Gill Anlezark

Anticonvulsant action of ethanolamine-O-sulphate and di-n-propylacetate and the metabolism of γ-aminobutyric acid (GABA) in mice with audiogenic seizures

Abstract Mice susceptible to ‘audiogenic’ seizures (DBA/2, 21–25 days old) were treated with either di-n-propylacetate. DPA, (200–600 mg/kg, intraperitoneally) or ethanolamine-O-sulphate, EOS, (7.5–15 mg/kg, intracerebroventricularly). Motor behaviour was not moditied 45 min after DPA (except for slight changes after 600 mg/kg). Seizure responses to auditory stimulation were severely reduced after DPA 400 mg/kg, and totally absent after 600 mg/kg. Brain γ-aminobutyric acid (GABA) concentrations were unchanged after DPA 200–400 mg/kg, but increased by 57% after 600 mg/kg. The latter dose inhibited brain GABA-transaminase (4-aminobutyrate-2-oxoglutarate aminotransferase) activity by 33%. Kinetic studies with brain homogenates failed to show inhibition of GABA-transaminase activity by DPA (5–15 mM), but demonstrated inhibition of succinic Semialdehyde dehydrogenase by substrate competition. Mice tested 24 hr after EOS injection showed mild to moderate alaxia and were completely protected against ‘audiogenic’ seizures. Brain GABA concentration was increased 4–10 fold. GABA-transaminase activity was inhibited by 54–58% There was no inhibition of succinic Semialdehyde dehydrogenase activity.

Monoamine and GABA metabolism and the anticonvulsant action of DI-n-propylacetate and ethanolamine-O-sulphate

The time course of changes in behaviour, seizure response and cerebral monoamine and gamma-aminobutyric acid (GABA) metabolism has been studied in relation to the anticonvulsant actions of di-n-propylacetic acid (DPA) and ethanolamine-O-sulphate (EOS) on sound-induced seizures in DBA/2 mice. Changes in cerebral monoamine metabolism after EOS (75 or 150 mug, intracerebroventricularly) were not related to its anticonvulsant action. The primary effect was GABA-transaminase inhibition (by 50-70%) leading to a 2-4 fold increase in cerebral GABA concentration. Increases in brain GABA concentration (maximally 36%), 5-hydroxyindoleacetic acid (5HIAA, maximally 134%) and homovanillic acid (HVA, maximally 183%) were seen after DPA (400-600 mg/kg, i.p.). The time course of the increases in HVA and 5HIAA did not correlate with the anticonvulsant effect. Elimination of these increases by the use of inhibitors of monoamine synthesis (alpha-methyl-p-tyrosine and p-chlorophenyl-alanine) did not alter the anticonvulsant effect of DPA. Experiments using probenecid suggested that the increases in 5HIAA and HVA after DPA result from inhibition of their active transport out of the brain.

Seizure activity in photosensitive baboons following antidepressant drugs and the role of serotoninergic mechanisms

Laboratory and clinical evidence indicates that tricyclic antidepressants lower seizure threshold and in high doses may induce generalised seizures. In baboons with photosensitive epilepsy (Papio papio) the effects of 2 tricyclic antidepressants (imipramine and chlorimipramine) and of maprotiline and Nomifensine have been studied (i.v. dose range 1–20 mg/kg. Imipramine, chlorimipramine and maprotiline (10 mg/kg i.v.) lowered seizure threshold to a comparable extent, whereas Nomifensine (10 mg/kg i.v.) did not enhance myoclonic responses to photic stimulation.Generalised seizures were seen 15–30 min after imipramine or chlorimipramine (20 mg/kg), and these two drugs showed no difference in their epileptogenicity. Administration of 5-hydroxytryptophan (25 mg/kg i.v.) 90 min before chlorimipramine or imipramine (10 mg/kg) completely blocked the usual augmentation of photically-induced epileptic responses. It is concluded that enhancement of serotoninergic activity following blockade of 5-HT re-uptake within the brain is unlikely to be responsible for enhanced myoclonic responses and epileptogenic seizures seen after tricyclic antidepressants. Nomifensine is significantly less epileptogenic than imipramine or chlorimipramine.

GABA agonists and audiogenic seizures

Abstract Muscimol, 0.5–2.0 mg/kg intraperitoneally, blocked all phases of the epileptiform response to loud sound on DBA/2 mice, and induced a toxic syndrome similar to that produced by catalytic inhibitors of GABA-transaminase. Isoguvacine, 1–32 mg/kg intraperitoneally, was without effect on audiogenic seizures or locomotor activity. Muscimol, 0.1–0.25 μg intracerebroventricularly, acutely depressed respiration. Seizures were partially blocked 1 h after 0.25 μg. Isoguvacine, 8 μg intracerebroventricularly, also produced partial protection against seizures. Isoguvacine is stated to be as potent as muscimol as a GABA-agonist (assessed by microiontophoresis). However, systemically it is at least 64 times less potent than muscimol in toxicity and as an anticonvulsant.

Ergot alkaloids as dopamine agonists: comparison in two rodent models.

A series of ergot alkaloids, together with the DA agonists apomorphine and piribedil, were tested for protective effects against audiogenic seizures in an inbred strain of mice (DBA/2) and for induction of circling behaviour in mice with unilateral destruction of one nigrostriatal DA pathway. The order of potency against audiogenic seizures was apomorphine greater than ergocornine greater than bromocryptine greater than ergometrine greater than LSD greater than methysergide greater than piribedil while that observed in the rotating mouse model was apomorphine greater than ergometrine greater than ergocornine greater than bromocryptine greater than piribedil. LSD caused only weak circling behaviour even when administered in high doses (greater than 1 mg/kg). Methysergide was ineffective. Prior administration of the neuroleptic agent haloperidol blocked the effect of DA agonists and of ergot alkaloids in both animal models. The possible action of ergot alkaloids as DA agonists is discussed.

Epileptogenic and anticonvulsant effects of GABA agonists and GABA uptake inhibitors

Abstract Among GABA agonists that produce bicuculline-sensitive post-synaptic inhibition, some facilitate the binding of benzodiazepines (e.g. muscimol) and some do not (e.g. THIP). Baclofen does not produce bicuculline-sensitive post-synaptic inhibition, but mimics the action of GABA at a presynaptic site on noradrenergic terminals. All these 3 classes of ‘GABA agonist’ produce EEG signs of epilepsy in baboons ( Papio papio ) with photosensitive epilepsy. Thus, spike and wave discharges are seen after muscimol, 0.5-1 mg/kg IV, THIP, 4–8 mg/kg, IV; baclofen, 10 mg/kg; or 4-hydroxybutyrate, 200–400 mg/kg. Photically-induced myoclonus is blocked by baclofen and 4-hydroxybutyrate, but not by muscimol and THIP. Among GABA-uptake blockers given intracerebroventricularly in DBA/2 mice, some are epileptogenic, e.g. (+)-2,4-diaminobutyric acid, 0.5-2 μmoles; (±) cis-3-aminocyclohexanecarboxylic acid, 3–6 μmoles; and some are anticonvulsant, against sound-induced seizures, e.g. (±) nipecotic acid, 1-6-3.2 μmoles; (+)ethyl nipetocate, 0.4-0.8 μmoles; or piperazic acid, 4-μmoles. Ethyl nipecotate, 0.24-0.32 mmole/kg is also anticonvulsant when given intraperitoneally.

Inhibition of reflex epilepsy by (±)-N-n-propylnorapomorphine

In baboons, Papio papio, spontaneously showing photosensitive epilepsy, myoclonic responses to intermittent photic stimulation were reduced or abolished for up to four hours by (+/-)-N-n-propylnorapomorphine (NPA) 0.05-0.2 mg/kg body weight, given i.v. In animals pretreated with allyglycine, 200 mg/kg, a transient abolition of myoclonic responses followed NPA, 0.2 mg/kg. In DBA/2 mice, seizures following auditory stimulation were attenuated or abolished by NPA 0.025-0.1 mg/kg given intraperitoneally (ED50 for abolition of clonic phase = 0.032 mg/kg). The ED50 for pentylenetetrazol seizures in MF 1 mice was not altered by NPA 0.25 mg/kg.

Blockade of photically induced epilepsy by ‘dopamine agonist’ ergot alkaloids

The effect of the intravenous administration of ergot alkaloids on epileptic responses to intermittent photic stimulation (IPS) has been studied in adolescent baboons, Papio papio, from Senegal. Ergocormine, 1–2 mg/kg, produced marked autonomic and behavioural effects, slowed the EEG, and abolished myoclonic responses to IPS for 30–90 min. Ergometrine, 1 mg/kg, activated the EEG and blocked the induction of myoclonic responses for 1–3 h. Bromocriptine, 0.5–4 mg/kg, did not consistently prevent myoclonic responses to IPS. After pretreatment with a subconvulsant dose of allylglycine (180–200 mg/kg), lysergic acid diethylamide, 0.1 mg/kg, retained the capacity to block myoclonic responses to IPS, and ergocornine 1 mg/kg reduced such responses. The convulsant effect of allylglycine was enhanced, however, so that prolonged seizure sequences began 19–96 min after ergocornine administration. The protective action of ergot alkaloids against epileptic responses induced by sensory stimulation is interpreted in terms of effects at several sites, including dopaminergic and serotoninergic synapses.