Maximal electroshock

It has become clear that drugs which are effective in protecting mice against PTZ are effective in absence seizures while those able to control the tonic response to maximal electroshock are effective in tonic-clonic seizure. Some drugs are effective in only one test and clinical condition whilst a few are active in both (Table 16.1). Experimental focal seizures are indicative of partial seizures. 

A series of 1-substituted 3-phenylbenzazepines have been evaluated. It was found that the aminopropyl derivative (6, n = 3 R1 = R2 = Et) counteracted amphetamine toxicity, and that the piperazinyl derivative (6) (n = 2 NR R2 = N(CH2CH2)2 = NCH2CH2OH) gave protection against maximal electroshock seizures (MES) [12]. None of the other derivatives such as the 2-oxo derivatives showed any significant effects on the central nervous or cardiovascular system, nor did any of them exhibit any diuretic or hypo-glycaemic activity [12]. Several similar compounds possess antiarrhythmic and antihypertensive effects this will be mentioned in a later section. 

Raines, A., HeIke, C.J., ladarola, M.J., Britton, L.W., and Anderson, R.J. Blockade of the tonic hindlimb extensor component of maximal electroshock and pentylenetetrazol-induced seizures by drugs acting on muscle and muscle spindle systems a perspective on method. Epilepsia 17 395-402, 1976. 

It is a new anticonvulsant drug and is a structural analogue of GABA. It increases the release of GABA by unknown mechanism. It modifies maximal electroshock as well as inhibits pentylenetetrazol induced convulsions. 

It is an inhibitor of GABA transaminase which degrades GABA. It suppresses maximal electroshock and kindled seizures and is used in partial seizure with or without generalization. 

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24-4). It also acts presynaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known. 

Ethosuximide was introduced in 1960 as the third of three marketed succinimides in the USA. Ethosuximide has very little activity against maximal electroshock but considerable efficacy against pentylenetetrazol seizures it was introduced as a "pure petit mal" drug. 

Phensuximide and methsuximide are phenylsuccinimides that were developed and marketed before ethosuximide. They are used primarily as antiabsence drugs. Methsuximide is generally considered more toxic, and phensuximide less effective, than ethosuximide. Unlike ethosuximide, these two compounds have some activity against maximal electroshock seizures, and methsuximide has been used for partial seizures by some investigators. 

Luszczki J. J., Mohamed M., and Czuczwar S. J. (2006). 2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice. Eur. J. Pharmacol. 531 66-73. 

Ethosuximide was introduced in 1960 as the third of three marketed succinimides in the USA. Ethosuximide has very little activity against maximal electroshock but considerable efficacy against pentylenetetrazol seizures and was introduced as a "pure petit mal" drug. Its continued popularity is based on its safety and efficacy, and its role as the first choice anti-absence drug remains undiminished—in part because of the idiosyncratic hepatotoxicity of the alternative drug, valproic acid. 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

The carbohydrate-based 1,3,2-dioxathiolane A, -dioxide 23 (Section 6.05.3.1) has demonstrated an exceptional anticonvulsant activity in the standard maximal electroshock seizure test. Compound 23 is much more potent than structural analogs, and approximately 8 times more potent than the isosteric topiramate <1998JME1315>. 

The leaf essential oil of L. nobilis, which has been used as an antiepileptic remedy in Iranian traditional medicine, was evaluated for anticonvulsant activity against experimental seizures (Sayyah et al., 2002). The essential oil protected mice against tonic seizures induced by maximal electroshock and especially by pentylenetetra-zole. Components responsible for this effect may be methyleugenol, eugenol and pinene present in the essential oil. At anticonvulsant doses, the essential oil produced sedation and motor impairment. This effect seems to be related in part to cineol, eugenol and methyleugenol (Sayyah et al., 2002). 

Sayyah, M., Valizadeh, J. and Kamalinejad, M. (2002) Anticonvulsant activity of the leaf essential oil of Laurus nobilis against pentylenetetrazole- and maximal electroshock-induced seizures. Phytomedicine 9(3), 212-216. 

The ECS method described above involves titration of the shock level between successive test animals to determine the mean intensity required to induce convulsions after different treatments. This procedure represents a variant of the more habitual procedure where a set level of ECS is selected to induce convulsions in 100 % of the animals (maximal electroshock). Another variant would be to select a low electroshock... 

To further examine the relationship between blood Mn concentration and seizure frequency, Papavasiliou and Miller (8) injected mice with 5 Mn at various times before and after inducing a seizure by either maximal electroshock or pentylene tetrazole injection. 

Dimmock IR, Sidhu KK, Chen M, Reid RS, Allen TM, Kao GY, Truitt GA (1993) Anticonvulsant activities of some arylsemicarbazones displaying potent oral activity in the maximal electroshock screen in rats accompanied by high protection indices. Eur J Med Chem 36 2243-2252... 

The maximal electroshock seizure (MES) test was used to show efficacy of antiepileptic agents against partial and generalized seizure type epilepsy among therapy-resistant epileptic patients. 

The one-pot, three-component synthesis of 1,2,4-triazoles from primary amines, acyl hydrazines and dimethoxy-A(-A(-dimethylmethanamine [84] was utilized for the preparation of compounds 235 (Scheme 41), which were evaluated for their anticonvulsant and neurotoxic properties [85]. The anticonvulsant activity was measured in mice by the maximal electroshock test (MES) and the neurotoxicity in mice by the rotarod neurotoxicity test (Tox). The majority of the compounds... 

Aminoethers such as 32 protected against maximal electroshock seizures in rats.79... 

A ter el at. (1984) documented the anticonvulsant properties of PBO and compared them with those of clinically established anti epileptic drugs. PBO administered inlrapcritoncally to mice exerted peak anti maximal electroshock activity and peak neurotoxicity at 5 and 7 hours, respectively. The median neuroluxic dose was I.69U mg kg"1. In the maximal electroshock seizure test I he median effective dose (HD j) was 457 mg kg"1 and the protective index (PI) was 3,69. In the subcutaneous pentylenetetrazol (PTZ) test the ED u was 443 mg kg 1 and PI was 3.81. PBO prevented seizure spread and elevated seizure threshold, and its PI compared favourably with those of clinically useful anticonvulsants,... 

Anticonvulsants - Clobazam (.2 ) blocked convulsive seizures in mice and baboons.The 7-bromobenzodlazepine Jn was the best of a series In protection against PTZ and maximal electroshock (MES)-lnduced convulsions in mice. 

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