Epilepsy GABA receptors

Olsen RW, DeLorey TM, Gordey M, Kang MH (1999) GABA receptor function and epilepsy. 

This herb has been part of folk medicine since pre-Christian times (247). It has been primarily used as a sedative and for the treatment of epilepsy. Consistent with this use, this herb reportedly can increase synaptic concentrations of GABA (248). GABA has also been isolated from Valeria and extracts of Valeria have been reported to bind to GABA receptors in rat brain. Although Valeria has been reported to be active in rodent models of depression, there have been no efficacy trials in humans. The potential adverse effects of Valeria include the sensation of strangeness ( 247) and several cases of liver damage (e.g., central lobular necrosis) (249). Mutagenicity in bacteria has been reported and attributed to unstable, water-insoluble valepotriates ( 238). As a result of these reports, many, but not all, commercial preparations of Valeria use water-soluble extracts standardized for their content of valeric acid. 

Epilepsy is caused by abnormal high-frequency firing of neurons, either in the whole of the cerebral cortex (generalized epilepsy) or in discrete areas of the cerebral cortex (partial epilepsy). The abnormal activity may be due to increased excitatory neuronal transmission, possibly involving abnormal sodium ion channels or decreased inhibitory transmission, possibly due to abnormality at GABA receptors. Certainly, most antiepileptic drugs either block sodium ion channels or enhance the action of GABA or both. 

Gabapentin, an anticonvulsant that stimulates gamma-aminobutyric acid (GABA) receptors, is used as an adjunctive therapy in treattnent of partial seizures with or without secondary generalization in patients older than 12 years of age with epilepsy adjunctive therapy for partial seizures in children 3 to 12 years of age and for management of postherpetic neuralgia in adults (see Figure 53). 

Recently, mutations in genes encoding for receptors and ion channels have been associated with naturally occurring human epilepsies. These include subunits of the GABA receptor (Baulac et al., 2001) sodium channel (Wallace et al., 2001), chloride channel (Haug et al., 2(X)3), potassium channels (Eunson et al., 2(X)0), calcium channels (Jouvenceau et al., 2(X)1), and nicotinic acetylcholine receptors (De Fusco et al., 2000). 

Olsen R W. and Leeb-Lundberg F. (1981) Convulsant and anticonvulsant drug binding sites related to the GABA receptor/ lonophore system, in Neurotransmitters, Seizures and Epilepsy (Morselli P, Lloyd K, Loscher W, Meldrum B, Chir B and Reynolds E., eds.) ppl51-164. Raven Press, New York,... 

Laudanosine or Af-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus, it can induce seizures if present at sufficient threshold concentrations however, such concentrations are unlikely to be produced consequent to chemodegradable metabolism of clinically admiiustered doses of cisatracurium or atracurium. Laudanosine also occurs naturally in minute amounts (0.1 %) in opium, from which it was first isolated in 1871. Partial dehydrogenation of laudanosine will lead to papaverine, the alkaloid found in the opium poppy plant (Papaver somniferum). Laudanosine is a benzyltetrahydroisoquinoline alkaloid. It has been shown to interact with GABA receptors, opioid receptors, and ificotinic acetylcholine receptors, but not benzodiazepinergic or muscarinic receptors which are also involved in epilepsy and other types of seizures. 

Mathew J, Peeyush Kumar T, Khan RS, Paulose CS (2010) Behaviraal deficit and decreased GABA receptor functional regulation in the cerebellum of epileptic rats effect of Bacopa monnieri and bacoside A. Epilepsy Behav 17 441-447... 

Benzodiazepines. Several BZs have anticonvulsant activity and ate used for the treatment of epilepsy producing their anticonvulsant actions via interactions with the GABA /BZ receptor complex to enhance inhibitory GABAergic transmission (1). The anticonvulsant actions of the BZs tend to tolerate upon chronic usage in six months, and BZs also lead to withdrawal symptomatology. Other side effects include sedation, ataxia, and cognitive impairment. 

Stelzer, A, Slater, NT and Bruggencate, G (1987) Activation of NMD A receptors blocks GABA ergic innervation in an in vitro model of epilepsy. Nature 326 698-701. 

The epilepsies constitute a common, serious neurological disorder in humans, affecting approximately 60 million people worldwide. Well in excess of 40 distinct epileptic syndromes have been identified to date. Current treatment is only symptomatic except in uncommon instances when surgical treatment is possible. While available antiseizure medications target ion channels such as the y-amino-butyric acid (GABA)a receptor and voltage activated sodium (Na+) channels, current research seeks to elucidate the cellular and molecular mechanisms by which a normal brain becomes epileptic. Hopefully, this research will lead to the identification of new targets for which small molecules can be identified and used for prevention or cure of epilepsy. 

Some drags block sodium channels, while others act on the GABA system. They enhance the GABA-dependent CNS inhibition. They also change the innacellular ratio of calcium and potassium ion concentrations, and block the A-methyl-o-aspartate (NMDA) receptor responsible for high-frequency discharges that appear during epilepsy. 

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