Article

GABAergic drugs in the treatment of epilepsy: modern or outmoded?

Department of Clinical & Experimental Medicine, Division of Neurology, University Hospital Maggiore della Carità, Italy.
Future medicinal chemistry (Impact Factor: 4). 02/2011; 3(2):177-82. DOI: 10.4155/fmc.10.296
Source: PubMed

ABSTRACT Antiepileptic drugs have a number of mechanisms of action that target brain excitability systems. The potentiation of GABAergic inhibitory neurotransmission represents a classic and well-known antiseizure effect. Currently available GABAergic antiepileptic drugs mainly target GABA(A) receptor-associated complexes, GABA reuptake or GABA catabolism. All these compounds, although generally effective, are limited by their deleterious effects on cognition and behavior. The challenge will be to find GABAergic drugs that exhibit the beneficial effects, without the adverse ones.

0 Followers
 · 
79 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Discovered more than three decades ago, vigabatrin is approved in more than 50 countries as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with infantile spasms. Contrary to a fairly common misperception, the compound's mechanism of action is very well-characterized in animal models and cell cultures. γ-Aminobutyric acid (GABA)-ergic synapses comprise approximately 30% of all synapses within the central nervous system, and therein underlies the primary mode of synaptic inhibition. Vigabatrin was rationally designed to have a specific effect on brain chemistry by inhibiting the GABA-degrading enzyme, GABA transaminase, resulting in a widespread increase in GABA concentrations in the brain. The increase in GABA functions as a brake on the excitatory processes that can initiate seizure activity. Despite the short half-life of vigabatrin in the body (5-7 h) and its relatively low concentration in cerebrospinal fluid (10% of the concentration observed in plasma), it has the profound effect of increasing GABA concentration in the brain for more than a week after a single dose in humans. This effect persists steadily over years of vigabatrin administration and results in significant and persistent decreases in seizure activity. Vigabatrin can be effective with once-daily dosing. Because of its specificity, vigabatrin has helped researchers explore the specific mechanisms within the brain that underlie seizure activity.
    Acta neurologica Scandinavica. Supplementum 12/2011; DOI:10.1111/j.1600-0404.2011.01596.x
  • [Show abstract] [Hide abstract]
    ABSTRACT: alpha-asarone is a major essential oil component of rhizomes of Acori Graminei Rhizoma (AGR), a traditional medicinal plant utilized in China to treat epilepsy. The objective of present study was to investigate the antiepileptic activity of alpha-asarone in various animal seizure models. Experimental seizure models were established in mice and rats in which the antiepileptic properties of alpha-asarone were compared with those of Valproic Acid (VPA), Carbamazepine (CBZ) and Clonazepam (CNP). The Maximal Electroshock Seizure (MES) test and Subcutaneous Pentylenetetrazol Seizure (scPTZ) test were done in Kunming (KM) mice. The lithium-pilocarpine model was employed to assess the antiepileptic activity in rats. The seizure incidence significantly decreased by 40-100% in the MES test, 50-90% in the scPTZ test and 40-80% in the lithium-pilocarpine model; the seizure latency dramatically prolonged by 180 sec in the scPTZ test and 4-15 min in the lithium-pilocarpine model; the seizure severity score was markedly reduced by 1.96 in the lithium-pilocarpine model. The seizure frequency markedly reduced in the lithium pilocarpine model. In addition, significant differences in the above variables were noted between alpha-asarone at 200 mg kg(-1) (p.o.) and that at 50 or 100 mg kg(-1). These results suggest that alpha-asarone has favorable antiepileptic activity, is an active antiepileptic drug and has potential implication in the management of epilepsy.
    International Journal of Pharmacology 06/2012; 8(6):567-571. DOI:10.3923/ijp.2012.567.571 · 0.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To test the hypothesis that a triazolyloxazolidinone (PH084) has anticonvulsant activity by examining its effects on in vitro seizure models in the rat hippocampus. Materials and Methods: Whole-cell synaptic currents, action potentials and extracellular population spikes (PS) were recorded in the cell body area of rat hippocampal CA1 region in acutely prepared slices. Chemical [picrotoxin (100 µM) and zero magnesium] and electrical seizures were induced and the effect of PH084 (10 µM) was tested on cellular responses, multiple spikes and spontaneous bursting frequencies. Results: PH084 depressed evoked excitatory postsynaptic currents, action potential firing frequency and PS amplitude. All of these responses did not recover to baseline after 15-20 min washout of PH084. Perfusion with zero magnesium ion (Mg(2+))-containing buffer converted a single PS to multiple PS (mPS) accompanied by spontaneous burst. PH084 suppressed the mPS and the spontaneous burst frequency and it also suppressed the picrotoxin-induced mPS number. However, it did not affect the frequency of stimulus train-induced after discharge or bursts. Furthermore, 8-10 min pretreatment with PH084 did not affect the ability of zero Mg(2+) buffer, picrotoxin or stimulus train to induce epileptiform activity. Conclusions: Thus, while PH084 may have potential for anticonvulsant activity against chemically induced seizures, it has little or no potential against electrically induced seizures or in preventing epileptiform discharge.
    Medical Principles and Practice 12/2012; 22(4). DOI:10.1159/000346005 · 1.11 Impact Factor