Adjudin protects against cerebral ischemia reperfusion injury by inhibition of neuroinflammation and blood-brain barrier disruption.

Abstract

Neuroinflammation mediated by activation of microglia and interruption of the blood-brain barrier (BBB) is an important factor that contributes to neuron death and infarct area diffusion in ischemia reperfusion injury. Finding novel molecules to regulate neuroinflammation is of significant clinical value. We have previously shown that adjudin, a small molecule compound known to possess antispermatogenic function, attenuates microglia activation by suppression of the NF-κB pathway. In this study we continued to explore whether adjudin could be neuroprotective by using the transient middle cerebral artery occlusion (tMCAO) model. Adjudin treatment after reperfusion significantly decreased the infarction volume and neuroscore compared to the vehicle group. Staining of CD11b showed that adjudin markedly inhibited microglial activation in both the cortex and the striatum, accompanied by a reduction in the expression and release of cytokines TNF-α, IL-1β and IL-6. Concomitantly, adjudin noticeably prevented BBB disruption after ischemia and reperfusion, as indicated by the reduction of IgG detection in the brain cortex and striatum versus the vehicle group. This finding was also corroborated by immunofluorescence staining and immunoblotting of tight junction-related proteins ZO-1, JAM-A and Occludin, where the reduction of these proteins could be attenuated by adjudin treatment. Moreover, adjudin obviously inhibited the elevated MMP-9 activity after stroke. Together these data demonstrate that adjudin protects against cerebral ischemia reperfusion injury, and we present an effective neuroinflammation modulator with clinical potential.

• Authors: Tengyuan Liu, Tingting Zhang, Hemei Yu, Hailian Shen, Weiliang Xia
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 11 Pg. 107 (Jun 14 2014) ISSN: 1742-2094 [Electronic] England
• PMID: 24927761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide
• CD11b Antigen
• Cytokines
• Hydrazines
• Indazoles
• Neuroprotective Agents
• Occludin
• Tjp1 protein, mouse
• Zonula Occludens-1 Protein
• Nitric Oxide Synthase Type II
• Matrix Metalloproteinase 9

Topics

• Animals
• Blood-Brain Barrier (drug effects, physiology)
• Brain (drug effects, metabolism, pathology)
• Brain Infarction (drug therapy, etiology)
• CD11b Antigen (metabolism)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation (drug effects)
• Hydrazines (administration & dosage)
• Indazoles (administration & dosage)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Microglia (drug effects, metabolism)
• Neurologic Examination
• Neuroprotective Agents (administration & dosage)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Occludin (metabolism)
• Reperfusion Injury (complications, prevention & control)
• Zonula Occludens-1 Protein (metabolism)