Nitric oxide-related drug targets in headache.
Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so-called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-nitromonomethylarginine effectively treats attacks of migraine without aura. Similar results have been obtained for chronic the tension-type headache and cluster headache. Inhibition of the breakdown of cyclic guanylate phosphate (cGMP) also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Similar evidence suggests an important role of NO in the tension-type headache and cluster headache. These very strong data from human experimentation make it highly likely that antagonizing NO effects will be effective in the treatment of primary headaches. Nonselective NOS inhibitors are likely to have side effects whereas selective compounds are now in early clinical trials. Antagonizing the rate limiting cofactor tetrahydrobiopterin seems another very likely new treatment. It is more unlikely that antagonism of cGMP or its formation will be feasible, but augmenting its breakdown via phosphodiesterase activation is a possibility, as well as other ways of inhibiting the NO-cGMP pathway.
Olesen
Jes
J
Department of Neurology, University of Copenhagen, Glostrup Hospital, Copenhagen, DK-2600 Denmark. jeol@glo.regionh.dk
D006152:Cyclic GMP / Q000378:metabolism; D006261:Headache / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000009:adverse effects; D005996:Nitroglycerin / Q000009:adverse effects; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects; D010879:Piperazines / Q000009:adverse effects; D011687:Purines / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000009:adverse effects
D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D005996:Nitroglycerin; D006152:Cyclic GMP