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Protective effect of Ginkgolids (A+B) is associated with inhibition of NIK/IKK/IkappaB/NF-kappaB signaling pathway in a rat model of permanent focal cerebral ischemia.
Brain Res. 2008 Oct 09; 1234:8-15.BR

Abstract

BACKGROUND AND PURPOSE

We have previously reported that Ginkgolids which contain Ginkgolids A and B (Ginkgolids (A+B), GKAB) reduce infarct size in a rat model of focal ischemia. NF-kappaB-inducing kinase (NIK)-IkappaBalpha kinase (IKK) pathway plays an important role in activation of nuclear factor kappaB (NF-kappaB). A previous study demonstrated that Ginkgolid B inhibited lipopolysaccharide (LPS)- and platelet activating factor (PAF)-induced NF-kappaB activation in rat pleural polymorphonuclear granulocytes. However, little is known about the inhibitory mechanisms of Ginkgolids on the activation of NF-kappaB. The present study evaluated the effects of GKAB on NIK/IKK/IkappaB/NF-kappaB signaling pathway in a rat model of permanent focal cerebral ischemia.

METHODS

Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by intraluminal suture blockade. GKAB was injected intravenously (iv) immediately after ischemic onset. Western blot analysis was employed to determine alterations in IkappaBalpha, phosphorylated NIK (p-NIK) and phosphorylated IKKalpha (p-IKKalpha). Immunohistochemistry was used to confirm the nuclear translocation of NF-kappaB p65. RT-PCR was used to detect induction of NF-kappaB target gene c-Myc mRNA.

RESULTS

The results showed a brief increase in p-NIK levels after ischemia. GKAB blocked ischemia-induced increases in p-NIK and p-IKKalpha levels, and reversed the decline in IkappaBalpha levels. Ischemia-induced nuclear translocation of NF-kappaB p65 was attenuated by GKAB(.) GKAB also repressed the ischemia-induced increase in expression of NF-kappaB target gene c-Myc mRNA.

CONCLUSIONS

These findings suggest that GKAB-mediated neuroprotective effect against ischemia appears to be associated with blocking NF-kappaB activation by suppressing the NIK-IKK pathway.

Authors+Show Affiliations

Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18722355

Citation

Wang, Xuan, et al. "Protective Effect of Ginkgolids (A+B) Is Associated With Inhibition of NIK/IKK/IkappaB/NF-kappaB Signaling Pathway in a Rat Model of Permanent Focal Cerebral Ischemia." Brain Research, vol. 1234, 2008, pp. 8-15.
Wang X, Qin ZH, Shi H, et al. Protective effect of Ginkgolids (A+B) is associated with inhibition of NIK/IKK/IkappaB/NF-kappaB signaling pathway in a rat model of permanent focal cerebral ischemia. Brain Res. 2008;1234:8-15.
Wang, X., Qin, Z. H., Shi, H., Savitz, S. I., Qin, A. P., Jiang, Y., & Zhang, H. L. (2008). Protective effect of Ginkgolids (A+B) is associated with inhibition of NIK/IKK/IkappaB/NF-kappaB signaling pathway in a rat model of permanent focal cerebral ischemia. Brain Research, 1234, 8-15. https://doi.org/10.1016/j.brainres.2008.07.102
Wang X, et al. Protective Effect of Ginkgolids (A+B) Is Associated With Inhibition of NIK/IKK/IkappaB/NF-kappaB Signaling Pathway in a Rat Model of Permanent Focal Cerebral Ischemia. Brain Res. 2008 Oct 9;1234:8-15. PubMed PMID: 18722355.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protective effect of Ginkgolids (A+B) is associated with inhibition of NIK/IKK/IkappaB/NF-kappaB signaling pathway in a rat model of permanent focal cerebral ischemia. AU - Wang,Xuan, AU - Qin,Zheng-Hong, AU - Shi,Hong, AU - Savitz,Sean Isaac, AU - Qin,Ai-Ping, AU - Jiang,Yan, AU - Zhang,Hui-Ling, Y1 - 2008/08/05/ PY - 2007/11/15/received PY - 2008/04/01/revised PY - 2008/07/18/accepted PY - 2008/8/30/pubmed PY - 2008/12/17/medline PY - 2008/8/30/entrez SP - 8 EP - 15 JF - Brain research JO - Brain Res VL - 1234 N2 - BACKGROUND AND PURPOSE: We have previously reported that Ginkgolids which contain Ginkgolids A and B (Ginkgolids (A+B), GKAB) reduce infarct size in a rat model of focal ischemia. NF-kappaB-inducing kinase (NIK)-IkappaBalpha kinase (IKK) pathway plays an important role in activation of nuclear factor kappaB (NF-kappaB). A previous study demonstrated that Ginkgolid B inhibited lipopolysaccharide (LPS)- and platelet activating factor (PAF)-induced NF-kappaB activation in rat pleural polymorphonuclear granulocytes. However, little is known about the inhibitory mechanisms of Ginkgolids on the activation of NF-kappaB. The present study evaluated the effects of GKAB on NIK/IKK/IkappaB/NF-kappaB signaling pathway in a rat model of permanent focal cerebral ischemia. METHODS: Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by intraluminal suture blockade. GKAB was injected intravenously (iv) immediately after ischemic onset. Western blot analysis was employed to determine alterations in IkappaBalpha, phosphorylated NIK (p-NIK) and phosphorylated IKKalpha (p-IKKalpha). Immunohistochemistry was used to confirm the nuclear translocation of NF-kappaB p65. RT-PCR was used to detect induction of NF-kappaB target gene c-Myc mRNA. RESULTS: The results showed a brief increase in p-NIK levels after ischemia. GKAB blocked ischemia-induced increases in p-NIK and p-IKKalpha levels, and reversed the decline in IkappaBalpha levels. Ischemia-induced nuclear translocation of NF-kappaB p65 was attenuated by GKAB(.) GKAB also repressed the ischemia-induced increase in expression of NF-kappaB target gene c-Myc mRNA. CONCLUSIONS: These findings suggest that GKAB-mediated neuroprotective effect against ischemia appears to be associated with blocking NF-kappaB activation by suppressing the NIK-IKK pathway. SN - 0006-8993 UR - https://www.unboundmedicine.com/medline/citation/18722355/Protective_effect_of_Ginkgolids__A+B__is_associated_with_inhibition_of_NIK/IKK/IkappaB/NF_kappaB_signaling_pathway_in_a_rat_model_of_permanent_focal_cerebral_ischemia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(08)01821-0 DB - PRIME DP - Unbound Medicine ER -