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 ... -  《-》

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 ... -  《-》

Daphnetin Protects against Cerebral Ischemia/Reperfusion Injury in Mice via Inhibition of TLR4/NF-κB Signaling Pathway.

Liu J ，Chen Q ，Jian Z ，Xiong X ，Shao L ，Jin T ，Zhu X ，Wang L ... -  《-》

Neuroprotective effect of naringenin is mediated through suppression of NF-κB signaling pathway in experimental stroke.

Oxidative stress and inflammation play an integral role in the pathogenesis of cerebral ischemia that leads to a cascade of events culminating in the death of neurons and their supporting structures. The signaling pathways that link these events are not fully understood. Recent studies have demonstrated a close link between the nuclear factor-κB (NF-κB) signaling pathway and cerebral ischemia/reperfusion (I/R)-induced inflammation. Flavonoids have been suggested to exert human health benefits by anti-oxidant and anti-inflammatory mechanisms. In this study we undertook a pharmacological approach to investigate the ability of naringenin, a potent flavonoid, to prevent oxidative stress and NF-κB-mediated inflammatory brain damage in the rat model of focal cerebral I/R injury. To test this hypothesis, male Wistar rats were pretreated with naringenin once daily for 21 days and then subjected to 1h of middle cerebral artery occlusion followed by 23 h of reperfusion. Naringenin treatment successfully upregulates the antioxidant status, decreases the infarct size and lowers the levels of myeloperoxidase, nitric oxide and cytokines, besides functional recovery returned close to the baseline. Moreover, immunohistochemical and Western blot analyses clearly demonstrated that naringenin treatment limits glial activation and downregulates the NF-κB expression level and their target genes. These results show, prophylactic treatment with naringenin improved functional outcomes and abrogated the ischemic brain injury by suppressing NF-κB-mediated neuroinflammation. The present study suggests that naringenin may be used as a potential neuroprotectant in patients at high risk of ischemic stroke.

Raza SS ，Khan MM ，Ahmad A ，Ashafaq M ，Islam F ，Wagner AP ，Safhi MM ，Islam F ... -  《-》

Neuroprotective effects of pioglitazone in a rat model of permanent focal cerebral ischemia are associated with peroxisome proliferator-activated receptor gamma-mediated suppression of nuclear factor-κB signaling pathway.

Previous studies have demonstrated that pioglitazone (Piog), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. Piog has also been shown to exert anti-inflammatory effects by attenuation of nuclear factor-κB (NF-κB) activation after myocardial ischemia/reperfusion injury. Because NF-κB is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to elucidate whether pioglitazone attenuates ischemic neuronal damage through PPARγ-mediated suppression of NF-κB apoptotic signaling pathway. Permanent middle cerebral artery occlusion (pMCAO) model was induced by using an intraluminal filament technique in rats. Piog was administrated i.p. twice (24 h before and at the time of ischemia insult) or once (10 min after ischemia). The neuroprotection of Piog was analyzed by assessing neurological deficits, infarction volume and morphological changes. The inhibition of NF-κB signaling pathway by Piog was evaluated by detecting the nuclear translocation of NF-κB p65 with immunohistochemistry and its target gene p53 by real-time PCR, and the expression of phospholated NF-κB p65 (p- NF-κB p65) in primary cultured neurons and the protein levels of IκBα and p-ERK in the ischemic cortex or striatum with Western blotting analysis. The contribution of a PPARγ mechanism to Piog's inhibitory effects on NF-κB and neuroprotection was evaluated by pretreatment with the PPARγ irreversible antagonist GW9662. In vitro ischemia in cultured primary neurons was induced by the oxygen-glucose deprivation (OGD) and the protective effect of Piog on cultured neurons was measured by lactate dehydrogenase (LDH) assay. Piog (0.5, 1, 2 mg/kg) reduced infarction volume, and improved morphological changes and motor deficits. Piog markedly up-regulated the protein levels of IκBα or p-ERK 6 h or 12 h after ischemia. Piog reduced the nuclear translocation of NF-κB p65 in the ischemic cortical cells and repressed the expression of p53 12 h after ischemia. Pre-treatment with GW9662 blocked Piog-elicited reduction in infarction volume, the increase in protein levels of IκBα and p-ERK, the reduction in the nuclear translocation of NF-κB subunit p65 and the repression of p53 mRNA expression. In addition, Piog attenuated the OGD-induced neuronal damage and inhibited the OGD-induced increases in p- NF-κB p65 in neurons. The present findings suggest that Piog's neuroprotection appears to be associated with PPARγ-mediated suppression of NF-κB signaling pathway.

Zhang HL ，Xu M ，Wei C ，Qin AP ，Liu CF ，Hong LZ ，Zhao XY ，Liu J ，Qin ZH ... -  《-》