Skip to main content

Advertisement

SpringerLink
Log in

Role of the AMPK signaling pathway in early brain injury after subarachnoid hemorrhage in rats

  • Experimental Research - Vascular
  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Abstract

Background

AMP-activated protein kinase (AMPK) is a key metabolic and stress sensor/effector. Few investigations have been performed to study the role of AMPK in subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). This study was undertaken to investigate the time course of AMPK activation in the early stage of SAH and to evaluate the influence of AICAR (which is known to mimic AMP and activates AMPK) and compound C (a commonly used AMPK inhibitor) on EBI in rats following SAH.

Methods

Adult male rats were divided into six groups: control, sham, SAH, SAH + vehicle, SAH + AICAR and SAH + compound C. SAHs were induced by a modified endovascular perforation method. Immunohistochemistry, real-time PCR and Western blot were used to detect the spatial and dynamic expression of AMPK after SAH. Cortical apoptosis and the expressions of apoptosis-related proteins such as FOXO3a (forkhead box, class O, 3a) and Bim (Bcl-2-interacting mediator of cell death) were detected after different drug interventions.

Results

We found SAH induced prolonged activation of AMPK. Treatment with AICAR markedly induced overactivation of AMPK and upregulation of FOXO3a and Bim. AICAR also significantly exacerbated cerebral apoptosis and neurological impairment following SAH. On the other hand, pre-administration of compound C attenuated EBI in this SAH model by modulating cerebral apoptosis by inhibiting FOXO3a and Bim.

Conclusions

Our findings suggest that the AMPK pathway may play an important role in SAH-induced neuronal apoptosis, and the use of AMPK inhibitors can provide neuroprotection in EBI after SAH.

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

Access this article

Log in via an institution

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

References

  1. Whitfield J, Neame SJ, Paquet L, Bernard O, Ham J (2001) Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29:629–643

    Article  CAS  PubMed  Google Scholar 

  2. Lee JY, He Y, Sagher O, Keep R, Hua Y, Xi G (2009) Activated autophagy pathway in experimental subarachnoid hemorrhage. Brain Res 1287:126–135

    Article  CAS  PubMed  Google Scholar 

  3. Sehba FA, Pluta RM, Zhang JH (2011) Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol 43:27–40

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19

    Article  CAS  PubMed  Google Scholar 

  5. Wu AG, Ying Z, Gomez-Pinilla F (2007) Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury. J Neurotrauma 24:1587–1595

    Article  PubMed  Google Scholar 

  6. Biswas SC, Shi Y, Sproul A, Greene LA (2007) Pro-apoptotic Bim induction in response to nerve growth factor deprivation requires simultaneous activation of three different death signaling pathways. J Biol Chem 282:29368–29374

    Article  CAS  PubMed  Google Scholar 

  7. Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP, Brunet A (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282:30107–30119

    Article  CAS  PubMed  Google Scholar 

  8. Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, Meijer AJ (2006) AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem 281:34870–34879

    Article  CAS  PubMed  Google Scholar 

  9. Poels J, Spasić MR, Callaerts P, Norga KK (2009) Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. Bioessays 31:944–952

    Article  CAS  PubMed  Google Scholar 

  10. Ronnett GV, Ramamurthy S, Kleman AM, Landree LE, Aja S (2009) AMPK in the brain: its roles in energy balance and neuroprotection. J Neurochem 109:17–23

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Turnley AM, Stapleton D, Mann RJ, Witters LA, Kemp BE, Bartlett PF (1999) Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J Neurochem 72:1707–1716

    Article  CAS  PubMed  Google Scholar 

  12. Li DY, Qu Y, Mao M, Zhang XL, Li JH, Ferriero D, Mu DZ (2009) Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia. J Cerebr Blood F Met 29:1903–1913

    Article  CAS  Google Scholar 

  13. Yatsushige H, Ostrowski RP, Tsubokawa T, Colohan A, Zhang JH (2007) Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage. J Neurosci Res 85:1436–1448

    Article  CAS  PubMed  Google Scholar 

  14. McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett GV (2005) Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J Biol Chem 280:20493–20502

    Article  CAS  PubMed  Google Scholar 

  15. Davila D, Connolly NMC, Bonner H, Weisova P, Dussmann H, Concannon CG, Huber HJ, Prehn JHM (2012) Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate. Cell Death Differ 19:1677–1688

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Weisova P, Concannon CG, Devocelle M, Prehn JH, Ward MW (2009) Regulation of glucose transporter 3 surface expression by the AMP-activated protein kinase mediates tolerance to glutamate excitation in neurons. J Neurosci 29:2997–3008

    Article  CAS  PubMed  Google Scholar 

  17. Weisova P, Davila D, Tuffy LP, Ward MW, Concannon CG, Prehn JHM (2011) Role of 5′-adenosine monophosphate-activated protein kinase in cell survival and death responses in neurons. Antioxid Redox Sign 14:1863–1876

    Article  CAS  Google Scholar 

  18. Harris CA, Johnson EM Jr (2001) BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons. J Biol Chem 276:37754–37760

    CAS  PubMed  Google Scholar 

  19. Germano AF, Dixon CE, Avella D, Hayes RL, Tomasello F (1994) Behavioral deficits following experimental subarachnoid hemorrhage in the rat. J Neurotrauma 11:345–353

    Article  CAS  PubMed  Google Scholar 

  20. Van Der Heide LP, Hoekman MF, Smidt MP (2004) The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J 380:297–309

    Article  Google Scholar 

  21. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  CAS  PubMed  Google Scholar 

  22. Ren DC, Tu HC, Kim H, Wang GX, Bean GR, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJD, Cheng EHY (2010) BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330:1390–1393

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 279:19970–19976

    Article  CAS  PubMed  Google Scholar 

  24. Gilley J, Coffer PJ, Ham J (2003) FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162:613–622

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Concannon CG, Tuffy LP, Weisová P, Bonner HP, Dávila D, Bonner C, Devocelle MC, Strasser A, Ward MW, Prehn JH (2010) AMP kinase-mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis. J Cell Biol 189:83–94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Sharma S, Zhuang Y, Ying Z, Wu A, Gomez-Pinilla F (2009) Dietary curcumin supplementation counteracts reduction in levels of molecules involved in energy homeostasis after brain trauma. Neurosci 161:1037–1044

    Article  CAS  Google Scholar 

  27. Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341

    Article  CAS  PubMed  Google Scholar 

  28. King TD, Song L, Jope RS (2006) AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3. Biochem Pharmacol 71:1637–1647

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Culmsee C, Monnig J, Kemp BE, Mattson MP (2001) AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 17:45–58

    Article  CAS  PubMed  Google Scholar 

  30. Meisse D, Van de Casteele M, Beauloye C, Hainault I, Kefas BA, Rider MH, Foufelle F, Hue L (2002) Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells. FEBS Lett 526:38–42

    Article  CAS  PubMed  Google Scholar 

  31. Bederson JB, Germano IM, Guarino L (1995) Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke 26:1086–1091

    Article  CAS  PubMed  Google Scholar 

  32. Li J, Benashski S, McCullough LD (2011) Post-stroke hypothermia provides neuroprotection through inhibition of AMP-activated protein kinase. J Neurotrauma 28:1281–1288

    Article  PubMed Central  PubMed  Google Scholar 

  33. Li J, Zeng Z, Viollet B, Ronnett GV, McCullough LD (2007) Neuroprotective effects of adenosine monophosphate-activated protein kinase inhibition and gene deletion in stroke. Stroke 38:2992–2999

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Tzatsos A, Tsichlis PN (2007) Energy depletion inhibits phosphatidylinositol 3-kinase/Akt signaling and induces apoptosis via AMP-activated protein kinase dependent phosphorylation of IRS-1 at Ser-794. J Biol Chem 282:18069–18082

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National 863 Project of China, no. 2006AA02Z4Z4; the National Natural Science Foundation of China, no. 30870844; the New Century Excellent Talent Support Project of Ministry of Education, no. NCET-05-0831; the “13115” Special Fund for Major Science and Technology Projects of Shaanxi Province, no. 2008ZDKG-66

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, the First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China

    Ji-Yang An, Peng Sun, Hong-Gang Pang, Dan-Dong Li, Yu Li, Ming Zhang & Jin-Ning Song

  2. Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China

    Ji-Yang An

  3. Department of General Surgery, the Second Affiliated Hospital of Medical College, Xi’an, Shaanxi, P. R. China

    Li-Li Zhou

Authors
  1. Ji-Yang An
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li-Li Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Gang Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dan-Dong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jin-Ning Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin-Ning Song.

Additional information

Ji-Yang An and Li-Li Zhou contributed equally to this work and should be considered co-first authors

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

An, JY., Zhou, LL., Sun, P. et al. Role of the AMPK signaling pathway in early brain injury after subarachnoid hemorrhage in rats. Acta Neurochir 157, 781–792 (2015). https://doi.org/10.1007/s00701-015-2370-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00701-015-2370-3

Keywords

Search

Navigation