Abstract
Background and purposeThe 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.MethodsWe 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.ResultsChloroquine 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.ConclusionsWhile 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.
Highlights
Autophagy, a cell survival process has recently been recognized as being involved in human strokes [1,2]
Autophagy in the brain We demonstrated that the brain has the highest level of autophagy relative to other metabolically active tissues
We found a trend for LC3II to accumulate following brief chloroquine treatment (Figure 1D-E)
Summary
A cell survival process has recently been recognized as being involved in human strokes [1,2]. Normal regulation of protective autophagy may be overwhelmed following large ischemic injuries, which either allow apoptotic cell death to precede, or even lead to an autophagic mediated form of cell death [7] As such, it is controversial whether increasing, or inhibiting, autophagy is protective following stroke. While autophagy has been studied in animal models of adult and neonatal brain ischemia, most of the studies are inconclusive, or have produced contradictory outcomes [1,3,4,7] This lack of consensus on the role of autophagy in stroke injury may in large part be due to methodological approaches where autophagy has been either “induced” or “inhibited”, but not compared side by side in the same study. We sought to clarify this by comparing pharmacologic modulation of autophagy in two clinically relevant murine models of stroke
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