ex-527 and Brain-Ischemia

Maresin 1 (MaR1) confers brain-protective effects against cerebral ischemia/reperfusion (I/R) injury. Activation of silent information regulator 1 (SIRT1) signaling has also been demonstrated to inhibit cerebral I/R injury. We hypothesize that MaR1 may protect against cerebral I/R injury by activating SIRT1 signaling. The present study investigated the protective effect of MaR1 treatment on cerebral I/R injury and elucidated the potential mechanisms. Mice were exposed to the treatment in the presence or absence of MaR1 or the SIRT1 inhibitor EX527 and then subjected to the middle cerebral artery occlusion (MCAO) operation. MaR1 conferred a brain-protective effect by up-regulating SIRT1 and Bcl2 expression, down-regulating acetylated neuclear factor kappaB (AC-NF-κB) and Bax expression, reducing pro-inflammatory factor levels (IL-1, IL-6 and TNF-α), increasing the mitochondrial membrane potential, and diminishing neuronal degeneration, the infarct size and the neurological defects of cerebral I/R. These protective effects were partially blocked by the SIRT1 inhibitor EX527, indicating that SIRT1 signaling might be specifically involved in the protection provided by MaR1 against cerebral I/R injury. In summary, our results demonstrate that MaR1 treatment attenuates cerebral I/R injury by reducing inflammatory responses and mitochondrial damage via activation of SIRT1 signaling.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Carbazoles; Docosahexaenoic Acids; Female; Infarction, Middle Cerebral Artery; Inflammation; Male; Membrane Potential, Mitochondrial; Mice; Oxidative Stress; Reperfusion; Reperfusion Injury; Signal Transduction; Sirtuin 1

Silent information regulator 1 (SIRT1), a type of histone deacetylase, is a highly effective therapeutic target for protection against ischemia reperfusion (IR) injury (IRI). Previous studies showed that melatonin preserves SIRT1 expression in neuronal cells of newborn rats after hypoxia-ischemia. However, the definite role of SIRT1 in the protective effect of melatonin against cerebral IRI in adult has not been explored. In this study, the brain of adult mice was subjected to IRI. Prior to this procedure, the mice were given intraperitoneal with or without the SIRT1 inhibitor, EX527. Melatonin conferred a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema, and increased neurological scores. The melatonin-induced upregulation of SIRT1 was also associated with an increase in the anti-apoptotic factor, Bcl2, and a reduction in the pro-apoptotic factor Bax. Moreover, melatonin resulted in a well-preserved mitochondrial membrane potential, mitochondrial Complex I activity, and mitochondrial cytochrome c level while it reduced cytosolic cytochrome c level. However, the melatonin-elevated mitochondrial function was reversed by EX527 treatment. In summary, our results demonstrate that melatonin treatment attenuates cerebral IRI by reducing IR-induced mitochondrial dysfunction through the activation of SIRT1 signaling.

Topics: Animals; Antioxidants; Brain Ischemia; Carbazoles; Cell Death; Male; Melatonin; Mice; Mitochondria; Rats; Signal Transduction; Sirtuin 1; Stroke

Silent information regulator 1 (SIRT1), a histone deacetylase, has been suggested to be effective in ischemic brain diseases. Salvianolic acid B (SalB) is a polyphenolic and one of the active components of Salvia miltiorrhiza Bunge. Previous studies suggested that SalB is protective against ischemic stroke. However, the role of SIRT1 in the protective effect of SalB against cerebral ischemia has not been explored. In this study, the rat brain was subjected to middle cerebral artery occlusion (MCAO). Before this surgery, rats were intraperitoneally administrated SalB with or without EX527, a specific SIRT1 inhibitor. The infarct volume, neurological score and brain water content were assessed. In addition, levels of TNF-α and IL-1β in the brain tissues were detected by commercial ELISA kits. And the expression levels of SIRT, Ac-FOXO1, Bcl-2 and Bax were detected by Western blot. The results suggested that SalB exerted a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema and increased neurological scores. SalB also exerted anti-inflammatory effects as indicated by the decreased TNF-α and IL-1β levels in the brain tissue. Moreover, SalB upregulated the expression of SIRT1 and Bcl-2 and downregulated the expression of Ac-FOXO1 and Bax. These effects of SalB were abolished by EX527 treatment. In summary, our results demonstrate that SalB treatment attenuates brain injury induced by ischemic stoke via reducing apoptosis and inflammation through the activation of SIRT1 signaling.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Benzofurans; Brain; Brain Edema; Brain Ischemia; Carbazoles; Central Nervous System Agents; Disease Models, Animal; Infarction, Middle Cerebral Artery; Inflammation; Male; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Severity of Illness Index; Sirtuin 1; Stroke; Treatment Outcome

Our previous studies have shown that hyperbaric oxygen preconditioning (HBO-PC) induces tolerance to cerebral ischemia/reperfusion (I/R). This study aimed to investigate whether SirT1, a class III histone deacetylase, is involved in neuroprotection elicited by HBO-PC in animal and cell culture models of ischemia. Rats were subjected to middle cerebral artery occlusion for 120 minutes after HBO-PC (once a day for 5 days). Primary cultured cortical neurons were exposed to 2 hours of HBO-PC after 2 hours of oxygen-glucose deprivation (OGD). We showed that HBO-PC increased SirT1 protein and mRNA expression, promoted neurobehavioral score, reduced infarct volume, and improved morphology at 24 hours and 7 days after cerebral I/R. Neuroprotection of HBO-PC was attenuated by SirT1 inhibitor EX527 and SirT1 knockdown by short interfering RNA (siRNA), whereas it was mimicked by SirT1 activator resveratrol. Furthermore, HBO-PC enhanced SirT1 expression and cell viability and reduced lactate dehydrogenase release 24 hours after OGD/re-oxygenation. The neuroprotective effect of HBO-PC was emulated through upregulating SirT1 and, reversely, attenuated through downregulating SirT1. The modulation of SirT1 was made by adenovirus infection carrying SirT1 or SirT1 siRNA. Besides, SirT1 increased B-cell lymphoma 2 (Bcl-2) expression and decrease cleaved caspase 3. These results indicate that SirT1 mediates HBO-PC-induced tolerance to cerebral I/R through inhibition of apoptosis.

Topics: Animals; Apoptosis; Brain Ischemia; Carbazoles; Caspase 3; Cell Hypoxia; Cell Survival; Cells, Cultured; Cerebral Cortex; Gene Expression Regulation, Enzymologic; Gene Knockdown Techniques; Hyperbaric Oxygenation; Nerve Tissue Proteins; Neurons; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sirtuin 1; Up-Regulation