Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.
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PMID:Retigabine: chemical synthesis to clinical application. 1586 50

We proposed recently that induction of delayed activation of trigeminovascular neurons by cortical spreading depression (CSD) can explain the delayed onset of headache after the migraine aura ("aura"). This prompted us to search for ways to block the neuronal activation by CSD - a preclinical correlate of an attempt to find a drug that can block the initiation of headache when administered shortly after onset of aura (i.e., preemptively). Because migraine headache and epileptic seizures are comorbid chronic neurological disorders characterized by hyperexcitable brain networks, we began the search for such goal with an M-type potassium channel opener. We opted to use ezogabine, recently approved by the FDA as adjunctive treatment of partial onset seizures in adults, because it is a selective KCNQ2/3 channel opener. When CSD was induced before ezogabine injection (8.25 mg/kg, i.p.), 40% (6/15) of the units doubled their firing rate about 45 min later for about 95 min. Similarly, when CSD was induced before vehicle was injected (4% DMSO, 0.5% methylcellulose), 50% (3/6) of the units doubled their firing rate about 30 min later for about 120 min. When CSD was triggered 1h after ezogabine injection, it activated only 8% of the units. By itself, ezogabine injection resulted in a 30% attenuation of ongoing firing in all 10 control units. Thus, activation of KCNQ2/3 channels during the aura is unlikely to preempt the onset of headache but may reduce the incidence of migraine if given during prodromes that precede the headache by hours. Given the mechanistic similarities between migraine aura and epileptic seizures, it may be worthwhile to determine whether preemptive administration of ezogabine can prevent oncoming seizures in patients whose warning signs precede their seizures by more than an hour.
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PMID:Ezogabine (KCNQ2/3 channel opener) prevents delayed activation of meningeal nociceptors if given before but not after the occurrence of cortical spreading depression. 2373 71