TY - JOUR
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 R.
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
N1 - Funding Information:
The authors thank Marina A Zemskova for her help with TTC analysis. This publication is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development with VA Merit Award 104462 (WDH), by the National Institutes of Health with NIA-AG036675-01 (WDH), R21NS081143 (DCH), R21-NS072318 (IYS), and by the American Legion Department of Georgia (WDH). This work was also partially supported by GRU start-up funds (MNH and IYS). The contents of this publication do not represent the views of the Department of Veterans Affairs, or the United States Government.
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
UR - http://www.scopus.com/inward/record.url?scp=84902722491&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902722491&partnerID=8YFLogxK
U2 - 10.1186/2040-7378-6-8
DO - 10.1186/2040-7378-6-8
M3 - Article
AN - SCOPUS:84902722491
VL - 6
JO - Experimental and Translational Stroke Medicine
JF - Experimental and Translational Stroke Medicine
SN - 2040-7378
IS - 1
M1 - 8
ER -