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

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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Article number8
JournalExperimental and Translational Stroke Medicine
Volume6
Issue number1
DOIs
StatePublished - Jun 21 2014

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Autophagy
Middle Cerebral Artery
Sirolimus
Ligation
Up-Regulation
Stroke
Chloroquine
Middle Cerebral Artery Infarction
Reperfusion
Survival
Outcome Assessment (Health Care)
Pharmacology
Apoptosis

Keywords

  • Autophagy
  • Cerebral ischemia
  • Chloroquine
  • Embolic stroke
  • Rapamycin

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Cognitive Neuroscience

Cite this

Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. / Buckley, Kathleen M.; Hess, Daniel L.; Sazonova, Irina Yurievna; Periyasamy Thandavan, Sudharsan; Barrett, John Ryan; Kirks, Russell; Grace, Harrison; Kondrikova, Galina; Johnson, Maribeth H; Hess, David C; Schoenlein, Patricia V; Hoda, MD Nasrul; Hill, William D.

In: Experimental and Translational Stroke Medicine, Vol. 6, No. 1, 8, 21.06.2014.

Research output: Contribution to journalArticle

Buckley, Kathleen M. ; Hess, Daniel L. ; Sazonova, Irina Yurievna ; Periyasamy Thandavan, Sudharsan ; Barrett, John Ryan ; Kirks, Russell ; Grace, Harrison ; Kondrikova, Galina ; Johnson, Maribeth H ; Hess, David C ; Schoenlein, Patricia V ; Hoda, MD Nasrul ; Hill, William D. / Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. In: Experimental and Translational Stroke Medicine. 2014 ; Vol. 6, No. 1.
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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.",
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T1 - Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke

AU - Buckley, Kathleen M.

AU - Hess, Daniel L.

AU - Sazonova, Irina Yurievna

AU - Periyasamy Thandavan, Sudharsan

AU - Barrett, John Ryan

AU - Kirks, Russell

AU - Grace, Harrison

AU - Kondrikova, Galina

AU - Johnson, Maribeth H

AU - Hess, David C

AU - Schoenlein, Patricia V

AU - Hoda, MD Nasrul

AU - Hill, William D

PY - 2014/6/21

Y1 - 2014/6/21

N2 - 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.

AB - 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.

KW - Autophagy

KW - Cerebral ischemia

KW - Chloroquine

KW - Embolic stroke

KW - Rapamycin

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