Antiepileptogenic effects of the novel synthetic neuroactive steroid,ganaxolone, against pentylenetetrazol-induced kindled seizures: Comparison with diazepam and valproate

Pharmacological treatment of epilepsy is often unsatisfactory due to side effects and the lack of drugs that control the progressive epileptogenic process. Modulation of inhibitory γ-aminobutyric acid (GABA)-ergic neurotransmission by synthetic agonists of the neuroactive steroid binding site on the GABA_A receptor complex is one approach toward the identification of improved antiepileptic agents. In this study, antiepileptogenic and anticonvulsive effects of the novel synthetic neuroactive steroid, ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), were evaluated in comparison with diazepam and valproate against pentylenetetrazol (PTZ)-induced kindled seizures in mice. Kindled seizures provide a model of the progressive epileptogenic process. Successive administration of 45 mg/kg PTZ on days 1, 3, 5, 8, and 10 resulted in the rapid development of kindled seizures and significant reductions in thresholds for clonic convulsions, tonic convulsions, and lethality induced by PTZ on day 10. Ganaxolone, diazepam, and valproate dose-dependently protected against clonic convulsions induced by acute submaximal dose of PTZ (70 mg/kg). The compounds also dose-dependently suppressed fully kindled seizures and blocked the expression of kindled seizures over successive treatments with PTZ (45 mg/kg). Relative to acute anticonvulsive potencies against 70 mg/kg PTZ, however, ganaxolone was more potent than valproate or diazepam against fully kindled seizures and in blocking the expression of kindled seizures over successive treatments with PTZ. Importantly, only ganaxolone demonstrated antiepileptogenic activity by blocking the development of kindling, as evidenced when PTZ was administered in the absence of anticonvulsant treatments. Both diazepam and valproate failed to prevent development of kindled seizures even at doses that fully suppressed motor expression of seizures during kindling acquisition. Unlike diazepam and valproate, ganaxolone did not impair ambulatory activity within the dose range used in this study. These data, taken in conjunction with other findings on the unique pharmacological actions of ganaxolone, predict an improvement in the pharmacological management of epilepsy with this synthetic neuroactive steroid. Drug Dev. Res. 44:21–33, 1998. © 1998 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.     

Pharmacological investigation of gamma-aminobutyric acid (gaba) and fully-developed generalized seizures in the amygdala-kindled rat

The effects of GABA-modulating drugs were assessed in a pharmacological study of amygdala-kindled seizures in the rat. Fully-kindled subjects were tested with a randomized dose regimen, including drug vehicle, for each of seven drugs. Afterdischarge duration, motor seizure latency, motor seizure duration and motor seizure stage were scored. The GABA synthesis inhibitor, 3-mercaptopro-pionic acid, the GABA antagonist, bicuculline, and the chloride ionophore blocker, picrotoxin, all decreased motor seizure latency, but did not otherwise alter the kindled seizure duration or seizure stage. The inhibitor of GABA metabolism, gamma-vinyl-GABA, and pentobarbital, which competes for the picrotoxin binding site, both antagonized kindled seizures. Gamma-vinyl-GABA, however, did not appear to antagonize kindled seizures by a specific effect on GABA neurotransmission. The GABA agonists, imidazole acetic acid and ¦alpha-(chloro-4'phenyl)fluoro-5-hydroxy-2-benzylidene-amino¦-4-butyramide (SL 76-002), did not alter the kindled seizures. The results of these experiments are not consistent with the hypothesis that kindled seizures result from a loss of GABA-mediated inhibition: however, GABA may have a role in the modulation of kindled seizure activity.     

Neuronal plasticity: implications in epilepsy progression and management

Epilepsy is a common neurological disease. A growing number of research studies provide evidence regarding the progressive neuronal damage induced by prolonged seizures or status epilepticus (SE), as well as recurrent brief seizures. Importantly, seizure is only one aspect of epilepsy. However, cognitive and behavioral deficits induced by progressive seizures or antiepileptic treatment can be detrimental to individual function. The neurobiology of epilepsy is poorly understood involving complex cellular and molecular mechanisms. The brain undergoes changes in its basic structure and function, e.g., neural plasticity with an increased susceptibility in neuronal synchronization and network circuit alterations. Some of these changes are transient, while others are permanent with an involvement of both glutamatergic and γ‐aminobutyric acid (GABA)ergic systems. Recent data suggest that impaired neuronal plasticity may underlie the cognitive impairment and behavioral changes associated with epilepsy. Many neurologists recognize that the prevention or suppression of seizures by the use of antiepileptic drugs (AEDs) alone is insufficient without clear predictions of disease outcome. Hence, it is important to understand the molecular mechanisms underlying epileptogenesis because this may allow the development of innovative strategies to prevent or cure this condition. In addition, this realization would have significant impact in reducing the long‐term adverse consequences of the disease, including neurocognitive and behavioral adverse effects. Drug Dev Res 68:498–511, 2007. © 2008 Wiley‐Liss, Inc.     

Involvement of catecholamines in kindled amygdaloid convulsions in the rat.

The seizure state induced by amygdaloid kindling in the rat was accompanied by a significant depletion of norepinephrine (NE) in the hippocampus, midbrain, limbic lobes and frontal cortex. In contrast, there was no change in NE levels of the hypothalamus, brain stem or basal ganglia, nor were the levels of dopamine affected in any of these brain regions. Drugs which impair central noradrenergic mechanisms, including α-methyl-p-tyrosine, disulfiram and propranolol, enhanced the rate of development of kindled seizures; disulfiram and propranolol also increased the duration of after discharges accompanying the seizures. In contrast, drugs affecting dopaminergic mechanisms, including pimozide and apomorphine, as well as drugs acting on α-adrenergic receptors, phenoxybenzamine and clonidine, had no influence on the seizure state. It appears that central noradrenergic mechanisms, particularly those involving β-adrenergic receptors, may be involved in the pathogenesis of amygdaloid kindled seizures.     

Research advances in basic mechanisms of seizures and antiepileptic drug action

Epilepsy is a common neurological disease but the mechanism of seizure generation has been only partially unraveled. Furthermore, almost 30% of epileptic patients are resistant to pharmacological treatment. Therefore, elucidation of the basic mechanism of seizures and search for new antiepileptics in order to treat the drug-resistant form of epilepsy and to improve the efficacy of current therapies seem justified. The aim of this overview is a brief presentation of some new concepts and research directions in pathogenesis and pharmacotherapy of epilepsy. Development of ideas on the mechanisms of seizures and antiepileptic drugs reflects the progress in our understanding of the central nervous system physiology, particularly of neurotransmission. Hyperactivity of excitatory amino acid systems, insufficient GABA_A receptor-mediated neurotransmission, and disturbances in intrinsic properties of neuronal membranes are still regarded as the most important mechanisms of seizures. New data add to the complexity of GABA-glutamate interaction showing both excitatory and inhibitory role of GABA and glutamatergic neurons in the central nervous system. Moreover, besides synaptic NMDA and GABA_A receptors, also extrasynaptic receptors for the amino acid transmitters have been recently implicated in the pathomechanism of epilepsy. Changes in expression, polymorphisms, lost- or gain-function mutations as well as cellular energetic imbalance can contribute to the disturbed function of the ligand- and voltage-dependent sodium, potassium, chloride and calcium channels, resulting in epileptiform activity. Voltage-dependent sodium and calcium channel blockers, and GABA mimetics are the most clinically useful groups of antiepileptic drugs and the newest research in this field is focused on more selective and subtle regulations of their molecular targets. Of interest is an emerging role of extrasynaptic GABAA receptors, various kinds of potassium ion channels, hyperpolarization-activated cyclic nucleotide gated (HCN) channels, acid-sensing ion channels, and gap junctions in the regulation of neuronal excitability and seizures. Iono- and metabotropic glutamate receptors used to be viewed as an attractive target for new anticonvulsants, however, opinions are now less enthusiastic, since their competitive and non-competitive antagonists possess undesired side effects. Positive or negative allosteric modulators of glutamate receptors with fewer side-effects can be more promising. The introduction of new compounds acting through novel pharmacological mechanisms gives hope that the proportion of patients with uncontrolled epilepsy will substantially decrease. However, this may be possible if molecular background of the pharmacoresistance in epilepsy is deciphered.     

Opiate modification of amygdaloid-kindled seizures in rats

Male Long-Evans rats were stereotaxically implanted bilaterally with bipolar electrodes in the central amygdala. Rats were then kindled once daily for 1 sec until 3 consecutive Stage V [25] kindled seizures were elicited. On the following day, animals were injected (IP) with either saline, naloxone (10 mg/kg), naltrexone (10 mg/kg) or morphine sulfate (10 mg/kg) and again stimulated parameters the kindling stimulation parameters. Saline injected animals continued to show long bilateral AD's and behaviors (i.e., forelimb clonus, rearing, falling) typical of Stage V kindled animals. In contrast, rats injected with naloxone or naltrexone showed reduced behavioral seizures. Potentiation of post-ictal spiking by morphine in amygdaloid-kindled rats was also observed supporting previous reports [7,21]. In a second experiment, the reduction of kindled seizure severity by naloxone was systematically replicated. It is concluded that opiates can significantly modify amygaloid-kindled seizures, and that brain endorphins may play a role in the development of maintenance of an amygdaloid-kindled seizure focus.     

Effects of Antiepileptics on Lateral Geniculate Nucleus–Kindled Seizures in Rats

The present study was undertaken to clarify the characteristics of lateral geniculate nucleus (LGN) kindling in rats, especially the efficacies of antiepileptics, in comparison with those of amygdala (AMG) kindling. Daily electrical stimulation of the LGN led to the development of a generalized convulsion (kangaroo posture and falling back) in all subjects, similar to AMG kindling. The kindling response of the LGN differed from that of the AMG in a number of respects, that is, a high after-discharge (AD) threshold, a large number of stimulations for completion of kindling, and a different pattern of electroencephalogram (EEG) development. On the other hand, the oral administration of sodium valproate, carbamazepine, clobazam, or zonisamide caused dose-dependent inhibitions of both seizure stage and AD duration of LGN-kindled seizures, whereas ethosuximide had no significant effects. In addition, seizure stage was more potently inhibited than AD duration by these antiepileptics, particularly with clobazam. In conclusion, LGN kindling possesses characteristics that are different from AMG kindling. In addition, it was demonstrated that LGN kindling is a useful model, similar to other types of limbic system kindling, for the evaluation of antiepileptics.     

Pharmacological properties of ketamine

Ketamine is a dissociative anaesthetic that is being used in non-medical contexts. The effects of ketamine are very similar to those of phencyclidine, another dissociative anaesthetic that has enjoyed considerable popularity as a recreational drug. The effects of ketamine include analgesia, cardiovascular and respiratory stimulation, dissociation, hallucinations and anaesthesia. The potential dangers of uncontrolled ketamine use include psychosis and violence, accidents and marked psychomotor and cognitive impairment. Although studies have shown potential for tolerance to and physical dependence on ketamine, further investigation of these phenomena is needed. Ketamine is thought to produce most of its effects through antagonist activity at the PCP site of the NMDA receptor complex. Ketamine has sympathomimetic properties resulting from enhancement of catecholamine, and particularly dopamine, activity. While opioid receptor activity has been identified, this is relatively weak and the contribution to the effects of ketamine is not clear. Although much is known of the clinical uses and effects of ketamine, as yet little is understood of ketamine as a recreational drug and potential drug of dependence.     

MK-801与抗癫痫药合用对大鼠杏仁核点燃的影响

目的在大鼠杏仁核点燃模型研究MK-801(地佐西平)及其联合用药的抗癫痫作用。方法建立大鼠杏仁核慢性电刺激点燃模型,测定不同剂量的MK-801对点燃模型各项指标的影响,探讨MK-801与其他抗癫痫药的协同作用,用氨基脲诱发的小鼠惊厥模型测定MK-801抗惊厥作用。 结果MK-801(0.1～0.25 mg·kg^-1)可剂量依赖性抑制杏仁核点燃,缩短后放电时程,降低Racine's分级;在对点燃均无明显影响的剂量下,MK-801(0.05 mg·kg^-1)与抗癫痫药(苯巴比妥、丙戊酸及尼卡地平)合用可缩短后放电时程或降低Racine's分级。MK-801(0.1～0.25 mg·kg^-1)显著降低小鼠氨基脲诱发的发作潜伏期、惊厥发生率和死亡率。结论MK-801具有抑制大鼠杏仁核点燃的作用,增强苯巴比妥、丙戊酸及尼卡地平的抗癫痫活性,为临床的合并用药提供实验依据。     

MK-801与抗癫痫药合用对大鼠杏仁核点燃的影响(英文)

目的　在大鼠杏仁核点燃模型研究MK 80 1(地佐西平 )及其联合用药的抗癫痫作用。方法　建立大鼠杏仁核慢性电刺激点燃模型 ,测定不同剂量的MK 80 1对点燃模型各项指标的影响 ,探讨MK 80 1与其他抗癫痫药的协同作用 ,用氨基脲诱发的小鼠惊厥模型测定MK 80 1抗惊厥作用。结果　MK 80 1(0 1～ 0 2 5mg·kg- 1)可剂量依赖性抑制杏仁核点燃 ,缩短后放电时程 ,降低Racine’s分级 ;在对点燃均无明显影响的剂量下 ,MK 80 1(0 0 5mg·kg- 1)与抗癫痫药 (苯巴比妥、丙戊酸及尼卡地平 )合用可缩短后放电时程或降低Racine’s分级。MK 80 1(0 1～ 0 2 5mg·kg- 1)显著降低小鼠氨基脲诱发的发作潜伏期、惊厥发生率和死亡率。结论　MK 80 1具有抑制大鼠杏仁核点燃的作用 ,增强苯巴比妥、丙戊酸及尼卡地平的抗癫痫活性 ,为临床的合并用药提供实验依据     

Pharmacological treatment of anxiety disorders in adults with epilepsy

ABSTRACT

Introduction: Anxiety disorders represent one of the most frequently encountered comorbidities in patients with epilepsy, affecting the quality of life and increasing, morbidity, mortality, and healthcare costs. However, they are still underdiagnosed and undertreated.

Areas covered: This is a narrative review of the pharmacological treatment of anxiety disorders in adult patients with epilepsy discussing also major issues regarding pathophysiology and diagnosis.

Expert opinion: There are a lack of studies concerning the treatment of anxiety disorders in epilepsy, which is a serious gap in the literature. There is an urgent need for treatment and outcome data in order to provide information to patients. Current evidence outside epilepsy focuses on Selective Serotonin Reuptake Inhibitors and Serotonin Noradrenalin Reuptake Inhibitor with strong evidence especially for the acute and long-term treatment of Generalized Anxiety Disorder and Social Anxiety Disorder. Although it is reasonable to adopt treatment guidelines outside of epilepsy, it is completely unknown whether anxiety disorders in people with epilepsy have the same response and remission rates observed outside epilepsy. Future research strategies for new drug treatments in epilepsy will probably take comorbidities into account. At this point, pregabalin and buspirone represent an interesting starting point for the development of new compounds potentially indicated in both conditions.     

The effect of cinromide on “kindled” seizures in the rat

Cinromide, an experimental anticonvulsant (Burroughs Wellcome Co.), was tested against focal cortical (simple partial analog), focal amygdala (complex partial analog), and generalized convulsive (tonic-clonic analog) seizures in the “kindled” rat. The toxicity in the CNS was measured by the ataxia scale devised by Desmedt. Niemegeers, Lewi and Janssen (Arzneimittel-Forsch.26: 1592–1602, 1976). Cinromide was found to suppress generalized convulsions in small, subtoxic doses, whereas larger, sometimes toxic doses were required to suppress focal seizure activity. The general pattern of response resembles that of the standard clinical anticonvulsants which the present authors have previously investigated. Cinromide, however, was relatively more potent against focal amygdala (complex partial analog) seizures than any drug previously tested, except carbamazepine. These data suggest that cinromide should be clinically effective, not only against tonic-clonic seizures, but also, toxicity permitting, against complex partial attacks as well.     

托吡酯对大鼠杏仁核点燃的抑制作用

目的　在大鼠杏仁核点燃模型研究抗癫痫新药托吡酯的抗癫痫作用及其作用机制。方法　建立大鼠杏仁核电刺激点燃模型 ,并通过联合用药探讨托吡酯对点燃的作用及其可能机制 ;测定托吡酯对小鼠氨基脲惊厥的影响。结果　托吡酯 (5 0～ 2 0 0mg·kg-1,ig)可剂量依赖性抑制杏仁核点燃 (P <0 0 5 )。在对点燃均无明显影响的低剂量下 ,托吡酯与丙戊酸钠或尼卡地平合用可缩短后放电时程 (P <0 0 5 )。托吡酯 2 0 0mg·kg-1,ig ,降低小鼠氨基脲诱发的惊厥发生率和死亡率 (P <0 0 1)。结论　托吡酯能抑制杏仁核点燃 ,与丙戊酸钠、尼卡地平有协同效应 ,其机制可能与GABA能神经功能增强以及Ca2 + 拮抗有关。     

The withdrawal of antiepileptic drugs in patients with non-epileptic seizures: safety considerations

The majority of patients with psychogenic non-epileptic seizures (PNES) do not have epilepsy. There are a number of compelling reasons to take these patients off antiepileptic drugs (AEDs), including drug toxicity and teratogenicity, as well as possibly poorer outcome of PNES and increased risk of iatrogenic harm when patients present to emergency rooms on AEDs as emergencies. However, many patients with PNES who do not have epilepsy remain on AEDs postdiagnosis. Some studies do report patients taken off medication as an outcome measure, but with no assessment of the safety of withdrawal, or specification of the criteria for ‘excluding’ epilepsy. One study has assessed the safety of taking patients satisfying some simple criteria for the absence of an underlying epilepsy off AEDs, and has found the procedure to be safe, given appropriate postwithdrawal follow-up. Patients with PNES who do not have evidence of epilepsy should be referred to a centre with appropriate expertise in epilepsy diagnosis so that AEDs can be withdrawn in safe conditions.     

Eslicarbazepine acetate: a new option for the treatment of focal epilepsy

Background: Epilepsy is a neurological condition with an increased probability of seizure occurrence through time. Although many anti-epileptic drugs (AEDs) exist, they fail to treat seizures in 30% of patients with epilepsy. For these patients, new AEDs potentially more efficacious and safe are developed. Objective: To evaluate the effectiveness of eslicarbazepine acetate (ESL) in the treatment of patients with refractory epilepsy. Methods: A review of the literature was carried out using PubMed central. A direct contact with the drug manufacturer and developer was made. Results/conclusion: ESL is an AED that acts by inhibiting voltage-gated sodium channels. It has proved efficacious in the treatment of patients with refractory focal-onset epilepsy with a good safety profile. Evaluation of its use for treating other epileptic syndromes and its role as an initial treatment option for patients with epilepsy is warranted.     

The pharmacological treatment of depression in adults with epilepsy

Background: Comorbid mood disorders may affect quality of life in people with epilepsy. Objective: To review available data on the use of antidepressant drugs in epilepsy taking into account major concerns that may be encountered by clinicians, namely pharmacokinetic interactions with antiepileptic medications and seizure aggravation. Results: Data on pharmacotherapy of depression in epilepsy are limited with no controlled clinical trials investigating efficacy and safety of antidepressants. Data on seizure risk come from psychiatric samples, thus limiting the general applicability to people with epilepsy. Conclusions: Antidepressant drug doses need to be used and adjusted according to individual clinical needs. Within the therapeutic range, the incidence of seizures in psychiatric populations is low for most antidepressants.     

Topiramate and its clinical applications in epilepsy

Topiramate, a derivative of the monosaccharide d-fructose, has shown a wide spectrum of antiepileptic efficacy in both animal models and clinical trials. Multiple putative mechanisms of action include voltage-sensitive sodium channel blockade, calcium channel inhibition, increase of potassium conductance, GABA-mediated chloride current increment, glutamate-mediated neurotransmission inhibition and carbonic anhydrase isoenzyme inhibition. In general, the clinical response is maintained in the long-term. The most common side effects include somnolence, fatigue, headache, psychomotor slowing, confusion, difficulty with memory, impaired concentration and attention, speech and language problems and weight loss. If slowly titrated and used at a low-to-medium dosage, it is well tolerated and offers a valid therapeutic option, the relevance of which is comparable to that of the most widely used ‘old’ antiepileptic drugs. As it is not yet wholly clear which specific epilepsy syndromes may benefit most from topiramate with respect to other drugs, more accurate indications for initial monotherapy would require syndrome-oriented trials and more clinical experience.     

A pharmacological study in the kindling model of epilepsy

The anticonvulsant properties of carbamazepine were evaluated in the kindled amygdaloid seizure model in rats. Carbamazepine significantly raised the threshold for seizures, reduced the duration of elicited afterdischarges and attenuated the severity of seizures in previously-kindled rats, at doses that did not cause sedation or ataxia. A similar reduction in the duration of elicited afterdischarges and severity of seizures was seen after suprathreshold stimulation (400 mu A) with doses of carbamazepine that were without obvious sedative or ataxic effects. After acute intraperitoneal injections (solvent = 2% Tween-80 and 70% propylene glycol), the maximum anticonvulsant effectiveness against suprathreshold stimulation was seen at 30 min. When administered daily (13 days) during acquisition or development of kindling, carbamazepine (25 and 50 mg/kg, i.p.) had variable effects on kindling. Neither dose consistently reduced the duration of elicited afterdischarges during the acquisition phase. Both groups tended to reduce the developing seizure, with the smaller dose of carbamazepine (25 mg/kg) resulting in a more consistent and significant reduction in severity of seizures. No significant differences in number of daily stimulations needed to reach fully kindled seizures were found. Previous studies have reported variable results with carbamazepine and the kindled amygdaloid seizure in rats. The present study provides a comprehensive evaluation of carbamazepine in this model of epilepsy and discusses the results with regard to the finding reported previously.     

Lacosamide in patients with pharmacoresistant epilepsy

Introduction: Lacosamide is a novel antiepileptic drug licensed in the US and Europe as adjunctive therapy for partial-onset seizures in adults. The efficacy, safety, tolerability and favorable pharmacokinetic profile in the adult population suggest that lacosamide could be of benefit for patients with partial-onset seizures.

Areas covered: This paper reviews the available evidence and most recent data concerning the efficacy, safety, tolerability and pharmacokinetics of lacosamide in adults, as well as in the pediatric population.

Expert opinion: Lacosamide is one of the newest drugs of the antiepileptic armamentarium, and it is expected to compete directly with compounds that are currently used for adjunctive therapy in adults with refractory partial epilepsy. The intravenous formulation may be used for replacement therapy in patients temporarily unable to take oral medication. An apparent lack of sedative or cognitive effects might render this drug preferable in patients with mental insufficiency and/or epileptic encephalopathy.