ex-527 and Infarction--Middle-Cerebral-Artery

Necroptosis, a novel type of programmed cell death, is involved in ischemia-reperfusion-induced brain injury. Sirtuin 1 (Sirt1), as a well-known member of histone deacetylase class III, plays pivotal roles in inflammation, metabolism, and neuron loss in cerebral ischemia. We explored the relationship between Sirt1 and the necroptosis signaling pathway and its downstream events by administration of ex-527, as a selective and potent inhibitor of Sirt1, and necrostatin-1 (nec-1), as a necroptosis inhibitor, in an animal model of focal cerebral ischemia. Our data showed different patterns of sirt1 and necroptosis critical regulators, including receptor-interacting protein kinase 3 and mixed lineage kinase domain-like protein gene expressions in the prefrontal cortex and the hippocampus after ischemia-reperfusion. We found that ex-527 microinjection reduces the infarction volume of ischemic brains and improves the survival rate, but not stroke-associated neurological deficits. Additionally, treatment with ex-527 effectively abolished the elevation of the critical regulators of necroptosis, whereas necroptosis inhibition through nec-1 microinjection did not influence Sirt1 expression levels. Our data also demonstrated that the ex-527 relieves ischemia-induced perturbation of necroptosis-associated metabolic enzymes activity in downstream. This study provides a new approach to the possible neuroprotective potential of ex-527 orchestrated by necroptosis pathway inhibition to alleviate ischemia-reperfusion brain injury.

Topics: Animals; Carbazoles; Cell Death; Disease Models, Animal; Energy Metabolism; Gene Expression Regulation; Hippocampus; Imidazoles; Indoles; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Prefrontal Cortex; Protein Kinases; Rats, Wistar; Receptor-Interacting Protein Serine-Threonine Kinases; Reperfusion Injury; Signal Transduction; Sirtuin 1

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 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