Atorvastatin pretreatment attenuates kainic acid-induced hippocampal neuronal death via regulation of lipocalin-2-associated neuroinflammation

Statins mediate vascular protection and reduce the prevalence of cardiovascular diseases. Recent work indicates that statins have anticonvulsive effects in the brain; however, little is known about the precise mechanism for its protective effect in kainic acid (KA)-induced seizures. Here, we investigated the protective effects of atorvastatin pretreatment on KA-induced neuroinflammation and hippocampal cell death. Mice were treated via intragastric administration of atorvastatin for 7 days, injected with KA, and then sacrificed after 24 h. We observed that atorvastatin pretreatment reduced KA-induced seizure activity, hippocampal cell death, and neuroinflammation. Atorvastatin pretreatment also inhibited KA-induced lipocalin-2 expression in the hippocampus and attenuated KA-induced hippocampal cyclooxygenase-2 expression and glial activation. Moreover, AKT phosphorylation in KA-treated hippocampus was inhibited by atorvastatin pretreatment. These findings suggest that atorvastatin pretreatment may protect hippocampal neurons during seizures by controlling lipocalin-2-associated neuroinflammation.

Cilostazol attenuates kainic acid-induced hippocampal cell death

Cilostazol is a selective inhibitor of type 3 phosphodiesterase (PDE3) and has been widely used as an antiplatelet agent. Cilostazol mediates this activity through effects on the cyclic adenosine monophosphate (cAMP) signaling cascade. Recently, it has attracted attention as a neuroprotective agent. However, little is known about cilostazol's effect on excitotoxicity induced neuronal cell death. Therefore, this study evaluated the neuroprotective effect of cilostazol treatment against hippocampal neuronal damage in a mouse model of kainic acid (KA)-induced neuronal loss. Cilostazol pretreatment reduced KA-induced seizure scores and hippocampal neuron death. In addition, cilostazol pretreatment increased cAMP response element-binding protein (CREB) phosphorylation and decreased neuroinflammation. These observations suggest that cilostazol may have beneficial therapeutic effects on seizure activity and other neurological diseases associated with excitotoxicity.

Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice

Sirtuin 1 (SIRT1) is a mammalian NAD+-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-kappaB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

Exendin-4 Improves Nonalcoholic Fatty Liver Disease by Regulating Glucose Transporter 4 Expression in ob/ob Mice

Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been known to reverse hepatic steatosis in ob/ob mice. Although many studies have evaluated molecular targets of Ex-4, its mechanism of action on hepatic steatosis and fibrosis has not fully been determined. In the liver, glucose transporter 4 (GLUT4) is mainly expressed in hepatocytes, endothelial cells and hepatic stellate cells (HSCs). In the present study, the effects of Ex-4 on GLUT4 expression were determined in the liver of ob/ob mice. Ob/ob mice were treated with Ex-4 for 10 weeks. Serum metabolic parameters, hepatic triglyceride levels, and liver tissues were evaluated for hepatic steatosis. The weights of the whole body and liver in ob/ob mice were reduced by long-term Ex-4 treatment. Serum metabolic parameters, hepatic steatosis, and hepatic fibrosis in ob/ob mice were reduced by Ex-4. Particularly, Ex-4 improved hepatic steatosis by enhancing GLUT4 via GLP-1R activation in ob/ob mice. Ex-4 treatment also inhibited hepatic fibrosis by decreasing expression of connective tissue growth factor in HSCs of ob/ob mice. Our data suggest that GLP-1 agonists exert a protective effect on hepatic steatosis and fibrosis in obesity and type 2 diabetes.

Curcumin Attenuates Radiation-Induced Inflammation and Fibrosis in Rat Lungs

A beneficial radioprotective agent has been used to treat the radiation-induced lung injury. This study was performed to investigate whether curcumin, which is known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric curcumin (200 mg/kg) prior to a single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage accumulation, interstitial edema, alveolar septal thickness, perivascular fibrosis, and collapse in radiation-treated lungs were inhibited by curcumin administration. Radiation-induced transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) expression, and collagen accumulation were also inhibited by curcumin. Moreover, western blot analysis revealed that curcumin lowered radiation-induced increases of tumor necrosis factor-alpha (TNF-alpha), TNF receptor 1 (TNFR1), and cyclooxygenase-2 (COX-2). Curcumin also inhibited the nuclear translocation of nuclear factor-kappa B (NF-kappaB) p65 in radiation-treated lungs. These results indicate that long-term curcumin administration may reduce lung inflammation and fibrosis caused by radiation treatment.

Resveratrol activates AMPK and suppresses LPS-induced NF-kappaB-dependent COX-2 activation in RAW 264.7 macrophage cells / 대한해부학회지

AMP-activated protein kinase (AMPK), an enzyme involved in energy homeostasis, regulates inflammatory responses, but its precise mechanisms are not fully understood. Recent evidence has shown that resveratrol (RES), an AMPK activator, reduces prostaglandin E2 production in lipopolysaccharide (LPS)-treated microglia. Here, we examined the effect of RES on nuclear factor kappa B (NF-kappaB) dependent cyclooxygenase (COX)-2 activation in LPS-treated RWA 264.7 macrophages. We found that treatment with RES increased AMPK activation. AMPK and acetyl CoA carboxylase phosphorylation were attenuated in cells treated with LPS+RES, compared to cells treated with LPS alone. RES inhibited tumor necrosis factor (TNF)-alpha and TNF receptor 1 in LPS-treated cells. Finally, RES inhibited LPS-induced NF-kappaB translocation into the nucleus and COX-2 expression. Moreover, the effects of 5-aminoimidazole-4-carboxamide ribose and compound C were consistent with the effects of RES in LPS-treated cells. Taken together, these results suggest that the anti-inflammatory action of RES in RAW 264.7 macrophages is dependent on AMPK activation and is associated with inhibition of the LPS-stimulated NF-kappaB-dependent COX-2 signaling pathway.

Streptozotocin-induced Diabetes Increases the Adiponectin-mediated AMP-activated Protein Kinase Cascade in the Hippocampus of Mice / 대한해부학회지

Adiponectin is an adipocyte-derived protein with anti-diabetic and anti-angiogenesis properties that improves both glucose metabolism and insulin resistance via the adenosine monophosphate-activated protein kinase (AMPK) cascade. Diabetic cognitive deficits are correlated with dysregulation of energy metabolism in the hippocampus. In the present study, we investigated the expression of adiponectin-mediated AMPK cascade proteins in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Diabetes was induced by STZ (55 mg/kg) injection intraperitoneally. Twenty-four weeks after induction of diabetes, mice were sacrificed. Results showed that decreased serum adiponectin levels and increased expression of hippocampal adiponectin receptor 1 (AdipoR1) was expressed in diabetic mice. Phosphorylated AMPK, acetyl CoA carboxylase (ACC), and eNOS expression levels were increased in the hippocampus of diabetic mice. The immunoreactivity of glucose transporter 1 in the endothelium of hippocampal blood vessels was also increased. These results indicate that adiponectin-mediated AMPK cascade activation may play a role in catabolic process that is involved in diabetic neurodegeneration.