An update on the novel methods for the discovery of antiseizure and antiepileptogenic medications: where are we in 2024?

INTRODUCTION: Despite the availability of around 30 antiseizure medications, 1/3 of patients with epilepsy fail to become seizure-free upon pharmacological treatment. Available medications provide adequate symptomatic control in two-thirds of patients, but disease-modifying drugs are still scarce. Recently, though, new paradigms have been explored. AREAS COVERED: Three areas are reviewed in which a high degree of innovation in the search for novel antiseizure and antiepileptogenic medications has been implemented: development of novel screening approaches, search for novel therapeutic targets, and adoption of new drug discovery paradigms aligned with a systems pharmacology perspective. EXPERT OPINION: In the past, worldwide leaders in epilepsy have reiteratively stated that the lack of progress in the field may be explained by the recurrent use of the same molecular targets and screening procedures to identify novel medications. This landscape has changed recently, as reflected by the new Epilepsy Therapy Screening Program and the introduction of many in vitro and in vivo models that could possibly improve our chances of identifying first-in-class medications that may control drug-resistant epilepsy or modify the course of disease. Other milestones include the study of new molecular targets for disease-modifying drugs and exploration of a systems pharmacology perspective to design new drugs.

Thalidomide Attenuates Epileptogenesis and Seizures by Decreasing Brain Inflammation in Lithium Pilocarpine Rat Model.

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1ß concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1ß concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation.

[A case of the successful treatment of severe myoclonus with Lance-Adams syndrome by add-on perampanel showing long term effects].

Perampanel is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist that has been marked as an antiepileptic drug for partial-onset and primary generalized tonic-clonic seizures. There have been some recent reports of perampanel being effective against cortical myoclonus by Lafora disease and Unverricht-Lundborg disease. We herein report a 49-year-old man who presented with myoclonus due to Lance-Adams syndrome (LAS) after cardiopulmonary arrest caused by a severe bronchial asthma attack. Perampanel was very effective against myoclonus induced by LAS even in the chronic state, over 10 years after the remote onset. Perampanel should be considered for the treatment of extremely refractory myoclonus due to LAS.

Efficacy of Cicuta virosa medicinal preparations against pentylenetetrazole-induced seizures.

Epileptic seizures are characterized by imbalanced inhibition-excitation cycle that triggers biochemical alterations responsible for jeopardized neuronal integrity. Conventional antiepileptic drugs (AEDs) have been the mainstay option for treatment and control; however, symptomatic control and potential to exacerbate the seizure condition calls for viable alternative to these chemical agents. In this context, natural product-based therapies have accrued great interest in recent years due to competent disease management potential and lower associated adversities. Cicuta virosa (CV) is one such herbal remedy that is used in traditional system of medicine against myriad of disorders including epilepsy. Homeopathic medicinal preparations (HMPs) of CV were assessed for their efficacy in pentylenetetrazole (PTZ)-induced acute and kindling models of epilepsy. CV HMPs increased the latency and reduced the duration of tonic-clonic phase in acute model while lowering the kindling score in the kindling model that signified their role in modulating GABAergic neurotransmission and potassium conductance. Kindling-induced impairment of cognition, memory, and motor coordination was ameliorated by the CV HMPs that substantiated their efficacy in imparting sustained neuronal fortification. Furthermore, biochemical evaluation showed attenuated oxidative stress load through reduced lipid peroxidation and strengthened free radical scavenging mechanism. Taken together, CV HMPs exhibited promising results in acute and kindling models and must be further assessed through molecular and epigenomic studies.

Proteomics for Studying the Effects of Ketogenic Diet Against Lithium Chloride/Pilocarpine Induced Epilepsy in Rats.

The ketogenic diet (KD) demonstrates antiepileptogenic and neuroprotective efficacy, but the precise mechanisms are unclear. Here we explored the mechanism through systematic proteomics analysis of the lithium chloride-pilocarpine rat model. Sprague-Dawley rats (postnatal day 21, P21) were randomly divided into control (Ctr), seizure (SE), and KD treatment after seizure (SE + KD) groups. Tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectroscopy (LC-MS/MS) were utilized to assess changes in protein abundance in the hippocampus. A total of 5,564 proteins were identified, of which 110 showed a significant change in abundance between the SE and Ctr groups (18 upregulated and 92 downregulated), 278 between SE + KD and SE groups (218 upregulated and 60 downregulated), and 180 between Ctr and SE + KD groups (121 upregulated and 59 downregulated) (all p < 0.05). Seventy-nine proteins showing a significant change in abundance between SE and Ctr groups were reciprocally regulated in the SD + KD group compared to the SE group (i.e., the seizure-induced change was reversed by KD). Of these, five (dystrobrevin, centromere protein V, oxysterol-binding protein, tetraspanin-2, and progesterone receptor membrane component 2) were verified by parallel reaction monitoring. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that proteins of the synaptic vesicle cycle pathway were enriched both among proteins differing in abundance between SE and Ctr groups as well as between SE + KD and SE groups. This comprehensive proteomics analyze of KD-treated epilepsy by quantitative proteomics revealed novel molecular mechanisms of KD antiepileptogenic efficacy and potential treatment targets.

Insights into Potential Targets for Therapeutic Intervention in Epilepsy.

Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/ß-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.

A review of clinically significant drug-drug interactions involving angiotensin II receptor antagonists and antiepileptic drugs.

INTRODUCTION: Angiotensin II receptor blockers are widely used for the treatment of arterial hypertension and heart failure. However, recent studies on animal models of seizures showed that in the brain, the renin-angiotensin-aldosterone system might be involved in neuroinflammation; therefore, the administration of angiotensin II receptor blockers that cross the blood/brain barrier, reduces not only blood pressure but reduces neuroinflammation-induced neuronal injury. Apart from this neuroprotective effect, these drugs exhibit anticonvulsant activity in animal models of seizures, and losartan is associated with a probable anti-epileptogenic activity. AREAS COVERED: In this review, we intended to highlight the role of drug-drug interactions involving angiotensin II receptor antagonists with antiepileptic drugs accompanied by a brief characteristic of the role of RAS in neuroinflammation. EXPERT OPINION: Some combinations of antiepileptic drugs (lamotrigine or valproate) with sartans are particularly effective in terms of enhanced seizure control. Considering a possible anti-epileptogenic activity of losartan, its combinations with antiepileptic drugs may prove especially beneficial in epileptogenesis inhibition.

How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

Although over 25 antiepileptic drugs (AEDs) have become currently available for clinical use, the incidence of epilepsy worldwide and the proportions of drug-resistant epilepsy among them are not significantly reduced during the past decades. Traditional screens for AEDs have been mainly focused on their anti-ictogenic roles, and their efficacies primarily depend on suppressing neuronal excitability or enhancing inhibitory neuronal activity, almost without the influence on the epileptogenesis or with inconsistent results from different studies. Epileptogenesis refers to the pathological process of a brain from its normal status to the alterations with the continuous prone of unprovoked spontaneous seizures after brain insults, such as stroke, traumatic brain injury, CNS infectious, and autoimmune disorders, and even some specific inherited conditions. Recently growing experimental and clinical studies have discovered the underlying mechanisms for epileptogenesis, which are multi-aspect and multistep. These findings provide us a number of interesting sites for antiepileptogenic drugs (AEGDs). AEGDs have been evidenced as significantly roles of postponing or completely blocking the development of epilepsy in experimental models. The present review will introduce potential novel candidate drug-targets for AEGDs based on the published studies.

Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unclear, which hinders the discovery of effective antiepileptogenic drugs. Here we adopted a systems-level approach integrating transcriptomic profiles of three epileptogenesis stages to identify key regulators underlying epilepsy progression. Associating stage-specific gene meta-signatures with brain cell-specialized modules revealed positive regulation of glial migration and adhesion, cytokine production, and neuron death, and downregulation of synaptic transmission and ion transport during epileptogenesis. We identified 265 key regulators driving these processes and 72 of them were demonstrated associating with seizure frequency and/or hippocampal sclerosis in human TLE. Importantly, the upregulation of FAM107A, LAMB2, LTBP1 and TGIF1, which are mainly involved in nervous system development, were found contributing to both conditions. Our findings present the evolution landscape of epileptogenesis and provide candidate regulators that may serve as potential antiepileptogenic targets.

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy.

Epileptogenesis is the process of developing an epileptic condition and/or its progression once it is established. The molecules that initiate, promote, and propagate remarkable changes in the brain during epileptogenesis are emerging as targets for prevention/treatment of epilepsy. Epileptogenesis is a continuous process that follows immediately after status epilepticus (SE) in animal models of acquired temporal lobe epilepsy (TLE). Both SE and epileptogenesis are potential therapeutic targets for the discovery of anticonvulsants and antiepileptogenic or disease-modifying agents. For translational studies, SE targets are appropriate for screening anticonvulsive drugs prior to their advancement as therapeutic agents, while targets of epileptogenesis are relevant for identification and development of therapeutic agents that can either prevent or modify the disease or its onset. The acute seizure models do not reveal antiepileptogenic properties of anticonvulsive drugs. This review highlights the important components of epileptogenesis and the long-term impact of intervening one of these components, nitric oxide (NO), in rat and mouse kainate models of TLE. NO is a putative pleotropic gaseous neurotransmitter and an important contributor of nitro-oxidative stress that coexists with neuroinflammation and epileptogenesis. The long-term impact of inhibiting the glial source of NO during early epileptogenesis in the rat model of TLE is reviewed. The importance of sex as a biological variable in disease modification strategies in epilepsy is also briefly discussed.

KA-11, a Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in Vitro Characterization.

Recently, compound KA-11 was identified as a promising candidate for a new broad-spectrum anticonvulsant. This compound revealed wide protective activity across the most important animal models of seizures such as the maximal electroshock test (MES), the subcutaneous pentylenetetrazole test ( scPTZ), and the six-hertz test (6 Hz, 32 mA). Importantly, KA-11 was devoid of acute neurological activity, which was assessed by applying the chimney test (TD50 value higher than 1500 mg/kg). The preliminary in vivo results confirmed favorable anticonvulsant and safety properties of KA-11. With the aim of further biological characterization of KA-11, in the current studies we evaluated its antiepileptogenic activity in the kindling model of epilepsy induced by repeated injection of PTZ in mice. Furthermore, we assessed the antinociceptive activity of KA-11 in several animal pain models. As a result, KA-11 (at all doses applied: 25, 50, and 100 mg/kg) significantly delayed the progression of kindling induced by repeated injection of PTZ in mice. Additionally, KA-11 revealed potent antinociceptive activity in the formalin-induced tonic pain and, importantly, in the oxaliplatin-induced neuropathic pain model in mice. Moreover, KA-11 did not induce motor deficits in the rotarod test. Patch-clamp experiments revealed that one of the mechanisms of action of KA-11 is inhibition of voltage-gated sodium currents. Compound KA-11 appeared to be safe in relation to hepatotoxic properties as no phospholipidosis induction was determined in HepG2 cells at 50 µM, and a small, statistically significant decrease of cell viability was observed only at the highest used dose of 100 µM. Moreover, KA-11 did not affect the function of CYP2D6. The aforementioned hybrid substance proved to penetrate the biological membranes in the in vitro permeability assays.

An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders.

INTRODUCTION: Neuroinflammation has a critical role in brain disorders. Cyclooxygenase (COX) is one of the principal drug targets for the reduction of neuroinflammation; however, studies have yielded mixed results for COX-inhibitors in the treatment of diverse acute and chronic models of epilepsy. AREAS COVERED: The article covers the effects of COX-inhibitors in epilepsy disorders. A considerable emphasis has been placed on the antiepileptic and 'disease-modifying' properties of COX-1 and COX-2 inhibitors in various preclinical epilepsy models. EXPERT OPINION: The effect of COX-inhibitors on epilepsy is inconclusive. Studies have indicated beneficial effects in preclinical models; however, proconvulsant or no effects have also been observed. These molecules may have a bidirectional role with early neuroprotective and delayed neurotoxic effects. Further systematic preclinical studies to establish the use of COX-inhibitors in epilepsy are necessary.

Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies.

The prevalence of epilepsy is estimated 5-10 per 1000 population and around 70% of patients with epilepsy can be sufficiently controlled by antiepileptic drugs (AEDs). Epileptogenesis is the process responsible for converting normal into an epileptic brain and mechanisms responsible include among others: inflammation, neurodegeneration, neurogenesis, neural reorganization and plasticity. Some AEDs may be antiepileptiogenic (diazepam, eslicarbazepine) but the correlation between neuroprotection and inhibition of epileptogenesis is not evident. Antiepileptogenic activity has been postulated for mTOR ligands, resveratrol and losartan. So far, clinical evidence gives some hope for levetiracetam as an AED inhibiting epileptogenesis in neurosurgical patients. Biomarkers for epileptogenesis are needed for the proper selection of patients for evaluation of potential antiepileptogenic compounds.

Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of neurological and neuropsychiatric abnormalities, including epilepsy affecting 70-90% of patients and being one of the major risk factors of intellectual disability. The first seizures in TSC patients appear usually between the 4th and the 6th months of life. Recent studies have shown the beneficial role of preventative antiepileptic treatment in TSC patients, with the possibility for improvement of cognitive outcome. Moreover, European recommendations suggest early introduction of Vigabatrin if ictal discharges occur on EEG recordings, with or without clinical manifestation. The aim of this study was to define the most useful approach to make the diagnosis of TSC before seizure onset (before age 4th months), in order to start early EEG monitoring with possible preventative treatment intervention. METHODS: We performed a retrospective review of children who were suspected of having TSC due to single or multiple cardiac tumors as the first sign of the disease. We analyzed the medical records in terms of conducted clinical tests and TSC signs, which were observed until the end of the 4th month of age. Subsequently, we described the different clinical scenarios and recommendations for early diagnosis. RESULTS: 82/100 children were diagnosed with TSC within the first 4 months of life. Apart from cardiac tumors, the most frequently observed early TSC signs were subependymal nodules (71/100, 71%), cortical dysplasia (66/100, 66%), and hypomelanotic macules (35/100, 35%). The most useful clinical studies for early TSC diagnosis were brain magnetic resonance imaging (MRI), skin examination and echocardiography. Genetic testing was performed in 49/100 of the patients, but the results were obtained within the first 4 months of life in only 3 children. CONCLUSIONS: Early diagnosis of TSC, before seizure onset, is feasible and it is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early TSC diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination and genetic testing should be performed early in every patient suspected of having TSC.

Antiepileptogenic and Neuroprotective Effects of Pergularia daemia on Pilocarpine Model of Epilepsy.

In this study, we investigated antiepileptogenic and neuroprotective effects of the aqueous extract of Pergularia daemia roots (PDR) using in vivo and in vitro experimental models. In in vivo studies, status epilepticus caused by pilocarpine injection triggers epileptogenesis which evolves during about 1-2 weeks. After 2 h of status epilepticus, mice were treated during the epileptogenesis period for 7 days with sodium valproate and vitamin C (standards which demonstrated to alter epileptogenesis), or Pergularia daemia. The animals were then, 1 week after status epilepticus, challenged with acute pentylenetetrazole (PTZ) administration to test behaviorally the susceptibility to a convulsant agent of animals treated or not with the plan extract. Memory was assessed after PTZ administration in the elevated plus maze and T-maze paradigms at 24 and 48 h. Antioxidant and acetylcholinesterase activities were determined in the hippocampus after sacrifice, in vitro studies were conducted using embryonic rat primary cortical cultures exposed to L-glutamate. Cell survival rate was measured and apoptotic and necrotic cell death determined. The results showed that chronic oral administration of PDR significantly and dose-dependently increased the latency to myoclonic jerks, clonic seizures and generalized tonic-clonic seizures, and the seizure score. In addition, PDR at all doses (from 4.9 to 49 mg/kg) significantly decreased the initial and retention transfer latencies in the elevated plus maze. Interestingly PDR at the same doses significantly increased the time spent and the number of entries in T-maze novel arm. PDR significantly increased the activities of acetylcholinesterase and antioxidant enzymes superoxide dismutase, catalase, and total glutathione and proteins, and decreased malondialdehyde level. Furthermore, PDR increased viability rate of primary cortical neurons after L-glutamate-induced excitotoxicity, in a dose dependent manner. Altogether these results suggest that PDR has antiepileptogenic and neuroprotective effects, which could be mediated by antioxidant and antiapoptotic activities.

Physicochemical and biological evaluation of a cinnamamide derivative R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608) for nervous system disorders.

A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, and additionally, thermal analysis showed that it exists in one crystalline form. The compound was evaluated in vivo in rodents as anticonvulsant, antiepileptogenic, analgesic, and neuroprotective agent. The beneficial properties of the compound were found in animal models of seizures evoked electrically (maximal electroshock test, 6-Hz) and chemically (subcutaneous pentylenetetrazole seizure test) as well as in three animal models of epileptogenesis: corneal-kindled mice, hippocampal-kindled rats, and lamotrigine-resistant amygdala-kindled rats. Quantitative pharmacological parameters calculated for the tested compound were comparable to those of currently used antiepileptic drugs. In vivo pharmacological profile of KM-608 corresponds with the activity of valproic acid.

Prevention of Epilepsy: Issues and Innovations.

Epilepsy is a common brain disease and preventing epilepsy is a very relevant public health concern and an urgent unmet need. Although 40 % of all epilepsy cases are thought to have acquired causes, there is a roadblock for successful prevention. Efforts to protect the brain from epileptogenic insults are severely hampered by our lack of biomarkers to identify the few percent at high risk meriting treatment among those exposed. Preventing brain injury has been moderately effective from around birth to middle age; however, the strategy has failed to stop a substantial increase over the last decades in symptomatic epilepsy in those aged 65 and above. The traditional concept of repurposing anti-seizure drugs used for symptomatic seizure relief to prevent the onset of epilepsy has completely failed up to now. More recently, however, hope is on the horizon with a search for biomarkers and discovery of a new class of agents, called anti-epileptogenic drugs, which were specifically developed for prevention of epilepsy.

Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies.

Animal seizure and epilepsy models continue to play an important role in the early discovery of new therapies for the symptomatic treatment of epilepsy. Since 1937, with the discovery of phenytoin, almost all anti-seizure drugs (ASDs) have been identified by their effects in animal models, and millions of patients world-wide have benefited from the successful translation of animal data into the clinic. However, several unmet clinical needs remain, including resistance to ASDs in about 30% of patients with epilepsy, adverse effects of ASDs that can reduce quality of life, and the lack of treatments that can prevent development of epilepsy in patients at risk following brain injury. The aim of this review is to critically discuss the translational value of currently used animal models of seizures and epilepsy, particularly what animal models can tell us about epilepsy therapies in patients and which limitations exist. Principles of translational medicine will be used for this discussion. An essential requirement for translational medicine to improve success in drug development is the availability of animal models with high predictive validity for a therapeutic drug response. For this requirement, the model, by definition, does not need to be a perfect replication of the clinical condition, but it is important that the validation provided for a given model is fit for purpose. The present review should guide researchers in both academia and industry what can and cannot be expected from animal models in preclinical development of epilepsy therapies, which models are best suited for which purpose, and for which aspects suitable models are as yet not available. Overall further development is needed to improve and validate animal models for the diverse areas in epilepsy research where suitable fit for purpose models are urgently needed in the search for more effective treatments.

Anticonvulsant properties of methanol leaf extract of Laggera Aurita Linn. F. (Asteraceae) in laboratory animals.

ETHNOPHARMACOLOGICAL RELEVANCE: Preparation of Laggera aurita Linn. (Asteraceae) is widely used in traditional medicine to treat various kinds of diseases such as epilepsy, malaria, fever, pain and asthma. Its efficacy is widely acclaimed among communities in Northern Nigeria. AIM OF THE STUDY: The present study is aimed at establishing the possible anticonvulsant effects of the methanol leaf extract of Laggera aurita using acute and chronic anticonvulsant models. MATERIALS AND METHOD: Median lethal dose (LD50) was determined in mice and rats via oral and intraperitoneal routes. Anticonvulsant screening of the extract was performed using maximal electroshock-induced seizure test in day-old chicks; pentylenetetrazole-, strychnine- and picrotoxin- induced seizure models in mice. Similarly; its effects on pentylenetetrazole-induce kindling in rats as well as when co-administered with fluphenamic and cyproheptadine in mice, were evaluated. RESULTS: Median lethal dose (LD50) values were found to be >5000mg/kg, p.o. and 2154mg/kg, i.p., each for both rats and mice. The extract showed dose dependent protection against tonic hind limb extension (THLE) and significantly (p<0.05) decreased the mean recovery from seizure in the maximal electroshock-induced seizure. In the pentylenetetrazole-induced seizure model, the extract offered 50% protection at 600mg/kg and also increased the mean onset of seizure at all doses with significant (p<0.05) increase at the highest dose (600mg/kg). Similarly the extract produced significant (p<0.05) increase in the onset of seizures in both strychnine- and picrotoxin- induced seizure models, at all the doses except at 150mg/kg for the picrotoxin model. Co-administration of fluphenamic acid (FFA) (5mg/kg) and the extract (600mg/kg) showed an enhanced effect with percentage protection of 70% while co-administration of FFA (5mg/kg) and phenytoin (5mg/kg) as well phenytoin (5mg/kg) and the extract (600mg/kg) produced an additive effect. Administration of the extract (600mg/kg), phenytoin (20mg/kg) and cyproheptadine (4mg/kg) offered 40%, 100% and 0% protection against THLE, each respectively, while co-administration of cyproheptadine (4mg/kg) and the extract (600mg/kg) as well as co-administration of cyproheptadine (4mg/kg) and phenytoin (20mg/kg) offered reduced protection of 20% and 50% each respectively. The extract at all doses reduced the severity of seizure episodes induced by PTZ-induced kindling. CONCLUSION: The results suggest that the methanol leaf extract of Laggera aurita possesses anticonvulsant and antiepileptogenic properties.