Protection of spinal cord ischemia-reperfusion injury mediated by N-methyl-D-aspartate receptors_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

 CHEN Hong , CHEN Suwei , WANG Shengyu , LI Yan , MENG Xu

Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, P.R.China;

Corresponding author：

CHEN Hong, Email: chenhongmd@qq.com

Keywords：

Spinal cord ischemia-reperfusion; K-1024; glutamate; neuronal nitric oxide synthase (nNOS); N-methyl-D-aspartate (NMDA) receptor

DOI：

10.7507/1007-4848.202002084

Video：

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Objective To analyze the protective mechanism of spinal cord ischemia-reperfusion injury mediated by N-methyl-D-aspartate (NMDA) receptor.Methods A total of 42 SD rats were randomly assigned to 4 groups: a non-blocking group (n=6), a saline group (n=12), a NMDA receptor blocker K-1024 (25 mg/kg) group (n=12) and a voltage-gated Ca²⁺ channel blocker nimodipine (0.5 mg/kg) group (n=12). The medications were injected intraperitoneally 30 min before ischemia. The neural function was evaluated. The neuronal histologic change of spinal cord lumbar region, the release of neurotransmitter amino acids and expression of spinal cord neuronal nitric oxide synthase (nNOS) were compared.Results At 8 h after reperfusion, the behavioral score of the K-1024 group was 2.00±0.00 points, which was statistically different from those of the saline group (5.83±0.41 points) and the nimodipine group (5.00±1.00 points, P<0.05). Compared with the saline group and nimodipine group, K-1024 group had more normal motor neurons (P<0.05). There was no significant difference in glutamic acid concentration in each group at 10 min after ischemia (P=0.731). The nNOS protein expression in the K-1024 group was significantly down-regulated compared with the saline group (P<0.01). After 8 h of reperfusion, the expression of nNOS protein in the K-1024 group was significantly up-regulated compared with the saline group (P<0.05).Conclusion K-1024 plays a protective role in spinal cord ischemia by inhibiting NMDA receptor and down-regulating nNOS protein expression; during the reperfusion, K-1024 has a satisfactory protective effect on spinal cord function, structure and biological activity of nerve cells.

Citation： CHEN Hong, CHEN Suwei, WANG Shengyu, LI Yan, MENG Xu. Protection of spinal cord ischemia-reperfusion injury mediated by N-methyl-D-aspartate receptors. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2020, 27(12): 1460-1465. doi: 10.7507/1007-4848.202002084 Copy

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3.	Sundström E, Mo LL. Polyamine and redox modulation of [3H]MK-801 binding to N-methyl-D-aspartate receptors in the spinal cord and cerebral cortex. Pharmacol Toxicol, 2001, 88(6): 342-348.
4.	Jayakumar J, Suzuki K, Sammut IA, et al. Heat shock protein 70 gene transfection protects mitochondrial and ventricular function against ischemia-reperfusion injury. Circulation, 2001, 104(12 Suppl 1): I303-I307.
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6.	Meldrum KK, Meldrum DR, Sezen SF, et al. Heat shock prevents simulated ischemia-induced apoptosis in renal tubular cells via a PKC-dependent mechanism. Am J Physiol Regul Integr Comp Physiol, 2001, 281(1): R359-R364.
7.	Liao WY, Tsai TH, Ho TY, et al. Neuroprotective effect of paeonol mediates anti-inflammation via suppressing toll-like receptor 2 and toll-like receptor 4 signaling pathways in cerebral ischemia-reperfusion injured rats. Evid Based Complement Alternat Med, 2016, 2016: 3704647.
8.	Tang N, Wu J, Zhu H, et al. Genetic mutation of GluN2B protects brain cells against stroke damages. Mol Neurobiol, 2018, 55(4): 2979-2990.
9.	Wu QJ, Tymianski M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain, 2018, 11(1): 15.
10.	Li XY, Liang J, Tang YB, et al. Ginsenoside Rd prevents glutamate-induced apoptosis in rat cortical neurons. Clin Exp Pharmacol Physiol, 2010, 37(2): 199-204.
11.	de Miranda AS, Brant F, Vieira LB, et al. A neuroprotective effect of the glutamate receptor antagonist MK801 on long-term cognitive and behavioral outcomes secondary to experimental cerebral malaria. Mol Neurobiol, 2017, 54(9): 7063-7082.
12.	Bovill JG. Anesthetic pharmacology: reflections of a section editor. Anesth Analg, 2007, 105(5): 1186-1190.
13.	Himmelseher S, Durieux ME. Revising a dogma: ketamine for patients with neurological injury? Anesth Analg, 2005, 101(2): 524-534.
14.	Proescholdt M, Heimann A, Kempski O. Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res, 2001, 904(2): 245-251.
15.	Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science, 1993, 262(5134): 689-695.
16.	梅和珊, 王永利. 脑缺血时谷氨酸释放机制. 中国药理学通报, 2005, 21(4): 393-396.
17.	Grewer C, Gameiro A, Zhang Z, et al. Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life, 2008, 60(9): 609-619.
18.	Zimmer ER, Torrez VR, Kalinine E, et al. Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype. Front Cell Neurosci, 2015, 9: 219.
19.	Ramdial K, Franco MC, Estevez AG. Cellular mechanisms of peroxynitrite-induced neuronal death. Brain Res Bull, 2017, 133: 4-11.
20.	Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimers Dis, 2017, 57(4): 1041-1048.

1. Dijkstra ML, Vainas T, Zeebregts CJ, et al. Editor's choice - spinal cord ischemia in endovascular thoracic and thoraco-abdominal aortic repair: review of preventive strategies. Eur J Vasc Endovasc Surg, 2018, 55(6): 829-841.
2. Riambau V, Bockler D, Brunkwall J, et al. Editor's choice - management of descending thoracic aorta diseases: clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg, 2017, 53(1): 4-52.
3. Sundström E, Mo LL. Polyamine and redox modulation of [3H]MK-801 binding to N-methyl-D-aspartate receptors in the spinal cord and cerebral cortex. Pharmacol Toxicol, 2001, 88(6): 342-348.
4. Jayakumar J, Suzuki K, Sammut IA, et al. Heat shock protein 70 gene transfection protects mitochondrial and ventricular function against ischemia-reperfusion injury. Circulation, 2001, 104(12 Suppl 1): I303-I307.
5. Nollen EA, Morimoto RI. Chaperoning signaling pathways: molecular chaperones as stress-sensing 'heat shock' proteins. J Cell Sci, 2002, 115(Pt 14): 2809-2816.
6. Meldrum KK, Meldrum DR, Sezen SF, et al. Heat shock prevents simulated ischemia-induced apoptosis in renal tubular cells via a PKC-dependent mechanism. Am J Physiol Regul Integr Comp Physiol, 2001, 281(1): R359-R364.
7. Liao WY, Tsai TH, Ho TY, et al. Neuroprotective effect of paeonol mediates anti-inflammation via suppressing toll-like receptor 2 and toll-like receptor 4 signaling pathways in cerebral ischemia-reperfusion injured rats. Evid Based Complement Alternat Med, 2016, 2016: 3704647.
8. Tang N, Wu J, Zhu H, et al. Genetic mutation of GluN2B protects brain cells against stroke damages. Mol Neurobiol, 2018, 55(4): 2979-2990.
9. Wu QJ, Tymianski M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain, 2018, 11(1): 15.
10. Li XY, Liang J, Tang YB, et al. Ginsenoside Rd prevents glutamate-induced apoptosis in rat cortical neurons. Clin Exp Pharmacol Physiol, 2010, 37(2): 199-204.
11. de Miranda AS, Brant F, Vieira LB, et al. A neuroprotective effect of the glutamate receptor antagonist MK801 on long-term cognitive and behavioral outcomes secondary to experimental cerebral malaria. Mol Neurobiol, 2017, 54(9): 7063-7082.
12. Bovill JG. Anesthetic pharmacology: reflections of a section editor. Anesth Analg, 2007, 105(5): 1186-1190.
13. Himmelseher S, Durieux ME. Revising a dogma: ketamine for patients with neurological injury? Anesth Analg, 2005, 101(2): 524-534.
14. Proescholdt M, Heimann A, Kempski O. Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res, 2001, 904(2): 245-251.
15. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science, 1993, 262(5134): 689-695.
16. 梅和珊, 王永利. 脑缺血时谷氨酸释放机制. 中国药理学通报, 2005, 21(4): 393-396.
17. Grewer C, Gameiro A, Zhang Z, et al. Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life, 2008, 60(9): 609-619.
18. Zimmer ER, Torrez VR, Kalinine E, et al. Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype. Front Cell Neurosci, 2015, 9: 219.
19. Ramdial K, Franco MC, Estevez AG. Cellular mechanisms of peroxynitrite-induced neuronal death. Brain Res Bull, 2017, 133: 4-11.
20. Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimers Dis, 2017, 57(4): 1041-1048.

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