Nuclear factor‐κB as a molecular target for migraine therapy

Abstract

Nitric oxide (NO) generated from inducible NO synthase (iNOS) participates in immune and inflammatory responses in many tissues. The NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into migraineurs and also causes iNOS expression and delayed inflammation within rodent dura mater. Sodium nitroprusside, an NO donor as well, also increases iNOS expression. Because inflammation and iNOS are potential therapeutic targets, we examined transcriptional regulation of iNOS following GTN infusion and the consequences of its inhibition within dura mater. We show that intravenous GTN increases NO production within macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor, attenuates the NO signal, emphasizing the importance of enzymatic activity to delayed NO production. iNOS expression is preceded by significant nuclear factor kappa B (NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-kappa-Balpha (IkappaBalpha) and activation of NF-kappaB after GTN infusion. IkappaBalpha degradation, NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg), the active constituent of feverfew, an anti-inflammatory drug used for migraine treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation with a time course consistent with migraine attacks in susceptible individuals. We conclude, based on results with this animal model, that blockade of NF-kappaB activity provides a novel transcriptional target for the development of anti-migraine drugs.

The p65 Subunit of NF-κB Inhibits COL1A1 Gene Transcription in Human Dermal and Scleroderma Fibroblasts through Its Recruitment on Promoter by Protein Interaction with Transcriptional Activators (c-Krox, Sp1, and Sp3)

“…To further corroborate the specific activating effect of TNF-␣ on NF-B, parthenolide (PT), a post-translational inhibitor of NF-B activation (39,40), was used. NF-B binding activity was found to be abolished by PT in a dose-dependent manner in basal or TNF-␣-stimulated conditions (supplemental Fig.…”

Dual roles of NF-κB in cell survival and implications of NF-κB inhibitors in neuroprotective therapy

“…These conditions, including aging [74] , headache [75] , pain [76] , stroke [77] , traumatic brain injury [78] , SCI [79] , Parkinson's disease [80,81] , multiple sclerosis [82] , Alzheimer's disease [83,84] , amyotrophic lateral sclerosis [85] , Huntington's disease [86] , and brain tumors [87][88][89][90][91] , have been associated with the NF-κB pathway. As NF-κB plays important roles in regulating cell survival and death in a broad array of physiological and pathological conditions, it is an attractive proposal to manipulate NF-κB functions to obtain its beneficial effects or abolish its harmful actions when it is required [92] .…”

Nitroglycerin enhances cGMP expression in specific neuronal and cerebrovascular structures of the rat brain

“…In addition, nitroglycerin induces a decrease of pain threshold at the tail flick and formalin tests in the rat (Tassorelli et al, 2003). Based on the above mentioned as well as other data (Lambert et al, 2000;Reuter et al, 2002;Srikiatkhachorn et al, 2002), the study of the effect of nitroglycerin on the brain and cranial vasculature is now widely accepted as a valid animal model of migraine. Torfgard et al (1989) have demonstrated that subcutaneous nitroglycerin induces the accumulation of NO and cGMP in the rat brain.…”