Effect of acupuncture on short-term memory and apoptosis after transient cerebral ischemia in gerbils

  • Choi, In-Ho (College of Korean Medicine, Gachon University) ;
  • Lim, Hyung-Ho (College of Korean Medicine, Gachon University)
  • Received : 2018.10.29
  • Accepted : 2018.11.07
  • Published : 2018.12.31


Objectives: Cerebral ischemia results from a variety of causes that cerebral blood flow is reduced due to a transient or permanent occlusion of cerebral arteries. Reactive astrocytes and microglial activation plays an important role in the neuronal cell death during ischemic insult. Acupunctural treatment is effective for symptom improvement in cerebrovascular accident, including cerebral ischemia. Methods: In the present study, the effects of acupuncture at the ST40 acupoint on short-term memory and apoptosis in the hippocampal CA1 region following transient global cerebral ischemia were investigated using gerbils. Transient global ischemia was induced by occlusion of both common carotid arteries with aneurysm clips for 5 min. Acupuncture stimulation was conducted once daily for 7 consecutive days, starting one day after surgery. Results: In the present results, ischemia induction deteriorated short term memory, increased apoptosis, and induced reactive astrocyte and microglial activation. Acupuncture at ST40 acupoint ameliorated ischemia-induced short-term memory impairment by suppressing apoptosis in the hippocampus through down-regulation of reactive astrocytes and microglial activation. Conclusion: The present study suggests that acupuncture at the ST40 acupoint can be used for treatment of patients with cerebral stroke.


  1. Leker RR, Shohami E. Cerebral ischemia and trauma-different etiologies yet similar mechanisms: Neuroprotective opportunities. Brain Res Brain Res Rev. 2002;39(1):55-73.
  2. Block F. Global ischemia and behavioural deficits. Prog Neurobiol. 1999;58(3):279-95.
  3. Olsson T, Wieloch T, Smith ML. Brain damage in a mouse model of global cerebral ischemia. Effect of nmda receptor blockade. Brain Res. 2003;982(2):260-69.
  4. Ma B, Li M, Nong H, Shi J, Liu G, Zhang J. Protective effects of extract of Coeloglossum viride var. Bracteatum on ischemia-induced neuronal death and cognitive impairment in rats. Behav Pharmacol. 2008;19(4):325-33.
  5. Min D, Mao X, Wu K, Cao Y, Guo F, Zhu S, et al. Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils. Neurosci Lett. 2012;510(1):29-33.
  6. Fischer U, Schulze-Osthoff K. New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev. 2005;57(2):187-215.
  7. Johnson EM Jr, Greenlund LJ, Akins PT, Hsu CY. Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma. 1995;12(5):843-52.
  8. Sim YJ, Kim H, Kim JY, Yoon SJ, Kim SS, Chang HK, et al. Long-term treadmill exercise overcomes ischemia-induced apoptotic neuronal cell death in gerbils. Physiol Behav. 2005;84(5):733-8.
  9. Lee CH, Moon SM, Yoo KY, Choi JH, Park OK, Hwang IK, et al. Long-term changes in neuronal degeneration and microglial activation in the hippocampal ca1 region after experimental transient cerebral ischemic damage. Brain Res. 2010;1342:138-49.
  10. Lee D, Park J, Yoon J, Kim MY, Choi HY, Kim H. Neuroprotective effects of Eleutherococcus senticosus bark on transient global cerebral ischemia in rats. J Ethnopharmacol. 2012;139(1):6-11.
  11. Sulkowski G, Bubko I, Struzynska L, Januszewski S, Walski M, Rafalowska U. Astrocytic response in the rodent model of global cerebral ischemia and during reperfusion. Exp Toxicol Pathol. 2002;54(1):31-8.
  12. Grosche J, Matyash V, Moller T, Verkhratsky A, Reichenbach A, Kettenmann H. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci. 1999;2(2):139-43.
  13. Ventura R, Harris KM. Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci. 1999;19(16):6897-906.
  14. Pivonkova H, Benesova J, Butenko O, Chvatal A, Anderova M. Impact of global cerebral ischemia on K+ channel expression and membrane properties of glial cells in the rat hippocampus. Neurochem Int. 2010;57(7):783-94.
  15. Wang Q, Peng Y, Chen S, Gou X, Hu B, Du J, et al. Pretreatment with electroacupuncture induces rapid tolerance to focal cerebral ischemia through regulation of endocannabinoid system. Stroke. 2009;40(6):2157-64.
  16. Zhang R, Kadar T, Sirimanne E, MacGibbon A, Guan J. Age-related memory decline is associated with vascular and microglial degeneration in aged rats. Behav Brain Res. 2012;235(2): 210-17.
  17. Hazelton JL, Balan I, Elmer GI, Kristian T, Rosenthal RE, Krause G, et al. Hyperoxic reperfusion after global cerebral ischemia promotes inflammation and long-term hippocampal neuronal death. J Neurotrauma. 2010;27(4):753-62.
  18. Schmidt-Kastner R, Szymas J, Hossmann KA. Immunohistochemical study of glial reaction and serum protein extravasation in relation to neuronal damage in rat hippocampus after ischemia. Neuroscience. 1990;38(2):527-40.
  19. Li H, Yoo KY, Lee CH, Choi JH, Hwang IK, Kim JD, et al. Neuroprotective effects of Alpinia katsumadai against neuronal damage in the gerbil hippocampus induced by transient cerebral ischemia. Int J Neurosci. 2011;121(9):490-96.
  20. Jang MH, Shin MC, Lee TH, Lim BV, Shin MS, Min BI, et al. Acupuncture suppresses ischemia-induced increase in c-Fos expression and apoptosis in the hippocampal CA1 region in gerbils. Neurosci Lett. 2003;347(1):5-8.
  21. Uchida S, Kagitani F, Suzuki A, Aikawa Y. Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats. Jpn J Physiol. 2000;50(5):495-507.
  22. Zhou Y, Jin J. Effect of acupuncture given at the HT 7, ST 36, ST 40 and KI 3 acupoints on various parts of the brains of Alzheimer's disease patients. Acupunct Electrother Res. 2008;33(1-2):9-17.
  23. Sim YJ, Kim SS, Kim JY, Shin MS, Kim CJ. Treadmill exercise improves short-term memory by suppressing ischemia-induced apoptosis of neuronal cells in gerbils. Neurosci Lett. 2004;372(3):2556-61.
  24. Yin CS, Jeong HS, Park HJ, Baik Y, Yoon MH, Choi CB, et al. A proposed transpositional acupoint system in a mouse and rat model. Res Vet Sci. 2008;84(2):159-65.
  25. von Euler M, Bendel O, Bueters T, Sandin J, von Euler G. Profound but transient deficits in learning and memory after global ischemia using a novel water maze test. Behav Brain Res. 2006;166(2):204-10.
  26. Li Z, Pang L, Fang F, Zhang G, Zhang J, Xie M, et al. Resveratrol attenuates brain damage in a rat model of focal cerebral ischemia via up-regulation of hippocampal bcl-2. Brain Res. 2012;1450:116-24.
  27. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4):609-19.
  28. Fan TJ, Han LH, Cong RS, Liang J. Caspase family proteases and apoptosis Acta Biochimica Et Biophysica Sinica (Shanghai). 2005;37(11):719-27.
  29. Yang T, Zhuang L, Terrando N, Wu X, Jonhson MR, Maze M, et al. A clinically relevant model of perinatal global ischemic brain damage in rats. Brain Res. 2011;1383:317-23.
  30. Ji X, Li C, Lu Y, Chen Y, Guo L. Post-ischemic continuous administration of galantamine attenuates cognitive deficits and hippocampal neurons loss after transient global ischemia in gerbils. Neurosci Lett. 2007;416(1):92-5.
  31. Sugawara T, Lewen A, Noshita N, Gasche Y, Chan PH. Effects of global ischemia duration on neuronal, astroglial, oligodendroglial, and microglial reactions in the vulnerable hippocampal CA1 subregion in rats. J Neurotrauma. 2002;19(1): 85-98.
  32. Tonchev AB, Yamashima T. Differential neurogenic potential of progenitor cells in dentate gyrus and CA1 sector of the postischemicadult monkey hippocampus. Exp Neurol. 2006;198(1): 101-13.
  33. Lee MY, Kim SY, Shin SL, Choi YS, Lee JH, Tsujimoto Y, et al. Reactive astrocytes express bis, a bcl-2-binding protein, after transient forebrain ischemia. Exp Neurol. 2002;175(2):338-46.
  34. Ko IG, Shin MS, Kim BK, Kim SE, Sung YH, Kim TS, et al. Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils. Pharmacol Biochem Behav. 2009;91(4):629-35.
  35. Park SW, Yi JW, Kim YM, Kang JM, Kim DO, Shin MS, et al. Remifentanil alleviates transient cerebral ischemia-induced memory impairment through suppression of apoptotic neuronal cell death in gerbils. Korean J Anesthesiol. 2011;61(1):63-8.
  36. Eberspacher E, Werner C, Engelhard K, Pape M, Laacke L, Winner D, et al. Long-term effects of hypothermia on neuronal cell death and the concentration of apoptotic proteins after incomplete cerebral ischemia and reperfusion in rats. Acta Anaesthesiol Scand. 2005;49(4):477-87.
  37. Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci. 1997;20:245-67.
  38. Barinaga M. Cell suicide: by ICE, not fire. Science. 1994;263(5148):754-6.
  39. Krajewski S, Krajewska M, Ehrmann J, Sikorska M, Lach B, Chatten J, et al. Immunohistochemical analysis of Bcl-2, Bcl-X, Mcl-1, and Bax in tumors of central and peripheral nervous system origin. Am J Pathol. 1997;150(3):805-14.
  40. Singh AK, Tiwari MN, Dixit A, Upadhyay G, Patel DK, Singh D, et al. Nigrostriatal proteomics of cypermethrin-induced dopaminergic neurodegeneration: microglial activation-dependent and -independent regulations. Toxicol Sci. 2011;122(2):526-538.
  41. Eddleston M, Mucke L. Molecular profile of reactive astrocytes-implications for their role in neurologic disease. Neuroscience. 1993;54(1):15-36.
  42. Piao CS, Che Y, Han PL, Lee JK. Delayed and differential induction of p38 MAPK isoforms in microglia and astrocytes in the brain after transient global ischemia. Brain Res Mol Brain Res. 2002;107(2):137-44.
  43. Bal-Price A, Brown GC. Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci. 2001;21(17):6480-91.
  44. Hwang IK, Yoo KY, Kim DW, Choi SY, Kang TC, Kim YS, et al. Ionized calcium-binding adapter molecule 1 immunoreactive cells change in the gerbil hippocampal CA1 region after ischemia/reperfusion. Neurochem Res. 2006;31(7): 957-65.
  45. Perego C, Fumagalli S, De Simoni MG. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation. 2011;8:174.
  46. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science. 2000;290(5497):1768-71.
  47. Lyons A, Downer EJ, Crotty S, Nolan YM, Mills KH, Lynch MA. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci. 2007;27(3):8309-13.
  48. Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Takahashi H, Imai Y, et al. Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion. Neurosci Lett. 2007;418(1):44-8.
  49. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003;304:1-7.
  50. Wang XJ, Ye M, Zhang YH, Chen SD. CD200-CD200R regulation of microglia activation in the pathogenesis of Parkinson's disease. J Neuroimmune Pharmacol. 2007;2:259-64.
  51. Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med. 2006;38:333-47.
  52. Kim EH, Kim YJ, Lee HJ, Huh Y, Chung JH, Seo JC, et al. Acupuncture increases cell proliferation in dentate gyrus after transient global ischemia in gerbils. Neurosci Lett. 2001;297(1): 21-4.
  53. Gao H, Guo J, Zhao P, Cheng J. The neuroprotective effects of electroacupuncture on cerebral ischemia in monkey. Acupunct Electro Ther Res. 2002;27(1):45-57.
  54. Inoue I, Chen L, Zhou L, Zeng X, Wang H. Reproduction of scalp acupuncture therapy on strokes in the model rats, spontaneous hypertensive rats-stroke prone (SHR-SP). Neurosci Lett. 2002;333(3):191-4.