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Hypothermia protects human neurons

Journal Article


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Abstract


  • Background and Aims: Hypothermia provides neuroprotection after cardiac arrest, hypoxic-ischemic encephalopathy, and in animal models of ischemic stroke. However, as drug development for stroke has been beset by translational failure, we sought additional evidence that hypothermia protects human neurons against ischemic injury.

    Methods: Human embryonic stem cells were cultured and differentiated to provide a source of neurons expressing β III tubulin, microtubule-associated protein 2, and the Neuronal Nuclei antigen. Oxygen deprivation, oxygen-glucose deprivation, and H 2 O 2 -induced oxidative stress were used to induce relevant injury.

    Results: Hypothermia to 33°C protected these human neurons against H 2 O 2 -induced oxidative stress reducing lactate dehydrogenase release and Terminal deoxynucleotidyl transferase dUTP nick end labeling-staining by 53% (P≤0·0001; 95% confidence interval 34·8-71·04) and 42% (P≤0·0001; 95% confidence interval 27·5-56·6), respectively, after 24h in culture. Hypothermia provided similar protection against oxygen-glucose deprivation (42%, P≤0·001, 95% confidence interval 18·3-71·3 and 26%, P≤0·001; 95% confidence interval 12·4-52·2, respectively) but provided no protection against oxygen deprivation alone. Protection (21%) persisted against H 2 O 2 -induced oxidative stress even when hypothermia was initiated six-hours after onset of injury (P≤0·05; 95% confidence interval 0·57-43·1).

    Conclusion: We conclude that hypothermia protects stem cell-derived human neurons against insults relevant to stroke over a clinically relevant time frame. Protection against H 2 O 2 -induced injury and combined oxygen and glucose deprivation but not against oxygen deprivation alone suggests an interaction in which protection benefits from reduction in available glucose under some but not all circumstances.

Authors


  •   Antonic, Ana (external author)
  •   Dottori, Mirella
  •   Leung, Jessie (external author)
  •   Sidon, Kate (external author)
  •   Batchelor, Peter (external author)
  •   Wilson, William J. (external author)
  •   Macleod, Malcolm (external author)
  •   Howells, D (external author)

Publication Date


  • 2014

Citation


  • Antonic, A., Dottori, M., Leung, J., Sidon, K., Batchelor, P. E., Wilson, W., Macleod, M. R. & Howells, D. W. (2014). Hypothermia protects human neurons. International Journal of Stroke, 9 (5), 544-552.

Scopus Eid


  • 2-s2.0-84902079187

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2186&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1160

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 544

End Page


  • 552

Volume


  • 9

Issue


  • 5

Place Of Publication


  • United Kingdom

Abstract


  • Background and Aims: Hypothermia provides neuroprotection after cardiac arrest, hypoxic-ischemic encephalopathy, and in animal models of ischemic stroke. However, as drug development for stroke has been beset by translational failure, we sought additional evidence that hypothermia protects human neurons against ischemic injury.

    Methods: Human embryonic stem cells were cultured and differentiated to provide a source of neurons expressing β III tubulin, microtubule-associated protein 2, and the Neuronal Nuclei antigen. Oxygen deprivation, oxygen-glucose deprivation, and H 2 O 2 -induced oxidative stress were used to induce relevant injury.

    Results: Hypothermia to 33°C protected these human neurons against H 2 O 2 -induced oxidative stress reducing lactate dehydrogenase release and Terminal deoxynucleotidyl transferase dUTP nick end labeling-staining by 53% (P≤0·0001; 95% confidence interval 34·8-71·04) and 42% (P≤0·0001; 95% confidence interval 27·5-56·6), respectively, after 24h in culture. Hypothermia provided similar protection against oxygen-glucose deprivation (42%, P≤0·001, 95% confidence interval 18·3-71·3 and 26%, P≤0·001; 95% confidence interval 12·4-52·2, respectively) but provided no protection against oxygen deprivation alone. Protection (21%) persisted against H 2 O 2 -induced oxidative stress even when hypothermia was initiated six-hours after onset of injury (P≤0·05; 95% confidence interval 0·57-43·1).

    Conclusion: We conclude that hypothermia protects stem cell-derived human neurons against insults relevant to stroke over a clinically relevant time frame. Protection against H 2 O 2 -induced injury and combined oxygen and glucose deprivation but not against oxygen deprivation alone suggests an interaction in which protection benefits from reduction in available glucose under some but not all circumstances.

Authors


  •   Antonic, Ana (external author)
  •   Dottori, Mirella
  •   Leung, Jessie (external author)
  •   Sidon, Kate (external author)
  •   Batchelor, Peter (external author)
  •   Wilson, William J. (external author)
  •   Macleod, Malcolm (external author)
  •   Howells, D (external author)

Publication Date


  • 2014

Citation


  • Antonic, A., Dottori, M., Leung, J., Sidon, K., Batchelor, P. E., Wilson, W., Macleod, M. R. & Howells, D. W. (2014). Hypothermia protects human neurons. International Journal of Stroke, 9 (5), 544-552.

Scopus Eid


  • 2-s2.0-84902079187

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2186&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1160

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 544

End Page


  • 552

Volume


  • 9

Issue


  • 5

Place Of Publication


  • United Kingdom