Abstract TP232: The Change Of Long-term Motor Functions After Post-stroke In Neuronal Cell Specific Sirt1 Knock-in Mice

Abstract

Background and Rationale: Ischemic stroke is one of the leading causes of morbidity and mortality. Sirt1 is an NAD+ dependent deacetylase known as an important regulator for stroke research. During ischemia, the expression of total Sirt1 is regulated down. To investigate the change of motor function in neuronal-specific Sirt1 overexpression, we generated the neuronal-specific Sirt1 knock-in (nSirt1 KI) mice and examined its behavior effect after post-stroke. Methods: To determine the role of Sirt1 in ischemic stroke, we tested the pharmacological effects of metformin and sirtinol, and to investigate the genetic role of neuronal Sirt1 in the brain, we generated the nSirt1 KI mice and induced the Ischemia/Reperfusion (I/R: 30 min. middle cerebral artery occlusion (MCAO)/1D-14D reperfusion after 30 min. MCAO) injury model. Infarction volume was measured by TTC staining and relative cerebral blood flow was measured by Laser Doppler. We also determined neurological deficit score (NDS), wire-hanging test, and cylinder test at 1D-14D after 30 min. MCAO. Protein levels from brain lysates in the cerebral cortex and hippocampus were studied by western blotting. Results: nSirt1 KI mice exhibited increased rCBF and reduced infarction volume compared to that of littermate control in I/R injury model. Based on western blotting analysis of brain tissue lysates in nSirt1 KI mice, the expression of Sirt1 was significantly increased by ~5 times. Overexpression of Sirt1 reduced infarction volume was reversed by sirtinol. The daily locomotor changes of neurological deficit score for 14 days were significantly changed compared to the littermate control. The Wire-hanging test shows that locomotor abnormality was improved in nSirt1 KI mice compared to littermate control. The Cylinder test shows that locomotor abnormality was improved in nSirt1 KI mice. We found that brain shrinkages at 14 days after post-stroke were not severe in nSirt1 KI mice compared to the littermate control. Conclusion: These findings indicate that the long-term enhancement of motor functions in neuronal Sirt1 overexpression may be an important therapeutic target for post-stroke and long survival.