Cortical spreading depression (CSD) is a phenomenon characterized by a slowly spreading depolarization of cortical cells and is postulated to cause aura associated with migraine. Recently drugs that block gap junctions have been developed to inhibit CSD. In this paper the authors tested the effect of one such drug, tonabersat in patients with migraine. They examined 39 patients in a double blind crossover study and measured attacks of aura with or without headache and migraine headache days with or without aura as primary outcomes. The results showed that tonabersat reduced the number of aura attacks and attacks of aura followed by headache but not the number of migraine headache days. These results suggest that migraine with aura and migraine without aura involve different pathophysiological mechanisms. The study also suggests that drugs targeting gap junctions may be effective in treating migraine with aura (Lancet Neurol 2009 8:718-723).
Showing posts with label tonabersat. Show all posts
Showing posts with label tonabersat. Show all posts
Friday, October 30, 2009
Monday, September 21, 2009
Neurological mechanisms of migraine: potential of the gap-junction modulator tonabersat in prevention of migraine.
Durham PL, Garrett FG.
Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO 65897, USA. pauldurham@missouristate.edu
Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal-glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.
Cephalalgia. 2009 Nov;29 Suppl 2:1-6
Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO 65897, USA. pauldurham@missouristate.edu
Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal-glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.
Cephalalgia. 2009 Nov;29 Suppl 2:1-6
Tonabersat, a novel gap-junction modulator for the prevention of migraine.
Silberstein SD.
Jefferson Headache Center, Philadelphia, PA 19107, USA. stephen.silberstein@jefferson.edu
Migraine is a common, recurrent, primary headache disorder associated with significant morbidity as well as high direct and indirect costs. Despite its impact, only a proportion of migraineurs who meet criteria for prophylactic treatment take preventive medication. Antiepileptic drugs and beta-blockers are among the most used preventive therapies, but their exact mechanisms of action in migraine prophylaxis are unknown. Recent research has pointed to the role of cortical spreading depression in the genesis of migraine aura and pain, with neuronal-glial gap junctions playing a prominent part in cortical spreading depression. Tonabersat is a unique compound with demonstrated activity as a gap-junction inhibitor in animal studies. In preclinical and clinical trials, tonabersat was well tolerated, with no cardiovascular effects; the pharmacokinetic profile suggested its usefulness in the prophylaxis of migraine.
Cephalalgia. 2009 Nov;29 Suppl 2:28-35.
Jefferson Headache Center, Philadelphia, PA 19107, USA. stephen.silberstein@jefferson.edu
Migraine is a common, recurrent, primary headache disorder associated with significant morbidity as well as high direct and indirect costs. Despite its impact, only a proportion of migraineurs who meet criteria for prophylactic treatment take preventive medication. Antiepileptic drugs and beta-blockers are among the most used preventive therapies, but their exact mechanisms of action in migraine prophylaxis are unknown. Recent research has pointed to the role of cortical spreading depression in the genesis of migraine aura and pain, with neuronal-glial gap junctions playing a prominent part in cortical spreading depression. Tonabersat is a unique compound with demonstrated activity as a gap-junction inhibitor in animal studies. In preclinical and clinical trials, tonabersat was well tolerated, with no cardiovascular effects; the pharmacokinetic profile suggested its usefulness in the prophylaxis of migraine.
Cephalalgia. 2009 Nov;29 Suppl 2:28-35.
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