Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke
| Autor: | Sudharsan Periyasamy-Thandavan, Kathleen M. Buckley, Harrison E. Grace, John R Barrett, Galina Kondrikova, David C. Hess, Patricia V. Schoenlein, Daniel L Hess, Irina Y Sazonova, Russell C. Kirks, Nasrul Hoda, William D. Hill, Maribeth H. Johnson |
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| Rok vydání: | 2014 |
| Předmět: |
Oncology
medicine.medical_specialty Neurology Cognitive Neuroscience Neuroscience (miscellaneous) 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Internal medicine Autophagy Medicine Rapamycin Stroke 030304 developmental biology 0303 health sciences business.industry Research Chloroquine Cerebral ischemia Infarct size medicine.disease Embolic stroke Ischemic stroke business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Experimental & Translational Stroke Medicine |
| ISSN: | 2040-7378 |
| DOI: | 10.1186/2040-7378-6-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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