Nitric Oxide

Nuclear Factor‐kappaB as a Molecular Target for Migraine TherapyNitric 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, a 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‐B‐alpha (IkappaBalpha) and activation of NF‐kappaB after GTN infusion. I‐kappa‐B‐alpha 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.Effects of the Nitric Oxide Donor, DEA/NO on Cortical Spreading DepressionCortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with Nomega‐nitro‐L‐arginine methyl ester (L‐NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2‐(N,N‐diethylamino)‐diazenolate‐2‐oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid‐base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 microM) had little effect on CSD by itself, but it reversed in a concentration‐dependent manner the effects of NOS inhibition by 1 mM L‐NAME. These data demonstrate that increased formation of endogenous NO associated with CSD is critical for the subsequent, rapid recovery of cellular ionic homeostasis. In this case, the molecular targets for NO may be located either on brain cells to suppress mechanisms directly involved in CSD genesis, or on local blood vessels to couple flow to the increased energy demand associated with CSD.