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The underlying mechanism of calcium toxicity-induced autophagic cell death and lysosomal degradation in early stage of cerebral ischemia

  • Received : 2024.01.05
  • Accepted : 2024.03.11
  • Published : 2024.06.30

Abstract

Cerebral ischemia is the important cause of worldwide disability and mortality, that is one of the obstruction of blood vessels supplying to the brain. In early stage, glutamate excitotoxicity and high level of intracellular calcium (Ca2+) are the major processes which can promote many downstream signaling involving in neuronal death and brain tissue damaging. Moreover, autophagy, the reusing of damaged cell organelles, is affected in early ischemia. Under ischemic conditions, autophagy plays an important role to maintain energy of the brain and its function. In the other hand, over intracellular Ca2+ accumulation triggers excessive autophagic process and lysosomal degradation leading to autophagic process impairment which finally induce neuronal death. This article reviews the association between intracellular Ca2+ and autophagic process in acute stage of ischemic stroke.

Keywords

Acknowledgement

This research work was partially supported by Excellence in Osteology Research and Training Center (ORTC), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

References

  1. Saini V, Guada L, Yavagal DR. Global epidemiology of stroke and access to acute ischemic stroke interventions. Neurology 2021;97(20 Suppl 2):S6-16. https://doi.org/10.1212/WNL.0000000000012781
  2. Feigin VL, Brainin M, Norrving B, Martins S, Sacco RL, Hacke W, Fisher M, Pandian J, Lindsay P. World Stroke Organization (WSO): global stroke fact sheet 2022. Int J Stroke 2022;17:18-29. Erratum in: Int J Stroke 2022;17:478.
  3. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008;371:1612-23. https://doi.org/10.1016/S0140-6736(08)60694-7
  4. Johnstone VP, Shultz SR, Yan EB, O'Brien TJ, Rajan R. The acute phase of mild traumatic brain injury is characterized by a distance-dependent neuronal hypoactivity. J Neurotrauma 2014;31:1881-95. https://doi.org/10.1089/neu.2014.3343
  5. DeSai C, Hays Shapshak A. Cerebral ischemia [Internet]. Stat-Pearls; 2023 Apr 3. [cited 2024 Mar 11]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560510/
  6. Anderson JA. The golden hour Performing an acute ischemic stroke workup. Nurse Pract 2014;39:22-9; quiz 29-30. https://doi.org/10.1097/01.NPR.0000452974.46311.0f
  7. Advani R, Naess H, Kurz MW. The golden hour of acute ischemic stroke. Scand J Trauma Resusc Emerg Med 2017;25:54.
  8. Singh V, Mishra VN, Chaurasia RN, Joshi D, Pandey V. Modes of calcium regulation in ischemic neuron. Indian J Clin Biochem 2019;34:246-53. https://doi.org/10.1007/s12291-019-00838-9
  9. Chen W, Sun Y, Liu K, Sun X. Autophagy: a double-edged sword for neuronal survival after cerebral ischemia. Neural Regen Res 2014;9:1210-6.
  10. Davis GW. Not fade away: mechanisms of neuronal ATP homeostasis. Neuron 2020;105:591-3. https://doi.org/10.1016/j.neuron.2020.01.024
  11. Agnati LF, Guidolin D, Cervetto C, Maura G, Marcoli M. Brain structure and function: insights from chemical neuroanatomy. Life (Basel) 2023;13:940.
  12. Bertrand PP. ATP and sensory transduction in the enteric nervous system. Neuroscientist 2003;9:243-60. https://doi.org/10.1177/1073858403253768
  13. Clarke SG, Scarnati MS, Paradiso KG. Neurotransmitter release can be stabilized by a mechanism that prevents voltage changes near the end of action potentials from affecting calcium currents. J Neurosci 2016;36:11559-72. https://doi.org/10.1523/JNEUROSCI.0066-16.2016
  14. Zbili M, Rama S, Debanne D. Dynamic control of neurotransmitter release by presynaptic potential. Front Cell Neurosci 2016;10:278.
  15. Sifat AE, Nozohouri S, Archie SR, Chowdhury EA, Abbruscato TJ. Brain energy metabolism in ischemic stroke: effects of smoking and diabetes. Int J Mol Sci 2022;23:8512.
  16. Liu F, Lu J, Manaenko A, Tang J, Hu Q. Mitochondria in ischemic stroke: new insight and implications. Aging Dis 2018;9:924-37. https://doi.org/10.14336/AD.2017.1126
  17. Suhail M. Na, K-ATPase: ubiquitous multifunctional transmembrane protein and its relevance to various pathophysiological conditions. J Clin Med Res 2010;2:1-17. https://doi.org/10.4021/jocmr2010.02.263w
  18. Shen Z, Xiang M, Chen C, Ding F, Wang Y, Shang C, Xin L, Zhang Y, Cui X. Glutamate excitotoxicity: potential therapeutic target for ischemic stroke. Biomed Pharmacother 2022;151:113125.
  19. Belov Kirdajova D, Kriska J, Tureckova J, Anderova M. Ischemia-triggered glutamate excitotoxicity from the perspective of glial cells. Front Cell Neurosci 2020;14:51.
  20. de Lores Arnaiz GR, Ordieres MG. Brain Na(+), K(+)-ATPase activity in aging and disease. Int J Biomed Sci 2014;10:85-102. https://doi.org/10.59566/IJBS.2014.10085
  21. Wang F, Xie X, Xing X, Sun X. Excitatory synaptic transmission in ischemic stroke: a new outlet for classical neuroprotective strategies. Int J Mol Sci 2022;23:9381.
  22. Nishizawa Y. Glutamate release and neuronal damage in ischemia. Life Sci 2001;69:369-81. https://doi.org/10.1016/S0024-3205(01)01142-0
  23. Franco R, Rivas-Santisteban R, Lillo J, Camps J, Navarro G, Reyes-Resina I. 5-hydroxytryptamine, glutamate, and ATP: much more than neurotransmitters. Front Cell Dev Biol 2021;9:667815.
  24. Mahmoud S, Gharagozloo M, Simard C, Gris D. Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells 2019;8:184.
  25. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 2010;62:405-96. Erratum in: Pharmacol Rev 2014;66:1141.
  26. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995;15:961-73. https://doi.org/10.1016/0896-6273(95)90186-8
  27. Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med 2003;3:65-94. https://doi.org/10.1385/NMM:3:2:65
  28. Hellas JA, Andrew RD. Neuronal swelling: a non-osmotic consequence of spreading depolarization. Neurocrit Care 2021;35(Suppl 2):112-34. https://doi.org/10.1007/s12028-021-01326-w
  29. Kahle KT, Simard JM, Staley KJ, Nahed BV, Jones PS, Sun D. Molecular mechanisms of ischemic cerebral edema: role of electroneutral ion transport. Physiology (Bethesda) 2009;24:257-65. https://doi.org/10.1152/physiol.00015.2009
  30. Akins PT, Atkinson RP. Glutamate AMPA receptor antagonist treatment for ischaemic stroke. Curr Med Res Opin 2002;18(Suppl 2):s9-13. https://doi.org/10.1185/030079902125000660
  31. Besancon E, Guo S, Lok J, Tymianski M, Lo EH. Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci 2008;29:268-75. https://doi.org/10.1016/j.tips.2008.02.003
  32. von Engelhardt J, Coserea I, Pawlak V, Fuchs EC, Kohr G, Seeburg PH, Monyer H. Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors. Neuropharmacology 2007;53:10-7. https://doi.org/10.1016/j.neuropharm.2007.04.015
  33. Zhou X, Ding Q, Chen Z, Yun H, Wang H. Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity. J Biol Chem 2013;288:24151-9. https://doi.org/10.1074/jbc.M113.482000
  34. Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 2014;115:157-88. https://doi.org/10.1016/j.pneurobio.2013.11.006
  35. Wu QJ, Tymianski M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain 2018;11:15.
  36. Lujan B, Liu X, Wan Q. Differential roles of GluN2A- and GluN2B-containing NMDA receptors in neuronal survival and death. Int J Physiol Pathophysiol Pharmacol 2012;4:211-8.
  37. Franchini L, Carrano N, Di Luca M, Gardoni F. Synaptic GluN2A-containing NMDA receptors: from physiology to pathological synaptic plasticity. Int J Mol Sci 2020;21:1538.
  38. Li Y, Cheng X, Liu X, Wang L, Ha J, Gao Z, He X, Wu Z, Chen A, Jewell LL, Sun Y. Treatment of cerebral ischemia through NMDA receptors: metabotropic signaling and future directions. Front Pharmacol 2022;13:831181.
  39. Sun Y, Zhang L, Chen Y, Zhan L, Gao Z. Therapeutic targets for cerebral ischemia based on the signaling pathways of the GluN2B C terminus. Stroke 2015;46:2347-53. https://doi.org/10.1161/STROKEAHA.115.009314
  40. Picon-Pages P, Garcia-Buendia J, Munoz FJ. Functions and dysfunctions of nitric oxide in brain. Biochim Biophys Acta Mol Basis Dis 2019;1865:1949-67. https://doi.org/10.1016/j.bbadis.2018.11.007
  41. Sulaiman Alsaadi M. Role of DAPK1 in neuronal cell death, survival and diseases in the nervous system. Int J Dev Neurosci 2019;74:11-7. https://doi.org/10.1016/j.ijdevneu.2019.02.003
  42. Kim N, Chen D, Zhou XZ, Lee TH. Death-associated protein kinase 1 phosphorylation in neuronal cell death and neurodegenerative disease. Int J Mol Sci 2019;20:3131.
  43. Lee JH, Rho SB, Chun T. Programmed cell death 6 (PDCD6) protein interacts with death-associated protein kinase 1 (DAPk1): additive effect on apoptosis via caspase-3 dependent pathway. Biotechnol Lett 2005;27:1011-5. https://doi.org/10.1007/s10529-005-7869-x
  44. Nair S, Hagberg H, Krishnamurthy R, Thornton C, Mallard C. Death associated protein kinases: molecular structure and brain injury. Int J Mol Sci 2013;14:13858-72. https://doi.org/10.3390/ijms140713858
  45. Ludhiadch A, Sharma R, Muriki A, Munshi A. Role of calcium homeostasis in ischemic stroke: a review. CNS Neurol Disord Drug Targets 2022;21:52-61. https://doi.org/10.2174/1871527320666210212141232
  46. Cross JL, Meloni BP, Bakker AJ, Lee S, Knuckey NW. Modes of neuronal calcium entry and homeostasis following cerebral ischemia. Stroke Res Treat 2010;2010:316862.
  47. Liu J, Liu MC, Wang KK. Calpain in the CNS: from synaptic function to neurotoxicity. Sci Signal 2008;1:re1.
  48. Bevers MB, Neumar RW. Mechanistic role of calpains in postischemic neurodegeneration. J Cereb Blood Flow Metab 2008;28:655-73. https://doi.org/10.1038/sj.jcbfm.9600595
  49. Cheng SY, Wang SC, Lei M, Wang Z, Xiong K. Regulatory role of calpain in neuronal death. Neural Regen Res 2018;13:556-62. https://doi.org/10.4103/1673-5374.228762
  50. Yamakawa H, Banno Y, Nakashima S, Yoshimura S, Sawada M, Nishimura Y, Nozawa Y, Sakai N. Crucial role of calpain in hypoxic PC12 cell death: calpain, but not caspases, mediates degradation of cytoskeletal proteins and protein kinase Calpha and -delta. Neurol Res 2001;23:522-30. https://doi.org/10.1179/016164101101198776
  51. Bano D, Nicotera P. Ca2+ signals and neuronal death in brain ischemia. Stroke 2007;38(2 Suppl):674-6. https://doi.org/10.1161/01.STR.0000256294.46009.29
  52. Xu W, Wong TP, Chery N, Gaertner T, Wang YT, Baudry M. Calpain-mediated mGluR1alpha truncation: a key step in excitotoxicity. Neuron 2007;53:399-412. https://doi.org/10.1016/j.neuron.2006.12.020
  53. Reggiori F, Klionsky DJ. Autophagy in the eukaryotic cell. Eukaryot Cell 2002;1:11-21. https://doi.org/10.1128/EC.01.1.11-21.2002
  54. Mehrpour M, Esclatine A, Beau I, Codogno P. Overview of macroautophagy regulation in mammalian cells. Cell Res 2010;20:748-62. https://doi.org/10.1038/cr.2010.82
  55. Yim WW, Mizushima N. Lysosome biology in autophagy. Cell Discov 2020;6:6.
  56. Dunlop EA, Tee AR. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol 2014;36:121-9. https://doi.org/10.1016/j.semcdb.2014.08.006
  57. Wong PM, Puente C, Ganley IG, Jiang X. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 2013;9:124-37. https://doi.org/10.4161/auto.23323
  58. McKnight NC, Zhenyu Y. Beclin 1, an essential component and master regulator of PI3K-III in health and disease. Curr Pathobiol Rep 2013;1:231-8.
  59. Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004;36:2503-18. https://doi.org/10.1016/j.biocel.2004.05.009
  60. Shibutani ST, Yoshimori T. A current perspective of autophagosome biogenesis. Cell Res 2014;24:58-68. https://doi.org/10.1038/cr.2013.159
  61. Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 2013;14:283-96. https://doi.org/10.1038/nrm3565
  62. Peng L, Hu G, Yao Q, Wu J, He Z, Law BY, Hu G, Zhou X, Du J, Wu A, Yu L. Microglia autophagy in ischemic stroke: a double-edged sword. Front Immunol 2022;13:1013311.
  63. Rami A, Langhagen A, Steiger S. Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis 2008;29:132-41. https://doi.org/10.1016/j.nbd.2007.08.005
  64. Wen YD, Sheng R, Zhang LS, Han R, Zhang X, Zhang XD, Han F, Fukunaga K, Qin ZH. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 2008;4:762-9. https://doi.org/10.4161/auto.6412
  65. Russo R, Berliocchi L, Adornetto A, Varano GP, Cavaliere F, Nucci C, Rotiroti D, Morrone LA, Bagetta G, Corasaniti MT. Calpain-mediated cleavage of Beclin-1 and autophagy deregulation following retinal ischemic injury in vivo. Cell Death Dis 2011;2:e144.
  66. Liu Y, Che X, Zhang H, Fu X, Yao Y, Luo J, Yang Y, Cai R, Yu X, Yang J, Zhou MS. CAPN1 (calpain1)-mediated impairment of autophagic flux contributes to cerebral ischemia-induced neuronal damage. Stroke 2021;52:1809-21. https://doi.org/10.1161/STROKEAHA.120.032749
  67. Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med 2016;48:e224.
  68. Mayer MP, Bukau B. Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 2005;62:670-84. https://doi.org/10.1007/s00018-004-4464-6
  69. Sharma D, Masison DC. Hsp70 structure, function, regulation and influence on yeast prions. Protein Pept Lett 2009;16:571-81. https://doi.org/10.2174/092986609788490230
  70. Rosenzweig R, Nillegoda NB, Mayer MP, Bukau B. The Hsp70 chaperone network. Nat Rev Mol Cell Biol 2019;20:665-80. https://doi.org/10.1038/s41580-019-0133-3
  71. Balogi Z, Multhoff G, Jensen TK, Lloyd-Evans E, Yamashima T, Jaattela M, Harwood JL, Vigh L. Hsp70 interactions with membrane lipids regulate cellular functions in health and disease. Prog Lipid Res 2019;74:18-30. https://doi.org/10.1016/j.plipres.2019.01.004
  72. Lee SH, Kim M, Yoon BW, Kim YJ, Ma SJ, Roh JK, Lee JS, Seo JS. Targeted hsp70.1 disruption increases infarction volume after focal cerebral ischemia in mice. Stroke 2001;32:2905-12. https://doi.org/10.1161/hs1201.099604
  73. Kim JY, Kim N, Zheng Z, Lee JE, Yenari MA. 70-kDa heat shock protein downregulates dynamin in experimental stroke: a new therapeutic target? Stroke 2016;47:2103-11. https://doi.org/10.1161/STROKEAHA.116.012763
  74. Zhou XY, Luo Y, Zhu YM, Liu ZH, Kent TA, Rong JG, Li W, Qiao SG, Li M, Ni Y, Ishidoh K, Zhang HL. Inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membrane in ischemic astrocytes. Cell Death Dis 2017;8:e2618.
  75. Villalpando Rodriguez GE, Torriglia A. Calpain 1 induce lysosomal permeabilization by cleavage of lysosomal associated membrane protein 2. Biochim Biophys Acta 2013;1833:2244-53. https://doi.org/10.1016/j.bbamcr.2013.05.019
  76. Qin AP, Zhang HL, Qin ZH. Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death. Neurosci Bull 2008;24:117-23. https://doi.org/10.1007/s12264-008-0117-3
  77. Terasaki Y, Liu Y, Hayakawa K, Pham LD, Lo EH, Ji X, Arai K. Mechanisms of neurovascular dysfunction in acute ischemic brain. Curr Med Chem 2014;21:2035-42. https://doi.org/10.2174/0929867321666131228223400
  78. Lipton P. Lysosomal membrane permeabilization as a key player in brain ischemic cell death: a "lysosomocentric" hypothesis for ischemic brain damage. Transl Stroke Res 2013;4:672-84. https://doi.org/10.1007/s12975-013-0301-2
  79. Li J, McCullough LD. Effects of AMP-activated protein kinase in cerebral ischemia. J Cereb Blood Flow Metab 2010;30:480-92. https://doi.org/10.1038/jcbfm.2009.255
  80. Chen H, Kim GS, Okami N, Narasimhan P, Chan PH. NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol Dis 2011;42:341-8. https://doi.org/10.1016/j.nbd.2011.01.027
  81. Yamashima T, Mathivanan A, Dazortsava MY, Sakai S, Kurimoto S, Zhu H, Funaki N, Liang H, Hullin-Matsuda F, Kobayashi T, Akatsu H, Takahashi H, Minabe Y. Calpainmediated Hsp70.1 cleavage in monkey CA1 after ischemia induces similar - lysosomal vesiculosis' to Alzheimer neurons. J Alzheimers Dis Parkinsonism 2014;4:139.
  82. Yamashima T. Hsp70.1 and related lysosomal factors for necrotic neuronal death. J Neurochem 2012;120:477-94. https://doi.org/10.1111/j.1471-4159.2011.07596.x
  83. Koriyama Y, Furukawa A. HSP70 cleavage-induced photoreceptor cell death caused by N-methyl-N-nitrosourea. Neural Regen Res 2016;11:1758-9. https://doi.org/10.4103/1673-5374.194721
  84. Wei R, Wang J, Xu Y, Yin B, He F, Du Y, Peng G, Luo B. Probenecid protects against cerebral ischemia/reperfusion injury by inhibiting lysosomal and inflammatory damage in rats. Neuroscience 2015;301:168-77. https://doi.org/10.1016/j.neuroscience.2015.05.070
  85. Tontchev AB, Yamashima T. Ischemic delayed neuronal death: role of the cysteine proteases calpain and cathepsins. Neuropathology 1999;19:356-65. https://doi.org/10.1046/j.1440-1789.1999.00259.x
  86. Chaitanya GV, Babu PP. Activation of calpain, cathepsin-b and caspase-3 during transient focal cerebral ischemia in rat model. Neurochem Res 2008;33:2178-86. https://doi.org/10.1007/s11064-007-9567-7
  87. Lang-Rollin IC, Rideout HJ, Noticewala M, Stefanis L. Mechanisms of caspase-independent neuronal death: energy depletion and free radical generation. J Neurosci 2003;23:11015-25. https://doi.org/10.1523/JNEUROSCI.23-35-11015.2003
  88. Chen J, Hu R, Liao H, Zhang Y, Lei R, Zhang Z, Zhuang Y, Wan Y, Jin P, Feng H, Wan Q. A non-ionotropic activity of NMDA receptors contributes to glycine-induced neuroprotection in cerebral ischemia-reperfusion injury. Sci Rep 2017;7:3575.
  89. Chen M, Lu TJ, Chen XJ, Zhou Y, Chen Q, Feng XY, Xu L, Duan WH, Xiong ZQ. Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 2008;39:3042-8. https://doi.org/10.1161/STROKEAHA.108.521898
  90. Kotwal A, Ramalingaiah AH, Shukla D, Radhakrishnan M, Konar SK, Srinivasaiah B, Chakrabarti D, Sundaram M. Role of nimodipine and milrinone in delayed cerebral ischemia. World Neurosurg 2022;166:e285-93. https://doi.org/10.1016/j.wneu.2022.06.150
  91. Liu S, Liu C, Xiong L, Xie J, Huang C, Pi R, Huang Z, Li L. Icaritin alleviates glutamate-induced neuronal damage by inactivating GluN2B-containing NMDARs through the ERK/DAPK1 pathway. Front Neurosci 2021;15:525615.
  92. Wang X, Fang Y, Huang Q, Xu P, Lenahan C, Lu J, Zheng J, Dong X, Shao A, Zhang J. An updated review of autophagy in ischemic stroke: from mechanisms to therapies. Exp Neurol 2021;340:113684.
  93. Yuan J, Zhang Z, Ni J, Wu X, Yan H, Xu J, Zhao Q, Yuan H, Yang L. Acupuncture for autophagy in animal models of middle cerebral artery occlusion: a systematic review and metaanalysis protocol. PLoS One 2023;18:e0281956.
  94. Lu X, Zhang J, Ding Y, Wu J, Chen G. Novel therapeutic strategies for ischemic stroke: recent insights into autophagy. Oxid Med Cell Longev 2022;2022:3450207.
  95. Ahsan A, Liu M, Zheng Y, Yan W, Pan L, Li Y, Ma S, Zhang X, Cao M, Wu Z, Hu W, Chen Z, Zhang X. Natural compounds modulate the autophagy with potential implication of stroke. Acta Pharm Sin B 2021;11:1708-20. https://doi.org/10.1016/j.apsb.2020.10.018
  96. Yao Y, Ji Y, Ren J, Liu H, Khanna R, Sun L. Inhibition of autophagy by CRMP2-derived peptide ST2-104 (R9-CBD3) via a CaMKKβ/AMPK/mTOR pathway contributes to ischemic postconditioning-induced neuroprotection against cerebral ischemia-reperfusion injury. Mol Brain 2021;14:123.
  97. Wicha P, Onsa-Ard A, Chaichompoo W, Suksamrarn A, Tocharus C. Vasorelaxant and antihypertensive effects of neferine in rats: an in vitro and in vivo study. Planta Med 2020;86:496-504. https://doi.org/10.1055/a-1123-7852
  98. Sengking J, Oka C, Wicha P, Yawoot N, Tocharus J, Chaichompoo W, Suksamrarn A, Tocharus C. Neferine protects against brain damage in permanent cerebral ischemic rat associated with autophagy suppression and AMPK/mTOR regulation. Mol Neurobiol 2021;58:6304-15. https://doi.org/10.1007/s12035-021-02554-z
  99. Liu CW, Liao KH, Tseng H, Wu CM, Chen HY, Lai TW. Hypothermia but not NMDA receptor antagonism protects against stroke induced by distal middle cerebral arterial occlusion in mice. PLoS One 2020;15:e0229499.
  100. Hu WW, Du Y, Li C, Song YJ, Zhang GY. Neuroprotection of hypothermia against neuronal death in rat hippocampus through inhibiting the increased assembly of GluR6-PSD95-MLK3 signaling module induced by cerebral ischemia/reperfusion. Hippocampus 2008;18:386-97. https://doi.org/10.1002/hipo.20402