본문 바로가기
KERD
논문KCI 등재

Inhibitory Effects of Isoquinoline Alkaloid Berberine on Ischemia-Induced Apoptosis via Activation of Phosphoinositide 3-Kinase/Protein Kinase B Signaling Pathway

1

조회

0

다운로드

5

인용

0

참고문헌

키워드

초록

Purpose: Berberine is a type of isoquinoline alkaloid that has been used to treat various diseases. A neuroprotective effect of berberine against cerebral ischemia has been reported; however, the effects of berberine on apoptosis in relation to reactive astrogliosis and microglia activation under ischemic conditions have not yet been fully evaluated. In the present study, we investigated the effects of berberine on global ischemia-induced apoptosis, and focused on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in the hippocampus using gerbils. Methods: Gerbils received berberine orally once a day for 14 consecutive days, starting one day after surgery. In this study, a step-down avoidance task was used to assess short-term memory. Furthermore, we employed the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay to evaluate DNA fragmentation, immunohistochemistry to investigate glial fibriallary acidic protein, CD11b, and caspase-3, and western blot to assess PI3K, Akt, Bax, Bcl-2, and cytochrome c. Results: Our results revealed that berberine treatment alleviated ischemia-induced short-term memory impairment. Treatment with berbeine also attenuated ischemia-induced apoptosis and inhibited reactive astrogliosis and microglia activation. Furthermore, berberine enhanced phospho-PI3K and phospho-Akt expression in the hippocampus of ischemic gerbils. Conclusions: Berberine exerted a neuroprotective effect against ischemic insult by inhibiting neuronal apoptosis via activation of the PI3K/Akt signaling pathway. The antiapoptotic effect of berberine was achieved through inhibition of reactive astrogliosis and microglia activation. Berberine may therefore serve as a therapeutic agent for stroke-induced neurourological problems.

Abstract

Purpose: Berberine is a type of isoquinoline alkaloid that has been used to treat various diseases. A neuroprotective effect of berberine against cerebral ischemia has been reported; however, the effects of berberine on apoptosis in relation to reactive astrogliosis and microglia activation under ischemic conditions have not yet been fully evaluated. In the present study, we investigated the effects of berberine on global ischemia-induced apoptosis, and focused on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in the hippocampus using gerbils. Methods: Gerbils received berberine orally once a day for 14 consecutive days, starting one day after surgery. In this study, a step-down avoidance task was used to assess short-term memory. Furthermore, we employed the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay to evaluate DNA fragmentation, immunohistochemistry to investigate glial fibriallary acidic protein, CD11b, and caspase-3, and western blot to assess PI3K, Akt, Bax, Bcl-2, and cytochrome c. Results: Our results revealed that berberine treatment alleviated ischemia-induced short-term memory impairment. Treatment with berbeine also attenuated ischemia-induced apoptosis and inhibited reactive astrogliosis and microglia activation. Furthermore, berberine enhanced phospho-PI3K and phospho-Akt expression in the hippocampus of ischemic gerbils. Conclusions: Berberine exerted a neuroprotective effect against ischemic insult by inhibiting neuronal apoptosis via activation of the PI3K/Akt signaling pathway. The antiapoptotic effect of berberine was achieved through inhibition of reactive astrogliosis and microglia activation. Berberine may therefore serve as a therapeutic agent for stroke-induced neurourological problems.

참고문헌 (35)

  1. Hartman RE, "Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats", Brain Res, 1043, pp.48~56 (2005)
  2. Walker EJ, "TIMP-3 and MMP-3 contribute to delayed inflammation and hippocampal neuronal death following global ischemia", Exp Neurol, 216, pp.122~131 (2009)
  3. Lively S, "SC1", hevin and reactive gliosis after transient ischemic stroke in young and aged rats, 2011, pp.70, 913~929
  4. McPherson CA, "Injury-induced neurogenesis: consideration of resident microglia as supportive of neural progenitor cells", Neurotox Res, 19, pp.341~352 (2011)
  5. 김기정, "Effects of endurance exercise on expressions of glial fibrillary acidic protein and myelin basic protein in developing rats with maternal infection-induced cerebral palsy", Journal of exercise rehabilitation, 10(1), pp.9~14 (2014), 한국운동재활학회[DOI]
  6. Singh AK, "Nigrostriatal proteomics of cypermethrin-induced dopaminergic neurodegeneration: microglial activation-dependent and -independent regulations", Toxicol Sci, 122, pp.526~538 (2011)
  7. Sung YH, "Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson’s disease mice", Life Sci, 91, pp.1309~1316 (2012)
  8. Cantley LC, "The phosphoinositide 3-kinase pathway", Science, 296, pp.1655~1657 (2002)
  9. Kawano T, "Neuroprotective effect of sodium orthovanadate on delayed neuronal death after transient forebrain ischemia in gerbil hippocampus", J Cereb Blood Flow Metab, 21, pp.1268~1280 (2001)
  10. Yano S, "Activation of Akt", protein kinase B contributes to induction of ischemic tolerance in the CA1 subfield of gerbil hippocampus, 2001, pp.21, 351~360
  11. Ko IG, "Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils", Pharmacol Biochem Behav, 91, pp.629~635 (2009)
  12. Kim M, "Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson’s disease", Int J Mol Med, 33, pp.870~878 (2014)
  13. Broughton BR, "Apoptotic mechanisms after cerebral ischemia", Stroke, 40, pp.e331~e339 (2009)
  14. Fan TJ, "Caspase family proteases and apoptosis", Acta Biochim Biophys Sin, 37, pp.719~727 (2005)
  15. Ghobrial IM, "Targeting apoptosis pathways in cancer therapy", CA Cancer J Clin, 55, pp.178~194 (2005)
  16. Bhutada P, "Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes", Behav Brain Res, 220, pp.30~41 (2011)
  17. Imanshahidi M, "Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine", Phytother Res, 22, pp.999~1012 (2008)
  18. Wang F, "Effects of berberine on potassium currents in acutely isolated CA1 pyramidal neurons of rat hippocampus", Brain Res, 999, pp.91~97 (2004)
  19. Yoo KY, "Berberry extract reduces neuronal damage and N-Methyl-D-aspartate receptor 1 immunoreactivity in the gerbil hippocampus after transient forebrain ischemia", Biol Pharm Bull, 29, pp.623~628 (2006)
  20. 윤진환, "Sudden detraining deteriorates swimming traininginduced enhancement of short-term and spatial learning memories in mice", Journal of exercise rehabilitation, 9(2), pp.243~249 (2013), 한국운동재활학회
  21. 김지은, "Alcohol exposure induces depression-like behavior by decreasing hippocampal neuronal proliferation through inhibition of the BDNF-ERK pathway in gerbils", Animal Cells and Systems, 16(3), pp.190~197 (2012), 한국통합생물학회[DOI]
  22. 서태범, "Treadmill exercise improves behavioral outcomes and spatial learning memory through up-regulation of reelin signaling pathway in autistic rats", Journal of exercise rehabilitation, 9(2), pp.220~229 (2013), 한국운동재활학회[DOI]
  23. 윤진환, "Age-dependent effect of treadmill exercise on hemorrhage-induced neuronal cell death in rats", Journal of exercise rehabilitation, 9(6), pp.506~510 (2013), 한국운동재활학회[DOI]
  24. Zhou XQ, "Neuroprotective effects of berberine on stroke models in vitro and in vivo", Neurosci Lett, 447, pp.31~36 (2008)
  25. Hwang IK, "Ionized calcium-binding adapter molecule 1 immunoreactive cells change in the gerbil hippocampal CA1 region after ischemia", reperfusion, 2006, pp.31, 957~965
  26. Hamby ME, "Reactive astrocytes as therapeutic targets for CNS disorders", Neurotherapeutics, 7, pp.494~506 (2010)
  27. Hwang L, "Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus", Int J Mol Med, 31, pp.1047~1056 (2013)
  28. Elmore S, "Apoptosis: a review of programmed cell death", Toxicol Pathol, 35, pp.495~516 (2007)
  29. Pollack M, "The role of apoptosis in the normal aging brain, skeletal muscle, and heart", Ann N Y Acad Sci, 959, pp.93~107 (2002)
  30. Baba T, "Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase", Akt signaling pathway, 2009, pp.40, e598~e605
  31. Koh PO, "17beta-estradiol pretreatment prevents the global ischemic injury-induced decrease of Akt activation and bad phosphorylation in gerbils", J Vet Med Sci, 68, pp.1019~1022 (2006)
  32. Wang HY, "The role of phosphoinositide-3-kinase", Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats, 2009, pp.1297, 177~184
  33. Carloni S, "Activation of autophagy and Akt", CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia, 2010, pp.6, 366~377
  34. Yan K, "Induction of G1 cell cycle arrest and apoptosis by berberine in bladder cancer cells", Eur J Pharmacol, 661, pp.1~7 (2011)
  35. Yu W, "Berberine protects human renal proximal tubular cells from hypoxia", reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways, 2013, pp.11, 24~

관련 논문AI추천

이 간행물의 다른 논문 (12건)