Tetramethylpyrazine Analogue CXC195 Protects against Cerebral Ischemia/Reperfusion Injury in the Rat by an Antioxidant Action via Inhibition of NADPH Oxidase and iNOS Expression

Abstract

Aims: This study was conducted to investigate the protective effects of CXC195, a tetramethylpyrazine analogue, in acute focal cerebral ischemia/reperfusion (I/R) injury in rats and to elucidate the potential mechanism. Methods: Middle cerebral artery occlusion for 2 h followed by reperfusion for 24 h was conducted in male Wistar rats and different doses of tetramethylpyrazine and CXC195 were intraperitoneally injected at 30 min after reperfusion. Results: Our results demonstrated that CXC195 at the dosage of 3 and 10 mg/kg significantly reduced the neurological deficit score and the infarct volume compared to the vehicle-treated group. In addition, CXC195 exhibited a protective effect against hippocampus neuronal cell death and significantly restored the brain ATP content. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidative capability (T-AOC), as well as production of malondialdehyde (MDA) and reactive oxygen species (ROS) were assayed in ipsilateral hemisphere homogenates to evaluate the redox status after I/R injury. Treatment with CXC195 significantly attenuated the decrease of SOD, GPx and T-AOC activities and inhibited the elevation of MDA content and ROS generation. Furthermore, CXC195 prevented the upregulation of the NADPH oxidase (NOX) 2 and NOX4, and reduced inducible nitric oxide synthase (iNOS) induction and production of nitric oxide induced by I/R. Conclusion: These results suggest that CXC195 has a neuroprotective effect in transient focal ischemia, which is most likely due to its antioxidant activity by inhibiting NOX and iNOS expression.

Endothelial nitric oxide synthase inhibition triggers inflammatory responses in the brain of male rats exposed to ischemia‐reperfusion injury

“…Accordingly, we have found that elevation of miR‐155 by ischemia and L‐NIO is paralleled by an elevation of the percentage of CD40 + /CD68 + M1 microglia macrophages, which is coincident with an increase of iNOS mRNA expression in immune cells isolated by Percoll gradient from the ischemic cortex. This latter finding is consistent with previous observations demonstrating elevation of iNOS protein levels after 1‐hr MCAo followed by 24 hr of reperfusion (Liu et al, ; Niu et al, ; Tsai et al, ) and suggests that eNOS inhibition promotes inflammatory responses in local microglia and infiltrating leukocytes that contribute to ischemic brain injury. Accordingly, previous findings have shown that iNOS both in neutrophils and endothelium mediates ischemic tissue damage (Garcia‐Bonilla et al, ).…”

Ischemic Postconditioning-Regulated miR-499 Protects the Rat Heart Against Ischemia/Reperfusion Injury by Inhibiting Apoptosis through PDCD4

“…MDA (a ROS and an index for oxidative stress) is a critical component of NADPH oxidase and is produced through lipid peroxidation. Increased MDA levels result in the release of myocardial enzymes and their subsequent attack on structural proteins and cells [38]. Given that oxidative stress is a crucial event in I/R injury, inhibition of oxidative stress is considered a viable approach to treat I/R-induced cardiac injury.…”

IRE1α-TRAF2-ASK1 complex-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to CXC195-induced apoptosis in human bladder carcinoma T24 cells

“…CXC195 are known as a TMP analog and have the antioxidant activity and anti-apoptotic effect in neuron [13,14] and HUVECs [15]. Recent studies have shown that CXC195 inhibit proliferation and inflammatory response of LPS-induced human hepatocellular carcinoma HepG2 cells [16].…”

“…CXC195 is a TMP analog showing the antioxidant activity and anti-apoptotic effect in transient focal ischemia via inhibiting NADPH Oxidase and iNOS expression [13] and regulating PI3K-AKT-GSK3b pathway [14]. In addition, CXC195 could prevent human umbilical vein endothelial cells (HUVECs) from H 2 O 2 -induced apoptosis through inhibition of the mitochondriaand caspase-dependent pathway [15].…”