Strategies in antiepileptic drug development: is rational drug design superior to random screening and structural variation?

1. Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed. 2. Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically-determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound-induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy. 3. In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man. 4. Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA-transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site. 5. Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA-transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1989.tb03454.x

GABAergic mechanisms in the pathogenesis and treatment of epilepsy.

Summary: Over the last 15 years, neurobiologists have begun to unravel the cellular mechanisms that underlie epileptiform activity. Such investigations have two main objectives: (I) to develop new methods for treating, “curing” or preventing epilepsy; and (2) to learn more about the normal functioning of the human brain at the cellular/ molecular and the neurological/psychological levels by analyzing abnormal brain functioning. The electroencephalogram (EEG) spike is a marker for the hyperexcitable cortex and arises in or near an area with a high epileptogenic potential. The depolarizing shift (DS) that underlies the interictal discharge (ID) appears to be generated by a combination of excitatory synaptic currents and intrinsic voltagedependent membrane currents. The hyperpolarization that follows the DS (post-DS HP) limits ID duration, determines ID frequency, and prevents ID deterioration into seizures. The disappearance of the post-DS HP in some models is related to the onset of seizures and the spread of epileptifonn activity. During the transition to seizures, the usually self-limited ID spreads in time and anatomical space. Several processes may intervene in the pathophysioogical dysfunction. These include enhancing GABA-mediated inhibition, dampening NMDA-mediated excitability, interfering with specific Ca2+ currents in central neurons, and perhaps stimulating “gating” pathways.

Cellular mechanisms of epilepsy and potential new treatment strategies.

Contemporary research indicates promising anticonvulsant effect of curcumin. However, its poor oral bioavailability is a major hindrance toward its pharmacological action. Thus, this study was carried out to evaluate the acute effect of liposome-entrapped curcumin on increasing current electroshock seizures (ICES) test, pentylenetetrazole (PTZ)-induced seizures, and status epilepticus in mice. Liposome-entrapped curcumin in doses 25 and 50 mg/kg demonstrated significant increase in seizure threshold current and latency to myoclonic and generalized seizures in ICES test and PTZ-induced seizures, respectively. Similarly, liposomal-entrapped curcumin also increased the latency to the onset and decreased the duration of seizures during status epilepticus in mice. To conclude, liposomal-entrapped curcumin possesses anticonvulsant activity against status epilepticus in mice.

Liposomal formulation of curcumin attenuates seizures in different experimental models of epilepsy in mice.

It has been known for almost 20 years that seizures due to electroshock or convulsants are associated with an accumulation of free fatty acids (FFAs) in the brain, particularly of arachidonic (AA, 20:4) and stearic acid (18:O). The original work came from the laboratory of Nicolas Bazan,14 who, as will be discussed later, is also responsible for a substantial part of the subsequent development in the field. These early observations were soon confirmed and extended, and it was established that the accumulation of 20:4 was accompanied by the formation of its cyclooxygenase and lipoxygenase product^^^ (for further literature, see Ref. 9). Other work showed that the FFAs and their oxidation products accumulated as a result of seizure activity per se, and not because of accompanying hypoxia.’&’’ Finally, it has become increasingly clear that a substantial part of the FFAs accumulating during seizures, particularly in the initial seizure period, emanates from inositol phospholipids enriched in 20:4 and 18:O. This was suspected on grounds that seizures caused the accumulation of diacylglycerol (DAG) with that FFA comp~sition,’*’~ and more directly shown in experiments in which short-lasting seizures were found to cause rapid breakdown of phosphatidylinositol bisphosphate (PIP2).I4 Although such findings suggest that activation of phospholipase C is a prominent cause of the accumulation of FFAs in seizures, a significant contribution from phospholipase A2 cannot be excluded, particularly during more long-lasting seizures. This raises the questions of the extent to which the enhanced arachidonic acid metabolism reflects stimulation of receptors coupled to phospholipase C, and of the contribution of increased cytosolic calcium concentrations (Ca:+). In the present article we will begin by considering FFA accumulation during ischemia and hypoglycemia. The purpose of this comparison is to provide information on rates of FFA accumulation in situations in which receptor stimulation of phospholipase C and a rise in Ca:+ are coupled to ATP failure, the latter preventing reacylation of lysophospholipids and resynthesis of phospholipids. We will then turn to corresponding events during seizures, asking whether energy failure is a t all involved and whether a rise in Caz+ seems likely. This discussion leads to another question: what information is there on the role played by receptor stimulation? Furthermore, why are the FFA levels decreasing during continuous seizures following their abrupt accumulation a t seizure onset? Finally, we will address the possibility that accumulation of AA and its continuous oxidation to potentially toxic substances contribute to the neuronal damage incurred after long-lasting seizures.

Arachidonic acid metabolism in seizures.

Summary: Sprague—Dawley rats with interictal and ictal spike activity induced by intraperitoneally injected isoniazid (INH) were treated, 5 min before or 30 min later, with liposome-entrapped γ-aminobutyric acid (GABA) (LEG) or GABA or phosphatidylserine. Crossover injections were given in random sequence and INH alone was also injected in every animal as a control. LEG inhibited either seizures or interictal spikes in both groups. No decrease of epileptogenic activity was seen after GABA or phosphatidylserine treatment alone. It is suggested that LEG could contribute to the reconstitution of the GABA pool decreased by INH.



RESUME

Vingt Sprague-Dawley rats injectes avec Isoniazid (INH) et demontrant une activite ictal et interictal de pointes, ont ete traites avec GABA associea une preparation liposomal de Phosphatidylserine (LEG), ou GABA, ou PS. Le LEG demontre une activite inhibitrice soit sur l'activite de pointes interictales. soit sur l'activite de crise epileptique tandis que le GABA ou la PS n'ont aucune action. Cet observation suggere que le LEG peut contribuer a la reconstitution du pool de GABA. reduit par le INH.



RESUMEN

Se ha utilizado el GABA (LEG), el GABA o la Fosfatidilserina unidos a liposomas. en el tratamiento de ratas Sprague-Dowley con puntas interictales e ictales inducidas mediante la inyeccien intraperitoneal de Isoniazida (INH). Las inyecciones se administraron mediante teenica “crossover” en secuencia randomizada y la INH tambien se inyecto a cada animal como control. El LEG inhibio tanto los ataques como las puntas interictales en ambos grupos. No se observe un decremento de la aclividad epileptogenica despues del GABA o despues de la fosfatidilserina. administrados independientemente. Se sugiere que el LEG puede contribuir a la reconstitucion del reducido acumulo de GABA producido por la INH.



ZUSAMMENFASSUNG

Sprague-Dowley-Ratten mit interiktaler und iktaler spike-Aktivitat als Folge i.p.-injizierten Isoniazids (INH) wurden funf Minulen vorher oder dreissig Minulen spater mit in Liposomen verkapselter GABA (LEG) oder GABA oder Phosphatidylserin behandelt. Die unterschiedlichen Injektionen wurden in zufal-liger Folge verabreicht und INH alleine wurde ebenso als Kontrolle jedem Tier injiziert. LEG inhibierte in beiden Gruppen entweder Anfalle oder interiktale spikes. Eine Abnahme der epileptogenen Aktivitat fehlte nach GABA oder Phosphatidylserin alleine. Es wird vermutet, das LEG einen Beitrag zum Wiederherstellen des GABA-Pools leisten konnte, der durch INH vermindert ist.

A. Portera Sanchez

Papers

Liposome‐Entrapped γ‐Aminobutyric Acid Inhibits Isoniazid‐Induced Epileptogenic Activity in Rats