ag-490 and Brain-Infarction

Tetramethylpyrazine (TMP) has been studied in depth and is widely used in the treatment of many kinds of diseases in China. However, whether it has neuroprotective effects on cerebral ischemia remains unclear. An ischemia/reperfusion (I/R) injury animal model was established via middle cerebral artery occlusion in this study. We set several different groups in which the rats were performed in different ways to explore the effects of TMP on blood-brainbarrier (BBB) disruption and determine whether TMP relieved BBB disruption through blocking the JAK/STAT signaling pathway. Our results showed that TMP could reduce the neurological functional loss, decrease the brain edema and BBB permeability, as well as increase the expression of tight junction proteins via inhibiting the activation of JAK/STAT signaling pathway. Overall, we demonstrated that TMP promoted neurological recovery after I/R injury via restoring the integrity and function of BBB.

Topics: Animals; Apoptosis; Blood-Brain Barrier; Brain Infarction; Cytoprotection; JNK Mitogen-Activated Protein Kinases; Neurons; Pyrazines; Rats; Reperfusion Injury; Signal Transduction; STAT Transcription Factors; Tyrphostins; Water

Cerebral ischemia and reperfusion increase superoxide anions (O(2)(*-)) in brain mitochondria. Manganese superoxide dismutase (Mn-SOD; SOD2), a primary mitochondrial antioxidant enzyme, scavenges superoxide radicals and its overexpression provides neuroprotection. However, the regulatory mechanism of Mn-SOD expression during cerebral ischemia and reperfusion is still unclear. In this study, we identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse Mn-SOD gene, and elucidated the mechanism of O(2)(*-) overproduction after transient focal cerebral ischemia (tFCI). We found that Mn-SOD expression is significantly reduced by reperfusion in the cerebral ischemic brain. We also found that activated STAT3 is usually recruited into the mouse Mn-SOD promoter and upregulates transcription of the mouse Mn-SOD gene in the normal brain. However, at early postreperfusion periods after tFCI, STAT3 was rapidly downregulated, and its recruitment into the Mn-SOD promoter was completely blocked. In addition, transcriptional activity of the mouse Mn-SOD gene was significantly reduced by STAT3 inhibition in primary cortical neurons. Moreover, we found that STAT3 deactivated by reperfusion induces accumulation of O(2)(*-) in mitochondria. The loss of STAT3 activity induced neuronal cell death by reducing Mn-SOD expression. Using SOD2-/+ heterozygous knock-out mice, we found that Mn-SOD is a direct target of STAT3 in reperfusion-induced neuronal cell death. Our study demonstrates that STAT3 is a novel transcription factor of the mouse Mn-SOD gene and plays a crucial role as a neuroprotectant in regulating levels of reactive oxygen species in the mouse brain.

Topics: Animals; Brain; Brain Infarction; Brain Ischemia; Cells, Cultured; Chromatin Immunoprecipitation; Cytochromes c; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Embryo, Mammalian; Glucose; Humans; Hypoxia; Interleukin-6; Male; Mice; Mice, Knockout; Neurons; Neuroprotective Agents; Reperfusion; RNA, Small Interfering; STAT3 Transcription Factor; Superoxide Dismutase; Time Factors; Transfection; Tyrphostins; Up-Regulation