Time dependent neuroprotection of dexamethasone in experimental focal cerebral ischemia: The involvement of NF-κB pathways.

We propose that the neuroprotective effect of glucocorticoid in ischemic damage may be time dependent. The present study was designed to test the proposal and its possible mechanismin cerebral ischemia/reperfusion (I/R) injury model. Reperfusion injury was induced after 120 min of middle cerebral artery occlusion (MCAO) in male Sprague-Dawley rats. Atdifferenttimepoints after MCAO, rats were treated with high dose dexamethasone (10 mg/kg), and neurological deficit and infarct sizes were measured 2 h, 24 h after MCAO. The expression of NF-κB target genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were determined by western blot analysis and ELISA. Dexamethasone delivered 30 min (but not 60 min, 120 min) after MCAO markedly decreased the infarct size, improved neurological deficits in I/R injury model. Dexamethasone delivered 30 min (but not 60 min) after MCAO significantly inhibited NF-κB p65 expression and phosphorylation, compared with I/R group. The expression of iNOS, COX-2, TNF-α and IL-1β, were also suppressed by dexamethasone delivered 30 min (but not 60 min) after MCAO. The results imply that neuroprotective action of dexamethasone in focal ischemic stroke model may be time dependent and attributed to inhibiting inflammation-related NF-κB p65 pathways.

Sun WH ，He F ，Zhang NN ，Zhao ZA ，Chen HS ... -  《-》

Ruscogenin reduces cerebral ischemic injury via NF-κB-mediated inflammatory pathway in the mouse model of experimental stroke.

Transient cerebral ischemia initiates a complex series of inflammatory events, which has been associated with an increase in behavioral deficits and secondary brain damage. Ruscogenin is a major steroid sapogenin in the traditional Chinese herb Ophiopogon japonicus that have multiple bioactivities. Recent studies have demonstrated that Ruscogenin is involved in down-regulation of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) activation in anti-inflammatory pathways. We hypothesized that Ruscogenin protects against brain ischemia by inhibiting NF-κB-mediated inflammatory pathway. To test this hypothesis, adult male mice (C57BL/6 strain) were pretreated with Ruscogenin and then subjected to transient middle cerebral artery occlusion (MCAO)/reperfusion. After 1 h MCAO and 24 h reperfusion, neurological deficit, infarct sizes, and brain water content were measured. Ruscogenin markedly decreased the infarct size, improved neurological deficits and reduced brain water content after MCAO. The activation of NF-κB Signaling pathway was observed after 1h of ischemia and 1h of reperfusion, and Ruscogenin significantly inhibited NF-κB p65 expression, phosphorylation and translocation from cytosol to nucleus at this time point in a dose-dependent manner. NF-κB DNA binding activity, and the expression of NF-κB target genes, including ICAM-1, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were also suppressed by Ruscogenin pretreatment after 1 h MCAO and 24 h reperfusion. The results indicated that Ruscogenin protected the brain against ischemic damage caused by MCAO, and this effect may be through downregulation of NF-κB-mediated inflammatory responses.

Guan T ，Liu Q ，Qian Y ，Yang H ，Kong J ，Kou J ，Yu B ... -  《-》

Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway.

Luteoloside, a flavonoid compound, has been reported to have anti-inflammatory, anti-oxidative, antibacterial, antiviral, anticancer, and cardioprotective effects, among others, but its neuroprotective effects have rarely been studied. The purpose of this study was to investigate the protective effect of luteoloside on cerebral ischemia and explore its potential mechanism. Middle cerebral artery occlusion (MCAO) was performed to investigate the effects of luteoloside on cerebral ischemia-reperfusion (I/R). Male Sprague-Dawley rats were randomly divided into six groups: sham, MCAO, luteoloside (20 mg/kg, 40 mg/kg, 80 mg/kg) and nimodipine (4 mg/kg). The results showed that luteoloside alleviated neurologic deficits and cerebral edema as well as improved cerebral infarction and histopathological changes in MCAO rats. Luteoloside significantly inhibited I/R-induced neuroinflammation, as demonstrated by reduced levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the brain tissues of MCAO rats. Furthermore, our results demonstrated that luteoloside significantly suppressed the activation of nuclear factor-kappa B (NF-κB) signaling, upregulated the protein expression of peroxisome proliferator activated receptor gamma (PPARγ) and increased NF-E2-related factor (Nrf2) nuclear accumulation in MCAO rats. Collectively, our findings suggested that luteoloside played a crucial neuroprotective role by inhibiting NF-κB signaling in focal cerebral ischemia in rats. Furthermore, PPARγ and Nrf2 were also important for the anti-inflammatory effect of luteoloside. In addition, our data suggested that luteoloside might be an effective treatment for cerebral ischemia and other neurological disorders.

Li Q ，Tian Z ，Wang M ，Kou J ，Wang C ，Rong X ，Li J ，Xie X ，Pang X ... -  《-》

Perillyl alcohol improves functional and histological outcomes against ischemia-reperfusion injury by attenuation of oxidative stress and repression of COX-2, NOS-2 and NF-κB in middle cerebral artery occlusion rats.

Perillyl alcohol (PA) is a monoterpene found in essential oils of mints, cherries, citreous fruits and lemon grass, reported to have antioxidant and anti-inflammatory properties. However, the role of PA in stroke is still illusive. Since oxidative stress and inflammation play a pivotal role in ischemia-reperfusion (I-R) injury, this study was designed to elucidate the potential effects of PA against I-R induced pathology in rat׳s brain. Middle cerebral artery occlusion (MCAO) for 2h followed by 22h reperfusion in Wistar male rats (250-280g, 14-16 weeks old) induced the behavioral and histological alterations along with exhausted antioxidant status and enhanced inflammatory mediators. However, PA administration (25, 50 and 100mg/kg b.wt orally once daily for 7 days) prior to MCAO significantly attenuated neurological deficits related to flexion test and spontaneous motor activity, improved grip strength and motor coordination in a dose dependent manner. PA treatment also inhibited oxidative stress in MCAO rats as evident from decreased lipid peroxidation and augmented level of reduced glutathione and restored activities of catalase, glutathione peroxidase, and glutathione reductase and thus, reduced infarct volume and protected the brain histology after I-R injury. Furthermore, PA markedly suppressed the level of proinflammatory cytokines (IL-1β, TNF α and IL-6) and down regulated expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (NOS-2) and nuclear factor κB (NF-κB) in MCAO group. In conclusion, PA mediates neuroprotection against I-R injury via mitigation of oxidative stress and inflammation and thus, may be a good therapeutic approach in stroke prone patient.

Tabassum R ，Vaibhav K ，Shrivastava P ，Khan A ，Ahmed ME ，Ashafaq M ，Khan MB ，Islam F ，Safhi MM ，Islam F ... -  《-》

Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia.

Tu XK ，Yang WZ ，Shi SS ，Chen Y ，Wang CH ，Chen CM ，Chen Z ... -  《-》