Skip to main content

Advertisement

SpringerLink
Log in

Neuroprotective effects of lithium treatment following hypoxic–ischemic brain injury in neonatal rats

  • Original Paper
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Purpose

Increasing evidence indicates that lithium is a neuroprotective agent against transient focal and global ischemic injury in the adult animal. In the developing brain, lithium has shown protective effects against neuroapoptosis induced by drugs. This study was designed to investigate the neuroprotective effects of lithium on hypoxic–ischemic brain injury in the neonatal rat.

Methods

Seven-day-old Sprague–Dawley rats underwent hypoxic–ischemic injury (HII) induced by ligation of the common carotid artery followed by exposure to ∼2.5 h of hypoxia (∼7% oxygen). After HII, rat pups were randomly assigned into two groups: a control group (n = 21), which received a daily subcutaneous injection of 0.9% normal saline for 14 days following HII; and a lithium group (n = 32), treated with daily injection of lithium chloride. N-acetylaspartate/creatinine, choline/creatinine, lipid/creatinine ratios at 1.3 ppm (Lip1.3/Cr) and 0.9 ppm (Lip0.9/Cr) lipid peaks were evaluated by proton magnetic resonance spectroscopy on the day of HII and on days 7 and 14 after HII. Infarct ratios based on magnetic resonance images were also determined at the same time points.

Results

Seven days after HII, the Lip1.3/Cr and Lip0.9/Cr ratios as well as the infarct ratio were significantly lower in the lithium group than in the control group. The Lip1.3/Cr and Lip0.9/Cr ratios were significantly correlated with infarct ratio.

Conclusion

This study showed that post-HII treatment with lithium may have a neuroprotective effect in the immature brain. Further studies are needed to elucidate the mechanism of neuroprotective properties of lithium against HII-induced neonatal brain damage.

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. Bian Q, Shi T, Chuang DM, Qian Y (2007) Lithium reduces ischemia-induced hippocampal CA1 damage and behavioral deficits in gerbils. Brain Res 1184:270–276

    Article  PubMed  CAS  Google Scholar 

  2. Blankenberg FG, Storrs RW, Naumovski L, Goralski T, Spielman D (1996) Detection of apoptotic cell death by proton nuclear magnetic resonance spectroscopy. Blood 87:1951–1956

    PubMed  CAS  Google Scholar 

  3. Brauer M (2003) In vivo monitoring of apoptosis. Prog Neuropsychopharmacol Biol Psychiatry 27:323–331

    Article  PubMed  CAS  Google Scholar 

  4. Cady EB, Penrice J, Amess PN, Lorek A, Wylezinska M, Aldridge RF, Franconi F, Wyatt JS, Reynolds EO (1996) Lactate, N-acetylaspartate, choline and creatine concentrations, and spin–spin relaxation in thalamic and occipito–parietal regions of developing human brain. Magn Reson Med 36:878–886

    Article  PubMed  CAS  Google Scholar 

  5. Calabresi P, Pisani A, Mercuri NB, Bernardi G (1993) Lithium treatment blocks long-term synaptic depression in the striatum. Neuron 10:955–962

    Article  PubMed  CAS  Google Scholar 

  6. Finley PR, Warner MD, Peabody CA (1995) Clinical relevance of drug interactions with lithium. Clin Pharmacokinet 29:172–191

    Article  PubMed  CAS  Google Scholar 

  7. Gasparovic C, Rosenberg GA, Wallace JA, Estrada EY, Roberts K, Pastuszyn A, Ahmed W, Graham GD (2001) Magnetic resonance lipid signals in rat brain after experimental stroke correlate with neutral lipid accumulation. Neurosci Lett 301:87–90

    Article  PubMed  CAS  Google Scholar 

  8. Ghribi O, Herman MM, Spaulding NK, Savory J (2002) Lithium inhibits aluminum-induced apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl-2 decrease, Bax elevation and caspase-3 activation. J Neurochem 82:137–145

    Article  PubMed  CAS  Google Scholar 

  9. Girard N, Confort-Gouny S, Schneider J, Barberet M, Chapon F, Viola A, Pineau S, Combaz X, Cozzone P (2007) MR imaging of brain maturation. J Neuroradiol 34:290–310

    Article  PubMed  CAS  Google Scholar 

  10. Groenendaal F, Veenhoven RH, van der Grond J, Jansen GH, Witkamp TD, de Vries LS (1994) Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy. Pediatr Res 35:148–151

    Article  PubMed  CAS  Google Scholar 

  11. Guo S, Arai K, Stins MF, Chuang DM, Lo EH (2009) Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. Stroke 40:652–655

    Article  PubMed  CAS  Google Scholar 

  12. Gwak M, Park P, Kim K, Lim K, Jeong S, Baek C, Lee J (2008) The effects of dantrolene on hypoxic–ischemic injury in the neonatal rat brain. Anesth Analg 106:227–233

    Article  PubMed  CAS  Google Scholar 

  13. Hakumaki JM, Poptani H, Sandmair AM, Yla-Herttuala S, Kauppinen RA (1999) 1H MRS detects polyunsaturated fatty acid accumulation during gene therapy of glioma: implications for the in vivo detection of apoptosis. Nat Med 5:1323–1327

    Article  PubMed  CAS  Google Scholar 

  14. Hakumaki JM, Brindle KM (2003) Techniques: visualizing apoptosis using nuclear magnetic resonance. Trends Pharmacol Sci 24:146–149

    Article  PubMed  CAS  Google Scholar 

  15. Harada K, Honmou O, Liu H, Bando M, Houkin K, Kocsis JD (2007) Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model. Brain Res 1134:206–213

    Article  PubMed  CAS  Google Scholar 

  16. Hashimoto R, Hough C, Nakazawa T, Yamamoto T, Chuang DM (2002) Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem 80:589–597

    Article  PubMed  CAS  Google Scholar 

  17. Houkin K, Nakayama N, Kamada K, Noujou T, Abe H, Kashiwaba T (1998) Neuroprotective effect of the free radical scavenger MCI-186 in patients with cerebral infarction: clinical evaluation using magnetic resonance imaging and spectroscopy. J Stroke Cerebrovasc Dis 7:315–322

    Article  PubMed  CAS  Google Scholar 

  18. Huppi PS, Lazeyras F (2001) Proton magnetic resonance spectroscopy ((1)H-MRS) in neonatal brain injury. Pediatr Res 49:317–320

    Article  PubMed  CAS  Google Scholar 

  19. Juranek I, Baciak L (2009) Cerebral hypoxia–ischemia: focus on the use of magnetic resonance imaging and spectroscopy in research on animals. Neurochem Int 54:471–480

    Article  PubMed  CAS  Google Scholar 

  20. Kim KS, Park SJ, Lim KH, Kim EJ, Lee JH, Pi SY (2000) In vivo 1H MR spectroscopic analysis of apoptosis in hypoxic-ischemic newborn rats. Proc Intl Soc Mag Reson Med 8:1090

    Google Scholar 

  21. Kim YR, van Meer MP, Tejima E, Murata Y, Mandeville JB, Dai G, Chuang DM, Rosen BR, Lo EH (2008) Functional MRI of delayed chronic lithium treatment in rat focal cerebral ischemia. Stroke 39:439–447

    Article  PubMed  Google Scholar 

  22. Kreis R, Hofmann L, Kuhlmann B, Boesch C, Bossi E, Huppi PS (2002) Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 48:949–958

    Article  PubMed  CAS  Google Scholar 

  23. Li H, Li Q, Du X, Sun Y, Wang X, Kroemer G, Blomgren K, Zhu C (2011) Lithium-mediated long-term neuroprotection in neonatal rat hypoxia–ischemia is associated with antiinflammatory effects and enhanced proliferation and survival of neural stem/progenitor cells. J Cereb Blood Flow Metab 31:2106–2115

    Article  PubMed  CAS  Google Scholar 

  24. Li Q, Li H, Roughton K, Wang X, Kroemer G, Blomgren K, Zhu C (2010) Lithium reduces apoptosis and autophagy after neonatal hypoxia–ischemia. Cell Death Dis 1:e56

    Article  PubMed  CAS  Google Scholar 

  25. Lindskog M, Kogner P, Ponthan F, Schweinhardt P, Sandstedt B, Heiden T, Helms G, Spenger C (2003) Noninvasive estimation of tumour viability in a xenograft model of human neuroblastoma with proton magnetic resonance spectroscopy (1H MRS). Br J Cancer 88:478–485

    Article  PubMed  CAS  Google Scholar 

  26. Lorenz JM, Wooliever DE, Jetton JR, Paneth N (1998) A quantitative review of mortality and developmental disability in extremely premature newborns. Arch Pediatr Adolesc Med 152:425–435

    PubMed  CAS  Google Scholar 

  27. Mikhailenko VM, Philchenkov AA, Zavelevich MP (2005) Analysis of 1H NMR-detectable mobile lipid domains for assessment of apoptosis induced by inhibitors of DNA synthesis and replication. Cell Biol Int 29:33–39

    Article  PubMed  CAS  Google Scholar 

  28. Nonaka S, Chuang DM (1998) Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport 9:2081–2084

    Article  PubMed  CAS  Google Scholar 

  29. Nonaka S, Hough CJ, Chuang DM (1998) Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-d-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci U S A 95:2642–2647

    Article  PubMed  CAS  Google Scholar 

  30. Omata N, Murata T, Takamatsu S, Maruoka N, Mitsuya H, Yonekura Y, Fujibayashi Y, Wada Y (2008) Neuroprotective effect of chronic lithium treatment against hypoxia in specific brain regions with upregulation of cAMP response element binding protein and brain-derived neurotrophic factor but not nerve growth factor: comparison with acute lithium treatment. Bipolar Disord 10:360–368

    Article  PubMed  CAS  Google Scholar 

  31. Palmer C, Vannucci RC, Towfighi J (1990) Reduction of perinatal hypoxic–ischemic brain damage with allopurinol. Pediatr Res 27:332–336

    Article  PubMed  CAS  Google Scholar 

  32. Peden CJ, Rutherford MA, Sargentoni J, Cox IJ, Bryant DJ, Dubowitz LM (1993) Proton spectroscopy of the neonatal brain following hypoxic–ischaemic injury. Dev Med Child Neurol 35:502–510

    Article  PubMed  CAS  Google Scholar 

  33. Pi SY, Kim KS, Yoon KH, Yoon HS, Lim KH, Kim EJ, Lee JH (2000) Investigation of hypoxic-ischemic injured newborn rat brain by in vivo 1H MR spectroscopy. Proc Intl Soc Mag Reson Med 8:1093

    Google Scholar 

  34. Rice JE 3rd, Vannucci RC, Brierley JB (1981) The influence of immaturity on hypoxic–ischemic brain damage in the rat. Ann Neurol 9:131–141

    Article  PubMed  Google Scholar 

  35. Serrai H, Senhadji L, Wang G, Akoka S, Stroman P (2003) Lactate doublet quantification and lipid signal suppression using a new biexponential decay filter: application to simulated and 1H MRS brain tumor time-domain data. Magn Reson Med 50:623–626

    Article  PubMed  CAS  Google Scholar 

  36. Straiko MM, Young C, Cattano D, Creeley CE, Wang H, Smith DJ, Johnson SA, Li ES, Olney JW (2009) Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology 110:862–868

    Article  PubMed  CAS  Google Scholar 

  37. Strbian D, Tatlisumak T, Ramadan UA, Lindsberg PJ (2007) Mast cell blocking reduces brain edema and hematoma volume and improves outcome after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 27:795–802

    PubMed  Google Scholar 

  38. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR (1990) A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290–293

    Article  PubMed  CAS  Google Scholar 

  39. Vannucci RC, Vannucci SJ (1997) A model of perinatal hypoxic–ischemic brain damage. Ann N Y Acad Sci 835:234–249

    Article  PubMed  CAS  Google Scholar 

  40. Vannucci RC, Vannucci SJ (2005) Perinatal hypoxic–ischemic brain damage: evolution of an animal model. Dev Neurosci 27:81–86

    Article  PubMed  CAS  Google Scholar 

  41. Xu J, Culman J, Blume A, Brecht S, Gohlke P (2003) Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death. Stroke 34:1287–1292

    Article  PubMed  CAS  Google Scholar 

  42. Yan XB, Hou HL, Wu LM, Liu J, Zhou JN (2007) Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. Neuropharmacology 53:487–495

    Article  PubMed  CAS  Google Scholar 

  43. Yan XB, Wang SS, Hou HL, Ji R, Zhou JN (2007) Lithium improves the behavioral disorder in rats subjected to transient global cerebral ischemia. Behav Brain Res 177:282–289

    Article  PubMed  CAS  Google Scholar 

  44. Young C, Straiko MM, Johnson SA, Creeley C, Olney JW (2008) Ethanol causes and lithium prevents neuroapoptosis and suppression of pERK in the infant mouse brain. Neurobiol Dis 31:355–360

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure statement

The authors declare that they have no conflicts of interest.

Funding source

This work was supported by a grant from Asan Institute for Life Sciences (Seoul, Korea).

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Pain Medicine, Asan Medical Center, Ulsan University College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul, South Korea

    Won-Jung Shin, Mijeung Gwak & Pyung-Hwan Park

  2. Department of Pediatrics, Asan Medical Center, Ulsan University College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul, South Korea

    Ki-Soo Kim

  3. Department of Anesthesiology and Pain Medicine, Chung-ang University Medical Center, 224-1 Heukseok-dong, Dongjak-gu, Seoul, South Korea

    Chong-Hwa Baek

Authors
  1. Won-Jung Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mijeung Gwak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chong-Hwa Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ki-Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pyung-Hwan Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mijeung Gwak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shin, WJ., Gwak, M., Baek, CH. et al. Neuroprotective effects of lithium treatment following hypoxic–ischemic brain injury in neonatal rats. Childs Nerv Syst 28, 191–198 (2012). https://doi.org/10.1007/s00381-011-1627-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-011-1627-2

Keywords

Search

Navigation