 110016, People's Republic of China. zhaoqingchun1967@163.com. LA - eng GR - 81673328/National Natural Science Foundation of China/ PT - Journal Article DEP - 20200905 PL - United States TA - Neurochem Res JT - Neurochemical research JID - 7613461 RN - 0 (NR2B NMDA receptor) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (kukoamine A) RN - 2FZ7Y3VOQX (Spermine) RN - 6384-92-5 (N-Methylaspartate) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Down-Regulation MH - Glycogen Synthase Kinase 3 beta/metabolism MH - N-Methylaspartate/*toxicity MH - Neurons/*drug effects MH - Neuroprotective Agents/*pharmacology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats, Sprague-Dawley MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Signal Transduction/*drug effects MH - Spermine/*analogs & derivatives/pharmacology OTO - NOTNLM OT - Apoptosis OT - GluN2B-containing NMDARs OT - Kukoamine A OT - NMDA OT - Neuroprotective effect OT - PI3K/Akt/GSK-3beta signaling pathway EDAT- 2020/09/07 06:00 MHDA- 2021/06/03 06:00 CRDT- 2020/09/06 20:36 PHST- 2020/04/06 00:00 [received] PHST- 2020/08/14 00:00 [accepted] PHST- 2020/08/07 00:00 [revised] PHST- 2020/09/07 06:00 [pubmed] PHST- 2021/06/03 06:00 [medline] PHST- 2020/09/06 20:36 [entrez] AID - 10.1007/s11064-020-03114-y [pii] AID - 10.1007/s11064-020-03114-y [doi] PST - ppublish SO - Neurochem Res. 2020 Nov;45(11):2703-2711. doi: 10.1007/s11064-020-03114-y. Epub 2020 Sep 5.