Skip to main content

Advertisement

Log in

Berberine Ameliorates MCAO Induced Cerebral Ischemia/Reperfusion Injury via Activation of the BDNF–TrkB–PI3K/Akt Signaling Pathway

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Cerebral ischemic injury remains associated with high mortality rates and lacks effective therapeutic intervention. Berberine (BBR) possesses anti-oxidant, anti-inflammatory, and anti-tumor activities, as well as potent neuroprotective effects. Although recent studies have examined the neuroprotective effects of berberine, little is known regarding its usefulness in treating cerebral ischemia. Thus, the aim of this study is to investigate the possible effect and the mechanism of berberine against cerebral ischemic injury using the middle cerebral artery occlusion (MCAO) model. Rats were randomly divided into three groups: control group, MCAO group, and MCAO + BBR group. Modified neurological severity score tests (mNSS) and infarct volumes were measured to determine the neuroprotective effects of berberine. Neuronal survival in striatum was examined by TUNEL staining and immunohistochemistry. Western blotting measured the expression of BDNF, TrkB, p-Akt and cleaved caspase-3. The results demonstrated that BBR could significantly protect against MCAO. Berberine also increased the expression of BDNF, TrkB, and p-Akt, which were reduced after MCAO. Furthermore, treatment with BBR declined the apoptosis-related proteins induced by MCAO. However, treatment with LY294002 (PI3K inhibitor) reversed the BBR-induced increases in BDNF and p-Akt proteins and decreased cleaved caspase-3 protein expression in focal cerebral ischemic rats. In summary, our results demonstrated that BBR could exert neuroprotective effects through reduction of striatum apoptosis via the BDNF–TrkB–PI3K/Akt signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

MCAO:

Middle cerebral artery occlusion

BBR:

Berberine

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tropomyosin receptor kinase B

mNSS:

Modified neurological severity score test

ECA:

External carotid artery

ICA:

Internal carotid artery

TTC:

2,3,5-Triphenyltetrazolium chloride

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

DAPI:

4,6-Diamidino-2-phenylindole

BCA:

Bicinchoninic acid

PVDF:

Polyvinylidenedifluoride

References

  1. Chu HX, Kim HA, Lee S, Broughton BR, Drummond GR, Sobey CG (2016) Evidence of CCR2-independent transmigration of Ly6C(hi) monocytes into the brain after permanent cerebral ischemia in mice. Brain Res 1637:118–127

    Article  CAS  PubMed  Google Scholar 

  2. Shi SS, Yang WZ, Chen Y, Chen JP, Tu XK (2014) Propofol reduces inflammatory reaction and ischemic brain damage in cerebral ischemia in rats. Neurochem Res 39:793–799

    Article  CAS  PubMed  Google Scholar 

  3. Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fanaei H, Karimian SM, Sadeghipour HR, Hassanzade G, Kasaeian A, Attari F, Khayat S, Ramezani V, Javadimehr M (2014) Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. Brain Res 1558:74–83

    Article  CAS  PubMed  Google Scholar 

  5. Sun J, Qu Y, He H, Fan X, Qin Y, Mao W, Xu L (2014) Protective effect of polydatin on learning and memory impairments in neonatal rats with hypoxicischemic brain injury by upregulating brainderived neurotrophic factor. Mol Med Rep 10:3047–3051

    Article  CAS  PubMed  Google Scholar 

  6. Han BH, D’Costa A, Back SA, Parsadanian M, Patel S, Shah AR, Gidday JM, Srinivasan A, Deshmukh M, Holtzman DM (2000) BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia. Neurobiol Dis 7:38–53

    Article  CAS  PubMed  Google Scholar 

  7. Sun X, Zhou H, Luo X, Li S, Yu D, Hua J, Mu D, Mao M (2008) Neuroprotection of brain-derived neurotrophic factor against hypoxic injury in vitro requires activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. Int J Dev Neurosci 26:363–370

    Article  CAS  PubMed  Google Scholar 

  8. Bothwell M (2016) Recent advances in understanding neurotrophin signaling. F1000Res 5. https://doi.org/10.12688/f1000research.8434.1

  9. Narumiya S, Ohno M, Tanaka N, Yamano T, Shimada M (1998) Enhanced expression of full-length TrkB receptors in young rat brain with hypoxic/ischemic injury. Brain Res 797:278–286

    Article  CAS  PubMed  Google Scholar 

  10. Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331–e339

    Article  Google Scholar 

  11. Wang WM, Liu Z, Liu AJ, Wang YX, Wang HG, An D, Heng B, Xie LH, Duan JL, Liu YQ (2015) The zinc ion chelating agent TPEN attenuates neuronal death/apoptosis caused by hypoxia/ischemia via mediating the pathophysiological cascade including excitotoxicity, oxidative stress, and inflammation. CNS Neurosci Ther 21:708–717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Guo L, Yang X, Lin X, Lin Y, Shen L, Nie Q, Ren L, Guo Q, Que S, Qiu Y (2015) Silencing of Id2 attenuates hypoxia/ischemia-induced neuronal injury via inhibition of neuronal apoptosis. Behav Brain Res 292:528–536

    Article  CAS  PubMed  Google Scholar 

  13. Qi B, Hu L, Zhu L, Shang L, Sheng L, Wang X, Liu N, Wen N, Yu X, Wang Q, Yang Y (2016) Metformin attenuates cognitive impairments in hypoxia-ischemia neonatal rats via improving remyelination. Cell Mol Neurobiol 37(7):1269–1278

    Article  PubMed  Google Scholar 

  14. Pei B, Yang M, Qi X, Shen X, Chen X, Zhang F (2016) Quercetin ameliorates ischemia/reperfusion-induced cognitive deficits by inhibiting ASK1/JNK3/caspase-3 by enhancing the Akt signaling pathway. Biochem Biophys Res Commun 478:199–205

    Article  CAS  PubMed  Google Scholar 

  15. Dong H, Wang N, Zhao L, Lu F (2012) Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evid Based Complement Alternat Med 2012:591654

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yoo KY, Hwang IK, Lim BO, Kang TC, Kim DW, Kim SM, Lee HY, Kim JD, Won MH (2006) Berberry extract reduces neuronal damage and N-methyl-d-aspartate receptor 1 immunoreactivity in the gerbil hippocampus after transient forebrain ischemia. Biol Pharm Bull 29:623–628

    Article  CAS  PubMed  Google Scholar 

  17. Zhu F, Qian C (2006) Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer’s disease. BMC Neurosci 7:78

    Article  PubMed  PubMed Central  Google Scholar 

  18. Eom KS, Hong JM, Youn MJ, So HS, Park R, Kim JM, Kim TY (2008) Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway. Biol Pharm Bull 31:558–562

    Article  CAS  PubMed  Google Scholar 

  19. Simoes Pires EN, Frozza RL, Hoppe JB, Menezes Bde M, Salbego CG (2014) Berberine was neuroprotective against an in vitro model of brain ischemia: survival and apoptosis pathways involved. Brain Res 1557:26–33

    Article  CAS  PubMed  Google Scholar 

  20. Hu Q, Chen C, Yan J, Yang X, Shi X, Zhao J, Lei J, Yang L, Wang K, Chen L, Huang H, Han J, Zhang JH, Zhou C (2009) Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat model. Exp Neurol 216:35–46

    Article  CAS  PubMed  Google Scholar 

  21. Shen JD, Ma LG, Hu CY, Pei YY, Jin SL, Fang XY, Li YC (2016) Berberine up-regulates the BDNF expression in hippocampus and attenuates corticosterone-induced depressive-like behavior in mice. Neurosci Lett 614:77–82

    Article  CAS  PubMed  Google Scholar 

  22. Jin K, Sun Y, Xie L, Peel A, Mao XO, Batteur S, Greenberg DA (2003) Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 24:171–189

    Article  CAS  PubMed  Google Scholar 

  23. Cai J, Kang Z, Liu K, Liu W, Li R, Zhang JH, Luo X, Sun X (2009) Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res 1256:129–137

    Article  CAS  PubMed  Google Scholar 

  24. Yao RQ, Qi DS, Yu HL, Liu J, Yang LH, Wu XX (2012) Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem Res 37:2777–2786

    Article  CAS  PubMed  Google Scholar 

  25. Yang X, Cheng J, Gao Y, Ding J, Ni X (2017) Downregulation of Iduna is associated with AIF nuclear translocation in neonatal brain after hypoxia-ischemia. Neurosci 346:74–80

    Article  CAS  Google Scholar 

  26. Zeng XH, Zeng XJ, Li YY (2003) Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 92:173–176

    Article  CAS  PubMed  Google Scholar 

  27. Maleki SN, Aboutaleb N, Souri F (2017) Berberine confers neuroprotection in coping with focal cerebral ischemia by targeting inflammatory cytokines. J Chem Neuroanat. https://doi.org/10.1016/j.jchemneu.2017.04.008

    Article  PubMed  Google Scholar 

  28. Zhang Q, Bian H, Guo L, Zhu H (2016) Pharmacologic preconditioning with berberine attenuating ischemia-induced apoptosis and promoting autophagy in neuron. Am J Transl Res 8:1197–1207

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang Q, Qian Z, Pan L, Li H, Zhu H (2012) Hypoxia-inducible factor 1 mediates the anti-apoptosis of berberine in neurons during hypoxia/ischemia. Acta Physiol Hung 99:311–323

    Article  CAS  PubMed  Google Scholar 

  30. Zhou XQ, Zeng XN, Kong H, Sun XL (2008) Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci Lett 447:31–36

    Article  CAS  PubMed  Google Scholar 

  31. Chen K, Li G, Geng F, Zhang Z, Li J, Yang M, Dong L, Gao F (2014) Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats. Apoptosis 19:946–957

    Article  CAS  PubMed  Google Scholar 

  32. Xiao J, Tan Y, Li Y, Luo Y (2016) The specific protein kinase R (PKR) inhibitor C16 protects neonatal hypoxia-ischemia brain damages by inhibiting neuroinflammation in a neonatal rat model. Med Sci Monit 22:5074–5081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang XT, Pei DS, Xu J, Guan QH, Sun YF, Liu XM, Zhang GY (2007) Opposing effects of Bad phosphorylation at two distinct sites by Akt1 and JNK1/2 on ischemic brain injury. Cell Signal 19:1844–1856

    Article  CAS  PubMed  Google Scholar 

  34. Galvin KA, Oorschot DE (2003) Continuous low-dose treatment with brain-derived neurotrophic factor or neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia/ischemia: a stereological study. Neuroscience 118:1023–1032

    Article  CAS  PubMed  Google Scholar 

  35. Yoshii A, Constantine-Paton M (2010) Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 70:304–322

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and-independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11:297–305

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Min Zhang.

Ethics declarations

Competing interest

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, J., Yan, H., Li, S. et al. Berberine Ameliorates MCAO Induced Cerebral Ischemia/Reperfusion Injury via Activation of the BDNF–TrkB–PI3K/Akt Signaling Pathway. Neurochem Res 43, 702–710 (2018). https://doi.org/10.1007/s11064-018-2472-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-2472-4

Keywords

Navigation