Skip to main content

Advertisement

SpringerLink
Log in

p38α MAP Kinase Mediates Hypoxia-Induced Motor Neuron Cell Death: A Potential Target of Minocycline’s Neuroprotective Action

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

Abstract

Hypoxia-ischemia (HI) may play a significant role in motor neuron death associated with the pathology of spinal cord injury and, perhaps, amyotrophic lateral sclerosis. The present study employs an in vitro model of HI to investigate the role of a stress kinase pathway, i.e., p38 MAP kinase, in cell death signaling in a motor neuron cell line, i.e., NSC34, subjected to oxygen-glucose deprivation (OGD). Although the neurons were essentially tolerant to either hypoxia (0.2% O2) or low glucose (1 mM) alone, more than 60% of them died in response to combined low oxygen and low-glucose exposure. Minocycline, a semi-synthetic tetracycline known for its neuroprotective effects in models of neurodegeneration, afforded substantial (∼50%) protection against hypoxic cell death, assessed by lactate dehydrogenase release and flow cytometry, while suppressing OGD-induced p38 MAP kinase activation. An inhibitor of p38 kinase, SB203580, as well as siRNA-mediated down-regulation of p38 kinase elicited an almost complete blockade of OGD-induced cell death. The use of p38 isoform-specific siRNAs further revealed preferential involvement of the α over the β isoform of p38 MAP kinase in hypoxic neuronal cell death in our model.

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

Similar content being viewed by others

References

  1. Khot S, Tirschwell DL (2006) Long-term neurological complications after hypoxic-ischemic encephalopathy. Semin Neurol 26:422–431

    Article  PubMed  Google Scholar 

  2. Volpe JJ (1998) Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis. Semin Pediatr Neurol 5:135–151

    Article  PubMed  CAS  Google Scholar 

  3. Hossain MA (2005) Molecular mediators of hypoxic-ischemic injury and implications for epilepsy in the developing brain. Epilepsy Behav 7:204–213

    Article  PubMed  Google Scholar 

  4. Back SA (2006) Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms. Ment Retard Dev Disabil Res Rev 12:129–140

    Article  PubMed  Google Scholar 

  5. Young C, Tenkova T, Dikranian K, Olney JW (2004) Excitotoxic versus apoptotic mechanisms of neuronal cell death in perinatal hypoxia/ischemia. Curr Mol Med 4:77–85

    Article  PubMed  CAS  Google Scholar 

  6. Sugawara T, Fujimura M, Noshita N, Kim GW, Saito A, Hayashi T, Narasimhan P, Maier CM, Chan PH (2004) Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx 1:17–25

    Article  PubMed  Google Scholar 

  7. Perlman JM (2007) Pathogenesis of hypoxic-ischemic brain injury. J Perinatol Suppl 1:S39–S46

    Article  CAS  Google Scholar 

  8. Clarkson AN, Sutherland BA, Appleton I (2005) The biology and pathology of hypoxia-ischemia: an update. Arch Immunol Ther Exp 53:213–225

    CAS  Google Scholar 

  9. Nozaki K, Nishimura M, Hashimoto N (2001) Mitogen-activated protein kinases and cerebral ischemia. Mol Neurobiol 23:1–19

    Article  PubMed  CAS  Google Scholar 

  10. Barone FC, Irving FA, Ray AM., Lee JC, Kassis S, Kumar S, Badger AM, Legos JJ, Erhardt JA, Ohlstein EH, Hunter AJ, Harrison DC, Philpott K, Smith BR, Adams JL, Parsons AA (2001) Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev 21:129–145

    Article  PubMed  CAS  Google Scholar 

  11. Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631–637

    Article  PubMed  CAS  Google Scholar 

  12. Lopez-Neblina F, Toledo-Pereyra LH (2006) Phosphoregulation of signal transduction pathways in ischemia and reperfusion. J Surg Res 134:292–299

    Article  PubMed  Google Scholar 

  13. Harper SJ, LoGrasso P (2001) Signalling for survival and death in neurones: the role of stress-activated kinases, JNK and p38. Cell Signal 13:299–310

    Article  PubMed  CAS  Google Scholar 

  14. Zhuang S, Schnellmann RG (2007) A death-promoting role for extracellular signal-regulated kinase. J Pharmacol Exp Ther 319:991–997

    Article  CAS  Google Scholar 

  15. Schieven GL (2005) The biology of p38 kinase: a central role in inflammation. Curr Top Med Chem 5:921–928

    Article  PubMed  CAS  Google Scholar 

  16. Zarubin T, Han J (2005) Activation and signaling of the p38 MAP kinase pathway. Cell Res 15:11–18

    Article  PubMed  CAS  Google Scholar 

  17. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W (2005) Minocycline as a neuroprotective agent. Neuroscientist 11:308–322

    Article  PubMed  CAS  Google Scholar 

  18. Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 98:14669–14674

    Article  PubMed  CAS  Google Scholar 

  19. Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factorα gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18:1633–1641

    PubMed  CAS  Google Scholar 

  20. Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, Ferrante RJ, Kristal BS, Friedlander RM (2003) Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 100:10483–10487

    Article  PubMed  CAS  Google Scholar 

  21. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC., Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74–78

    Article  PubMed  CAS  Google Scholar 

  22. Takeda K, Ichijo H (2002) Neuronal p38 MAPK signalling: an emerging regulator of cell fate and function in the nervous system. Genes Cells 7:1099–1111

    Article  PubMed  CAS  Google Scholar 

  23. Cashman NR, Durham HD, Blusztajn JK, Oda K, Tabira T, Shaw IT, Dahrouge S, Antel JP (1992) Neuroblastoma x spinal cord (NSC) hybrid cell lines resemble developing motor neurons. Dev Dyn 194:209–221

    PubMed  CAS  Google Scholar 

  24. Guo G, Bhat NR (2006) Hypoxia/reoxygenation differentially modulates NF-kappaB activation and iNOS expression in astrocytes and microglia. Antioxid Redox Signal 8:911–918

    Article  PubMed  CAS  Google Scholar 

  25. Haddad JJ (2004) Hypoxia and the regulation of mitogen-activated protein kinases: gene transcription and the assessment of potential pharmacologic therapeutic interventions. Int Immunopharmacol 4:1249–1285

    Article  PubMed  CAS  Google Scholar 

  26. Sumbayev VV, Yasinska IM (2005) Regulation of MAP kinase-dependent apoptotic pathway: implication of reactive oxygen and nitrogen species. Arch Biochem Biophys 436:406–412

    Article  PubMed  CAS  Google Scholar 

  27. Mattson MP, Duan W, Pedersen WA., Culmsee C (2001) Neurodegenerative disorders and ischemic brain diseases. Apoptosis 6:69–81

    Article  PubMed  CAS  Google Scholar 

  28. Takman R, Jiang H, Schaefer E, Levine RA, Lazarovici P (2004) Nerve growth factor pretreatment attenuates oxygen and glucose deprivation-induced c-Jun amino-terminal kinase 1 and stress-activated kinases p38alpha and p38beta activation and confers neuroprotection in the pheochromocytoma PC12 Model. J Mol Neurosci 22(3):237–250

    Article  PubMed  Google Scholar 

  29. Emerling BM, Platanias LC, Black E, Nebreda AR, Davis RJ, Chandel NS (2005) Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling. Mol Cell Biol 25:4853–4862

    Article  PubMed  CAS  Google Scholar 

  30. Zhu Y, Mao XO, Sun Y, Xia Z, Greenberg DA (2002) p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. J Biol Chem 277:22909–22914

    Article  PubMed  CAS  Google Scholar 

  31. Porras A, Zuluaga S, Black E, Valladares A, Alvarez AM, Ambrosino C, Benito M, Nebreda AR (2004) p38{alpha} mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol Biol Cell 15:1059–1524

    Google Scholar 

  32. Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23:2838–2849

    Article  PubMed  CAS  Google Scholar 

  33. Yanagawa Y, Marcillo A, Garcia-Rojas R, Loor KE, Dietrich WD (2001) Influence of post-traumatic hypoxia on behavioral recovery and histopathological outcome following moderate spinal cord injury in rats. J Neurotrauma 18:635–644

    Article  PubMed  CAS  Google Scholar 

  34. Nakahara S, Yone K, Sakou T, Wada S, Nagamine T, Niiyama T, Ichijo H (1999) Induction of apoptosis signal regulating kinase 1 (ASK1) after spinal cord injury in rats: possible involvement of ASK1-JNK and -p38 pathways in neuronal apoptosis. J Neuropathol Exp Neurol 58:442–450

    Article  PubMed  CAS  Google Scholar 

  35. Horiuchi H, Ogata T, Morino T, Chuai M, Yamamoto H (2003) Continuous intrathecal infusion of SB203580, a selective inhibitor of p38 mitogen-activated protein kinase, reduces the damage of hind-limb function after thoracic spinal cord injury in rat. Neurosci Res 47:209–217

    Article  PubMed  CAS  Google Scholar 

  36. Bendotti C, Bao Cutrona M, Cheroni C, Grignaschi G, Lo Coco D, Peviani M, Tortarolo M, Veglianese P, Zennaro E (2005) Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase. Neurodegener Dis 2:128–134

    Article  PubMed  CAS  Google Scholar 

  37. Raoul C, Buhler E, Sadeghi C, Jacquier A, Aebischer P, Pettmann B, Henderson CE, Haase G (2006) Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. Proc Natl Acad Sci USA 103:6007–6012

    Article  PubMed  CAS  Google Scholar 

  38. Dewil M, dela Cruz VF, Van Den Bosch L, Robberecht W (2007) Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death. Neurobiol Dis. 26:332–341

    Article  PubMed  CAS  Google Scholar 

  39. Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM (2002) Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann Neurol 52(1):54–61

    Article  PubMed  CAS  Google Scholar 

  40. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496–13500

    Article  PubMed  CAS  Google Scholar 

  41. Liu Z, Fan Y, Won SJ, Neumann M, Hu D, Zhou L, Weinstein PR, Liu J (2007) Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38:146–152

    Article  PubMed  CAS  Google Scholar 

  42. Wells JE, Hurlbert RJ, Fehlings MG, Yong VW (2003) Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 126:1628–1637

    Article  PubMed  Google Scholar 

  43. Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, Woodard EJ, Snyder EY, Eichler ME, Friedlander RM (2004) Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci USA 101:3071–3076

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by NIA grant P01 AG 023630 and a pilot grant from South Carolina spinal cord injury research fund.

Author information

Authors and Affiliations

  1. Department of Neurosciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425, USA

    Guiwen Guo & Narayan R. Bhat

Authors
  1. Guiwen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Narayan R. Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Narayan R. Bhat.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guo, G., Bhat, N.R. p38α MAP Kinase Mediates Hypoxia-Induced Motor Neuron Cell Death: A Potential Target of Minocycline’s Neuroprotective Action. Neurochem Res 32, 2160–2166 (2007). https://doi.org/10.1007/s11064-007-9408-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-007-9408-8

Keywords

Search

Navigation