Abstract

Objectives
We sought to evaluate the expression of two key inflammatory mediators, tumor necrosis factor-alpha(TNF-α) and matrix metalloproteinase-9(MMP-9) in a nitric oxide(NO) mediated animal model of migraine and investigated the effect of glucocorticoid on MMP-9 activation. Background: Migraine is thought to result from neuronal nociceptive activity in the trigeminovascular system, which results in meningeal inflammatory reaction. Despite considerable research into the patho- genesis of migraine, signaling pathways mediating neurogenic inflammation are poorly understood. TNF-α and MMP-9, which are regulated by transcription factor nuclear factor-kB(NF-kB), have been known to play important roles in many physiologic processes of immune and inflammatory responses. Method: TNF-α and MMP-9 expression were investigated in the meningeal blood vessels following continuous intravenous infusion of NO donor, glyceryl trinitrate(GTN, 10mg/kg/min), for 30 minutes in rats. Time course of TNF-α expression was evaluated by Western blot at 1, 3, 6, and 18 hours and the activity of MMP-9 was analysed by enzyme zymography. Expression of TNF-α and MMP-9 in the meningeal blood vessels was investigated using double immunofluorescence staining with endothelial cell marker vWF. To evaluate the effect of glucocorticoid on the inhibition of MMP-9 activation, methylpred- nisolone(MP, 30mg/kg) was administerd after GTN infusion. Furthermore, to understand whether the transcriptional modulation of MMP-9 activation, glucocorticoid receptor(GR) antagonist(RU486, 15mg/ kg) was pretreated before GTN infusion. Results: By Western blot analysis, TNF-α expression was increased at 3-6 hr after GTN infusion. MMP-9 activity was upregulated at 3 hr and reached the peak at 6 hr. Furthermore, TNF-α and MMP-9 immunoreactivity was extensively detected in the meningeal blood vessels in GTN-infused group as com- pared to controls. MP treatment inhibited MMP-9 activation and pretreatment with RU486 successfully reversed this MP effect. Conclusion: These results indicate TNF-α and MMP-9 are involved in NO-mediated inflammation in meningeal blood vessels. In addition, MMP-9 activation was affected by modulation of GR. Inhibition and blockade of proimflammatory transcription factors or their downstream effectors might have therapeutic implications for preventing migraneous headache. Korean Journal of Headache 5(1):103-103, 2004