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Buckley KM, Hess DL, Sazonova IY, et al. Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp Transl Stroke Med. 2014;6:8doi: 10.1186/2040-7378-6-8.
Buckley, K. M., Hess, D. L., Sazonova, I. Y., Periyasamy-Thandavan, S., Barrett, J. R., Kirks, R., Grace, H., Kondrikova, G., Johnson, M. H., Hess, D. C., Schoenlein, P. V., Hoda, M. N., & Hill, W. D. (2014). Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Experimental & translational stroke medicine, 68. https://doi.org/10.1186/2040-7378-6-8
Buckley, Kathleen M, et al. "Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke." Experimental & translational stroke medicine vol. 6 (2014): 8. doi: https://doi.org/10.1186/2040-7378-6-8
Buckley KM, Hess DL, Sazonova IY, Periyasamy-Thandavan S, Barrett JR, Kirks R, Grace H, Kondrikova G, Johnson MH, Hess DC, Schoenlein PV, Hoda MN, Hill WD. Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp Transl Stroke Med. 2014 Jun 21;6:8. doi: 10.1186/2040-7378-6-8. eCollection 2014. PMID: 24991402; PMCID: PMC4079187.
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Exp Transl Stroke Med. 2014 Jun 21;6:8. doi: 10.1186/2040-7378-6-8. eCollection 2014.

Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke.

Experimental & translational stroke medicine

Kathleen M Buckley, Daniel L Hess, Irina Y Sazonova, Sudharsan Periyasamy-Thandavan, John R Barrett, Russell Kirks, Harrison Grace, Galina Kondrikova, Maribeth H Johnson, David C Hess, Patricia V Schoenlein, Md Nasrul Hoda, William D Hill

Affiliations

  1. Charlie Norwood VA Medical Center, Augusta, GA, USA ; Department of Cellular Biology & Anatomy, Georgia Regents University, Augusta, GA, USA.
  2. The University of Virginia, School of Medicine, Charlottesville, VA, USA.
  3. Department of Neurology, Georgia Regents University, Augusta, GA, USA ; Department of Medicine, Georgia Regents University, Augusta, GA, USA.
  4. Department of Emergency Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
  5. Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA.
  6. Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
  7. Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, GA, USA.
  8. Department of Neurology, Georgia Regents University, Augusta, GA, USA.
  9. Department of Cellular Biology & Anatomy, Georgia Regents University, Augusta, GA, USA.
  10. Charlie Norwood VA Medical Center, Augusta, GA, USA ; Department of Neurology, Georgia Regents University, Augusta, GA, USA ; Medical Laboratory, Imaging & Radiologic Sciences, Georgia Regents University, Augusta, GA, USA ; Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA.
  11. Charlie Norwood VA Medical Center, Augusta, GA, USA ; Department of Cellular Biology & Anatomy, Georgia Regents University, Augusta, GA, USA ; Department of Neurology, Georgia Regents University, Augusta, GA, USA.

PMID: 24991402 PMCID: PMC4079187 DOI: 10.1186/2040-7378-6-8

Abstract

BACKGROUND AND PURPOSE: The role of autophagy in response to ischemic stroke has been confusing with reports that both enhancement and inhibition of autophagy decrease infarct size and improve post-stroke outcomes. We sought to clarify this by comparing pharmacologic modulation of autophagy in two clinically relevant murine models of stroke.

METHODS: We used rapamycin to induce autophagy, and chloroquine to block completion of autophagy, by treating mice immediately after stroke and at 24 hours post-stroke in two different models; permanent Middle Cerebral Artery Ligation (MCAL), which does not allow for reperfusion of distal trunk of middle cerebral artery, and Embolic Clot Middle Cerebral Artery Occlusion (eMCAO) which allows for a slow reperfusion similar to that seen in most human stroke patients. Outcome measures at 48 hours post-stroke included infarct size analysis, behavioral assessment using Bederson neurological scoring, and survival.

RESULTS: Chloroquine treatment reduced the lesion size by approximately 30% and was significant only in the eMCAO model, where it also improved the neurological score, but did not increase survival. Rapamycin reduced lesion size by 44% and 50% in the MCAL and eMCAO models, respectively. Rapamycin also improved the neurological score to a greater degree than chloroquine and improved survival.

CONCLUSIONS: While both inhibition and enhancement of autophagy by pharmacological intervention decreased lesion size and improved neurological scores, the enhancement with rapamycin showed a greater degree of improvement in outcomes as well as in survival. The protective action seen with chloroquine may be in part due to off-target effects on apoptosis separate from blocking lysosomal activity in autophagy. We conclude pharmacologic induction of autophagy is more advantageous than its blockade in physiologically-relevant permanent and slow reperfusion stroke models.

Keywords: Autophagy; Cerebral ischemia; Chloroquine; Embolic stroke; Rapamycin

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