Advertisement

Acta Neurochirurgica

, Volume 157, Issue 5, pp 781–792 | Cite as

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

  • Ji-Yang An
  • Li-Li Zhou
  • Peng Sun
  • Hong-Gang Pang
  • Dan-Dong Li
  • Yu Li
  • Ming Zhang
  • Jin-Ning SongEmail author
Experimental Research - Vascular

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.

Keywords

Subarachnoid hemorrhage Early brain injury Apoptosis Adenosine monophosphate-activated protein kinase Bim 

Notes

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.

References

  1. 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 29:629–643CrossRefPubMedGoogle Scholar
  2. 2.
    Lee JY, He Y, Sagher O, Keep R, Hua Y, Xi G (2009) Activated autophagy pathway in experimental subarachnoid hemorrhage. Brain Res 1287:126–135CrossRefPubMedGoogle Scholar
  3. 3.
    Sehba FA, Pluta RM, Zhang JH (2011) Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol 43:27–40CrossRefPubMedCentralPubMedGoogle Scholar
  4. 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 2:9–19CrossRefPubMedGoogle Scholar
  5. 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 24:1587–1595CrossRefPubMedGoogle Scholar
  6. 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 282:29368–29374CrossRefPubMedGoogle Scholar
  7. 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 282:30107–30119CrossRefPubMedGoogle Scholar
  8. 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 281:34870–34879CrossRefPubMedGoogle Scholar
  9. 9.
    Poels J, Spasić MR, Callaerts P, Norga KK (2009) Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. Bioessays 31:944–952CrossRefPubMedGoogle Scholar
  10. 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 109:17–23CrossRefPubMedCentralPubMedGoogle Scholar
  11. 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 72:1707–1716CrossRefPubMedGoogle Scholar
  12. 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 29:1903–1913CrossRefGoogle Scholar
  13. 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 85:1436–1448CrossRefPubMedGoogle Scholar
  14. 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 280:20493–20502CrossRefPubMedGoogle Scholar
  15. 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 19:1677–1688CrossRefPubMedCentralPubMedGoogle Scholar
  16. 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 29:2997–3008CrossRefPubMedGoogle Scholar
  17. 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 14:1863–1876CrossRefGoogle Scholar
  18. 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 276:37754–37760PubMedGoogle Scholar
  19. 19.
    Germano AF, Dixon CE, Avella D, Hayes RL, Tomasello F (1994) Behavioral deficits following experimental subarachnoid hemorrhage in the rat. J Neurotrauma 11:345–353CrossRefPubMedGoogle Scholar
  20. 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 380:297–309CrossRefGoogle Scholar
  21. 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 96:857–868CrossRefPubMedGoogle Scholar
  22. 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 330:1390–1393CrossRefPubMedCentralPubMedGoogle Scholar
  23. 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 279:19970–19976CrossRefPubMedGoogle Scholar
  24. 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 162:613–622CrossRefPubMedCentralPubMedGoogle Scholar
  25. 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 189:83–94CrossRefPubMedCentralPubMedGoogle Scholar
  26. 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 161:1037–1044CrossRefGoogle Scholar
  27. 27.
    Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341CrossRefPubMedGoogle Scholar
  28. 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 71:1637–1647CrossRefPubMedCentralPubMedGoogle Scholar
  29. 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 17:45–58CrossRefPubMedGoogle Scholar
  30. 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 526:38–42CrossRefPubMedGoogle Scholar
  31. 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 26:1086–1091CrossRefPubMedGoogle Scholar
  32. 32.
    Li J, Benashski S, McCullough LD (2011) Post-stroke hypothermia provides neuroprotection through inhibition of AMP-activated protein kinase. J Neurotrauma 28:1281–1288CrossRefPubMedCentralPubMedGoogle Scholar
  33. 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 38:2992–2999CrossRefPubMedCentralPubMedGoogle Scholar
  34. 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 282:18069–18082CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Ji-Yang An
    • 1
    • 2
  • Li-Li Zhou
    • 3
  • Peng Sun
    • 1
  • Hong-Gang Pang
    • 1
  • Dan-Dong Li
    • 1
  • Yu Li
    • 1
  • Ming Zhang
    • 1
  • Jin-Ning Song
    • 1
    Email author
  1. 1.Department of Neurosurgery, the First Affiliated Hospital of Medical CollegeXi’an Jiaotong UniversityXi’anP. R. China
  2. 2.Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou UniversityZhengzhouP. R. China
  3. 3.Department of General Surgery, the Second Affiliated Hospital of Medical CollegeXi’anP. R. China

Personalised recommendations