Antagonists epilepsies

On the basis of the events that occur in pain and LTP, it is easy to see how the actions of glutamate relate to the excessive firing of neurons — as yet no NMDA receptor antagonist has been tested in human epilepsy. 

A number of studies have shown that adenosine inhibits neuronal firing both in vitro and in vivo and is itself released during intense neuronal activity. It can protect against PTZ seizures in rodents while the antagonist theophylline is proconvulsant. No clear picture of its role in human epilepsy has emerged. 

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

Drugs that act on the H3 receptor are being developed for the treatment of obesity, sleep disturbances, epilepsy and cognitive disorders. The ability of histamine to promote arousal, suppress appetite, elevate seizure threshold and stimulate cognitive processes implies that compounds able to enhance the release of neuronal histamine should mimic these effects. Several H3 antagonists currently in development demonstrate such activity and show promise as effective and novel therapeutic agents [40, 84-86]. Because H3 agonists suppress the release of... 

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer s disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future. 

Flumazenil is a benzodiazepine antagonist that is used in anaesthesia for the reversal of central sedative effects of benzodiazepines. It should not be administered rapidly so as to avoid patient wakening too rapidly, which can lead to agitation, anxiety, fear and convulsions, particularly in high-risk patients, e.g. those with a history of epilepsy or head injury. 

Although epilepsy was one of the first suggested therapeutic appUcations of NMDA receptor antagonists (Czuczwar and Meldrum 1982 Meldrum 1985)... 

Sveinbjornsdottir S, Sander JWAS, Upton D,etal(1993) The excitatory amino acid antagonist d-CPP-ene (sdz eaa-494) in patients with epilepsy. Epilepsy Res 16 165-174 Takano T, Lin JH, Arcnino G, et al (2001) Glntamate release promotes growth of malignant gliomas. Nat Med 7 1010-1015... 

Epilepsy is an example of excessive neural signaling in the central nervous system. Relative cellular and extracellular space (ECS) volume has been demonstrated to play an important role in the propensity for epileptic seizures. For example, reducing ECS volume by exposure to hypotonic medium produces hyperexcitability and enhanced epileptiform activity, whereas hyperosmolar medium reduces excitability. The hypothesis that AQP4-dependent water transport in astrocytes might modulate intrinsic brain excitability was tested by seizure susceptibility in response to the GABAa antagonist convulsant pentylenetetrazol... 

Loscher, W. (1998) Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy. Prog Neurohiol 54 721-741. 

Engel J Jr, Ackermann RF, Caldecott-Hazard S, et al Epileptic activation of antagonistic systems may explain paradoxical features of experimental and human epilepsy, a review and hypothesis, in Kindling 2. Edited by Wada JA. New York, Raven, 1981, pp 193-217... 

Kramer MS, Cutler NR, Ballenger JC, et al A placebo-controUed trial of L-365,260, a CCKB antagonist, in panic disorder. Biol Psychiatry 37 462-466, 1995 Krauss GL, Fisher RS Cerebellar and thalamic stimulation for epilepsy, in Electrical and Magnetic Stimulation of the Brain and Spinal Cord. Edited by Devinsky O, Beric A. New York, Raven, 1993, pp 231-245 Krell RD, Goldberg AM Effect of acute and chronic administration of lithium on steady-state levels of mouse brain choline and acetylcholine. Biochem Pharmacol 22 3289-3291, 1973... 

Paczynski RP, Meyer FB, Anderson RE Effects of the dihydropyridine Ca " channel antagonist nimodipine on kainic acid-induced limbic seizures. Epilepsy Res 6 33-38, 1990... 

Taurine (2-aminoethanesulfonic acid 4.235) is an inhibitory neurochemical that probably acts primarily as a neuromodulator rather than a neurotransmitter. It is formed from cysteine, and its accumulation can be prevented by the cardiac glycoside ouabain. Although receptor sites and specific actions cannot be elucidated without an antagonist, taurine has been implicated in epilepsy and, potentially, in heart disease. There are a large number of physiological effects attributed to taurine, among them cardiovascular (antiarrythmic), central (anticonvulsant, excitability modulation), muscle (membrane stabilizer), and reproductive (sperm motility factor) activity. Analogs of taurine, phthalimino-taurinamide (4.236) and its iV-alkyl derivatives, are less polar than taurine and are potent anticonvulsant molecules. 

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