Mechanism of impaired hippocampal function in elderly cardiac arrest animals_West China Medical Journal

Authors：

CHU Lili ^1,2 , LIU Yi ^1,2 , ZHOU Tingyuan ^1,2 , TANG Songling ^1,2 , MA Wen ^1,2 , YAO Peng ^1,2 ,  CAO Yu ^1,2

1. Department of Emergency Medicine, Laboratory of Emergency Medicine, West China School of Medicine / West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Disaster Medical Center, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

CAO Yu, Email: yuyuer@126.com

Keywords：

Elderly; cardiac arrest; cardiopulmonary resuscitation; hippocampus; neurological function

DOI：

10.7507/1002-0179.202210222

Video：

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Elderly patients account for 80% of cardiac arrest patients. The incidence of poor neurological prognosis after return of spontaneous circulation of these patients is as high as 90%, much higher than that of young. This is related to the fact that the mechanism of hippocampal brain tissue injury after ischemia-reperfusion in elderly cardiac arrest patients is aggravated. Therefore, this study reviews the possible mechanisms of poor neurological prognosis after return of spontaneous circulation in elderly cardiac arrest animals, and the results indicate that the decrease of hippocampal perfusion and the number of neurons after resuscitation are the main causes of the increased hippocampal injury, among which oxidative stress, mitochondrial dysfunction and protein homeostasis disorder are the important factors of cell death. This review hopes to provide new ideas for the treatment of elderly patients with cardiac arrest and the improvement of neurological function prognosis through the comparative analysis of elderly and young animals.

Citation： CHU Lili, LIU Yi, ZHOU Tingyuan, TANG Songling, MA Wen, YAO Peng, CAO Yu. Mechanism of impaired hippocampal function in elderly cardiac arrest animals. West China Medical Journal, 2022, 37(11): 1711-1714. doi: 10.7507/1002-0179.202210222 Copy

1.	Matsuyama T, Kitamura T, Kiyohara K, et al. Assessment of the 11-year nationwide trend of out-of-hospital cardiac arrest cases among elderly patients in Japan (2005-2015). Resuscitation, 2018, 131: 83-90.
2.	Andersen LW, Holmberg MJ, Berg KM, et al. In-hospital cardiac arrest: a review. JAMA, 2019, 321(12): 1200-1210.
3.	Shao F, Li CS, Liang LR, et al. Incidence and outcome of adult in-hospital cardiac arrest in Beijing, China. Resuscitation, 2016, 102: 51-56.
4.	Witten L, Gardner R, Holmberg MJ, et al. Reasons for death in patients successfully resuscitated from out-of-hospital and in-hospital cardiac arrest. Resuscitation, 2019, 136: 93-99.
5.	Lupton JR, Kurz MC, Daya MR. Neurologic prognostication after resuscitation from cardiac arrest. J Am Coll Emerg Physicians Open, 2020, 1(4): 333-341.
6.	Chavez-Valdez R, Emerson P, Goffigan-Holmes J, et al. Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model. Hippocampus, 2018, 28(8): 617-630.
7.	Lana D, Ugolini F, Nosi D, et al. The emerging role of the interplay among astrocytes, microglia, and neurons in the hippocampus in health and disease. Front Aging Neurosci, 2021, 13: 651973.
8.	Escobar I, Xu J, Jackson CW, et al. Altered neural networks in the papez circuit: implications for cognitive dysfunction after cerebral ischemia. J Alzheimers Dis, 2019, 67(2): 425-446.
9.	Gofgan-Holmes J, Sanabria D, Diaz J, et al. Calbindin-1 expression in the hippocampus following neonatal hypoxia-ischemia and therapeutic hypothermia and defcits in spatial memory. Dev Neurosci, 2019, 12: 1-15.
10.	Lana D, Ugolini F, Wenk GL, et al. Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell-cell interglial interaction. FASEB J, 2019, 33(3): 4007-4020.
11.	Wada T. Coagulofibrinolytic changes in patients with post-cardiac arrest syndrome. Front Med (Lausanne), 2017, 4: 156.
12.	Xu K, Puchowicz MA, LaManna JC. Aging effect on post-recovery hypofusion and mortality following cardiac arrest and resuscitation in rats. Adv Exp Med Biol, 2016, 876: 265-270.
13.	Abdelkarim D, Zhao Y, Turner MP, et al. A neural-vascular complex of age-related changes in the human brain: anatomy, physiology, and implications for neurocognitive aging. Neurosci Biobehav Rev, 2019, 107: 927-944.
14.	Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron, 2017, 96(1): 17-42.
15.	Tarantini S, Tran CHT, Gordon GR, et al. Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol, 2017, 94: 52-58.
16.	Pannese E. Quantitative, structural and molecular changes in neuroglia of aging mammals: a review. Eur J Histochem, 2021, 65(s1): 3249.
17.	Xu K, Puchowicz MA, Sun X, et al. Decreased brainstem function following cardiac arrest and resuscitation in aged rat. Brain Res, 2010, 1328: 181-189.
18.	Brunetti D, Dykstra W, Le S, et al. Mitochondria in neurogenesis: implications for mitochondrial diseases. Stem Cells, 2021, 39(10): 1289-1297.
19.	陈寿权, 何爱文. 心搏骤停后心脑损伤: 线粒体相关途径. 中华急诊医学杂志, 2013, 22(1): 8-10.
20.	Ham PB 3rd, Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol, 2017, 157: 92-116.
21.	Kent AC, El Baradie KBY, Hamrick MW. Targeting the mitochondrial permeability transition pore to prevent age-associated cell damage and neurodegeneration. Oxid Med Cell Longev, 2021, 2021: 6626484.
22.	Neginskaya MA, Pavlov EV, Sheu SS. Electrophysiological properties of the mitochondrial permeability transition pores: channel diversity and disease implication. Biochim Biophys Acta Bioenerg, 2021, 1862(3): 148357.
23.	Lushchak VI. Interplay between bioenergetics and oxidative stress at normal brain aging. Aging as a result of increasing disbalance in the system oxidative stress-energy provision. Pflugers Arch, 2021, 473(5): 713-722.
24.	Dröge W. Free radicals in the physiological control of cell function. Physiol Rev, 2002, 82(1): 47-95.
25.	Sandroni C, Cronberg T, Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med, 2021, 47(12): 1393-1414.
26.	Wang Z, Yang W. Impaired capacity to restore proteostasis in the aged brain after ischemia: implications for translational brain ischemia research. Neurochem Int, 2019, 127: 87-93.
27.	Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438.
28.	Paz Gavilán M, Vela J, Castaño A, et al. Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiol Aging, 2006, 27(7): 973-982.
29.	Shen Y, Yan B, Zhao Q, et al. Aging is associated with impaired activation of protein homeostasis-related pathways after cardiac arrest in mice. J Am Heart Assoc, 2018, 7(17): e009634.
30.	Celen AB, Sahin U. Sumoylation on its 25th anniversary: mechanisms, pathology, and emerging concepts. FEBS J, 2020, 287(15): 3110-3140.
31.	Cimarosti H, Ashikaga E, Jaafari N, et al. Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurones. J Cereb Blood Flow Metab, 2012, 32(1): 17-22.
32.	Bernstock JD, Yang W, Ye DG, et al. SUMOylation in brain ischemia:patterns, targets, and translational implications. J Cereb Blood Flow Metab, 2018, 38(1): 5-16.
33.	Ma X, Li H, He Y, et al. The emerging link between O-GlcNAcylation and neurological disorders. Cell Mol Life Sci, 2017, 74(20): 3667-3686.
34.	Jiang M, Yu S, Yu Z, et al. XBP1 (X-Box-binding protein-1)-dependent O-GlcNAcylation is neuroprotective in ischemic stroke in young mice and its impairment in aged mice is rescued by thiamet-G. Stroke, 2017, 48(6): 1646-1654.
35.	Liu S, Sheng H, Yu Z, et al. O-linked β-N-acetylglucosamine modification of proteins is activated in post-ischemic brains of young but not aged mice: implications for impaired functional recovery from ischemic stress. J Cereb Blood Flow Metab, 2016, 36(2): 393-398.
36.	Li R, Shen Y, Li X, et al. Activation of the XBP1s/O-GlcNAcylation pathway improves functional outcome after cardiac arrest and resuscitation in young and aged mice. Shock, 2021, 56(5): 755-761.

1. Matsuyama T, Kitamura T, Kiyohara K, et al. Assessment of the 11-year nationwide trend of out-of-hospital cardiac arrest cases among elderly patients in Japan (2005-2015). Resuscitation, 2018, 131: 83-90.
2. Andersen LW, Holmberg MJ, Berg KM, et al. In-hospital cardiac arrest: a review. JAMA, 2019, 321(12): 1200-1210.
3. Shao F, Li CS, Liang LR, et al. Incidence and outcome of adult in-hospital cardiac arrest in Beijing, China. Resuscitation, 2016, 102: 51-56.
4. Witten L, Gardner R, Holmberg MJ, et al. Reasons for death in patients successfully resuscitated from out-of-hospital and in-hospital cardiac arrest. Resuscitation, 2019, 136: 93-99.
5. Lupton JR, Kurz MC, Daya MR. Neurologic prognostication after resuscitation from cardiac arrest. J Am Coll Emerg Physicians Open, 2020, 1(4): 333-341.
6. Chavez-Valdez R, Emerson P, Goffigan-Holmes J, et al. Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model. Hippocampus, 2018, 28(8): 617-630.
7. Lana D, Ugolini F, Nosi D, et al. The emerging role of the interplay among astrocytes, microglia, and neurons in the hippocampus in health and disease. Front Aging Neurosci, 2021, 13: 651973.
8. Escobar I, Xu J, Jackson CW, et al. Altered neural networks in the papez circuit: implications for cognitive dysfunction after cerebral ischemia. J Alzheimers Dis, 2019, 67(2): 425-446.
9. Gofgan-Holmes J, Sanabria D, Diaz J, et al. Calbindin-1 expression in the hippocampus following neonatal hypoxia-ischemia and therapeutic hypothermia and defcits in spatial memory. Dev Neurosci, 2019, 12: 1-15.
10. Lana D, Ugolini F, Wenk GL, et al. Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell-cell interglial interaction. FASEB J, 2019, 33(3): 4007-4020.
11. Wada T. Coagulofibrinolytic changes in patients with post-cardiac arrest syndrome. Front Med (Lausanne), 2017, 4: 156.
12. Xu K, Puchowicz MA, LaManna JC. Aging effect on post-recovery hypofusion and mortality following cardiac arrest and resuscitation in rats. Adv Exp Med Biol, 2016, 876: 265-270.
13. Abdelkarim D, Zhao Y, Turner MP, et al. A neural-vascular complex of age-related changes in the human brain: anatomy, physiology, and implications for neurocognitive aging. Neurosci Biobehav Rev, 2019, 107: 927-944.
14. Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron, 2017, 96(1): 17-42.
15. Tarantini S, Tran CHT, Gordon GR, et al. Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol, 2017, 94: 52-58.
16. Pannese E. Quantitative, structural and molecular changes in neuroglia of aging mammals: a review. Eur J Histochem, 2021, 65(s1): 3249.
17. Xu K, Puchowicz MA, Sun X, et al. Decreased brainstem function following cardiac arrest and resuscitation in aged rat. Brain Res, 2010, 1328: 181-189.
18. Brunetti D, Dykstra W, Le S, et al. Mitochondria in neurogenesis: implications for mitochondrial diseases. Stem Cells, 2021, 39(10): 1289-1297.
19. 陈寿权, 何爱文. 心搏骤停后心脑损伤: 线粒体相关途径. 中华急诊医学杂志, 2013, 22(1): 8-10.
20. Ham PB 3rd, Raju R. Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol, 2017, 157: 92-116.
21. Kent AC, El Baradie KBY, Hamrick MW. Targeting the mitochondrial permeability transition pore to prevent age-associated cell damage and neurodegeneration. Oxid Med Cell Longev, 2021, 2021: 6626484.
22. Neginskaya MA, Pavlov EV, Sheu SS. Electrophysiological properties of the mitochondrial permeability transition pores: channel diversity and disease implication. Biochim Biophys Acta Bioenerg, 2021, 1862(3): 148357.
23. Lushchak VI. Interplay between bioenergetics and oxidative stress at normal brain aging. Aging as a result of increasing disbalance in the system oxidative stress-energy provision. Pflugers Arch, 2021, 473(5): 713-722.
24. Dröge W. Free radicals in the physiological control of cell function. Physiol Rev, 2002, 82(1): 47-95.
25. Sandroni C, Cronberg T, Sekhon M. Brain injury after cardiac arrest: pathophysiology, treatment, and prognosis. Intensive Care Med, 2021, 47(12): 1393-1414.
26. Wang Z, Yang W. Impaired capacity to restore proteostasis in the aged brain after ischemia: implications for translational brain ischemia research. Neurochem Int, 2019, 127: 87-93.
27. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438.
28. Paz Gavilán M, Vela J, Castaño A, et al. Cellular environment facilitates protein accumulation in aged rat hippocampus. Neurobiol Aging, 2006, 27(7): 973-982.
29. Shen Y, Yan B, Zhao Q, et al. Aging is associated with impaired activation of protein homeostasis-related pathways after cardiac arrest in mice. J Am Heart Assoc, 2018, 7(17): e009634.
30. Celen AB, Sahin U. Sumoylation on its 25th anniversary: mechanisms, pathology, and emerging concepts. FEBS J, 2020, 287(15): 3110-3140.
31. Cimarosti H, Ashikaga E, Jaafari N, et al. Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurones. J Cereb Blood Flow Metab, 2012, 32(1): 17-22.
32. Bernstock JD, Yang W, Ye DG, et al. SUMOylation in brain ischemia:patterns, targets, and translational implications. J Cereb Blood Flow Metab, 2018, 38(1): 5-16.
33. Ma X, Li H, He Y, et al. The emerging link between O-GlcNAcylation and neurological disorders. Cell Mol Life Sci, 2017, 74(20): 3667-3686.
34. Jiang M, Yu S, Yu Z, et al. XBP1 (X-Box-binding protein-1)-dependent O-GlcNAcylation is neuroprotective in ischemic stroke in young mice and its impairment in aged mice is rescued by thiamet-G. Stroke, 2017, 48(6): 1646-1654.
35. Liu S, Sheng H, Yu Z, et al. O-linked β-N-acetylglucosamine modification of proteins is activated in post-ischemic brains of young but not aged mice: implications for impaired functional recovery from ischemic stress. J Cereb Blood Flow Metab, 2016, 36(2): 393-398.
36. Li R, Shen Y, Li X, et al. Activation of the XBP1s/O-GlcNAcylation pathway improves functional outcome after cardiac arrest and resuscitation in young and aged mice. Shock, 2021, 56(5): 755-761.

West China Medical Journal

Mechanism of impaired hippocampal function in elderly cardiac arrest animals

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