ucb L059, a novel anti-convulsant drug: pharmacological profile in animais

doi:10.1016/0014-2999(92)90855-X

European Journal of Pharmacology

Volume 222, Issues 2–3, 10 November 1992, Pages 193-203

https://doi.org/10.1016/0014-2999(92)90855-X Get rights and content

Abstract

The anticonvulsant activity of uch L059 ((S)-α-cthyl-2-oxo-pyrrolidinc acetamide) was evaluated in a range of animal models, uch L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of anticpilcptic drugs. The compound was active, with ED₅₀ values generally within the range of 5.0–30.0 mg/kg, in inhibiting audiogcnic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetra Me (PTZ), bicucullinc, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike ways discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Ncurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50–100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active, ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential anticpileptogenic and anti-absence actions.

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Cited by (199)

The optimized biocatalytic synthesis of (S)-methyl 2-chlorobutanoate by Acinetobacter sp. lipase
2022, Chirality
Epilepsy is a chronic disease caused by sudden abnormal discharge of brain neurons, leading to transient brain dysfunction. Levetiracetam, developed by the UCB company in Belgium, is an effective drug for the treatment of epilepsy. (S)‐Methyl 2‐chlorobutanoate is an important chiral building block of levetiracetam, which has attracted a great deal of attention. In this study, a strain of lipase‐produced Acinetobacter sp. zjutfet‐1 was screened from soil samples. At optimized conditions for fermentation and biocatalysis, the bacterial lipase exhibited high catalytic activity for hydrolysis and stereoselectivity toward racemic methyl 2‐chlorobutanoate. When the enzymatic reaction was carried out in 6% of racemic substrate, the enantiomeric excess (e.e._s) reached more than 95%, with a yield of over 86%. Therefore, this lipase can efficiently resolve racemic methyl 2‐chlorobutanoate and obtain (S)‐methyl 2‐chlorobutanoate, which presents great potential in the industrial production of levetiracetam.
Combination of levetiracetam with sodium selenite prevents pentylenetetrazole-induced kindling and behavioral comorbidities in rats
2022, Saudi Pharmaceutical Journal
Citation Excerpt :
Se was found capable to cause prominent latency in developing the myoclonic jerks and generalized seizures and polytherapy were found superior to monotherapy. These results are in agreement with the previous study carried out by Grover et al. in which LEV inhibited the development of PTZ-kindling in rodents (Gower et al., 1992). Similarly, Loscher et al. also reported the anti-epileptogenic effects of LEV in which drug inhibited the expression of seizures dose-dependently in the amygdala–kindled rats (Löscher et al., 1998).
The pentylenetetrazol (PTZ)-induced kindling model acts through the antagonism of central GABA_A receptors and is one of the most widely used experimental animal models to study the characteristics of seizure development, behavioral manifestations and evaluation of antiseizure effects of existing and new drug candidates.
In the current study, we investigated the impact of chronically administered levetiracetam (50 mg/kg) and sodium selenite (Sod.Se: 0.25 and 0.5 mg/kg) alone and in combination during the kindling process (21 days) in rats. Moreover, the behavioral changes (through the integration of a wide array of behavioral tests) and markers of oxidative stress in isolated brain homogenates were assessed in PTZ- kindled rats.
The outcomes from the fully kindled rats revealed the increased seizure score and severity over time with marked behavioral deficits. However, the animals treated with the selected dose of LEV alone showed partial protection from epileptogenesis and amelioration (P < 0.05) of anxiety-like behavior (open filed, light/dark, elevated plus maze tests), cognitive impairment (y-maze, novel object recognition and water maze tests) and depression (sucrose preference test). Moreover, combining the LEV with sodium selenite resulted in a significant neuroprotective effect in comparison to monotherapy by reducing the disease progression and ameliorating behavioral outcomes. The combination of Sod.Se in a dose-dependent manner with LEV produced additive effects as maximum animals remained seizure-free compared to kindled rats (P < 0.05). The attenuation of PTZ induced oxidative stress was evident from the reduced malondialdehyde and elevated superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) level with P < 0.05, as compared to control epileptic rats. These observed results of combination therapy might be due to the antioxidant and neuroprotective properties of Sod.Se, thus augmenting the seizure-modifying potentials of levetiracetam.
Overall, the current findings support the prominence of combining the Sod.Se with LEV, over monotherapy to deal with prevailing challenges of drug resistance and neuropsychiatric sufferings common in epileptic patients.
The piriform cortex in epilepsy: What we learn from the kindling model
2020, Experimental Neurology
Epilepsy is a circuit-level brain disorder characterized by excessive or hypersynchronous epileptic seizures involving a complex epileptogenic network. Cumulative evidence suggests that the piriform cortex (PC) is a crucial site in seizure initiation, propagation, and generalization in epilepsy. The kindling model is a classic animal model of complex partial seizures with secondarily generalized tonic seizures, which is usually used for the study of epilepsy pathogenesis and preclinical anti-epilepsy drug evaluation. Various essential functions of the PC in epilepsy were discovered in the kindling model, therefore, this review focuses on discussing the role of the PC in the kindling model. We review what pathological changes happen in the PC in the kindling model, how the PC is involved in the kindling model through different interventions, and finally we also provide perspectives on some possible research directions for future studies.
Levetiracetam combined with ACEA, highly selective cannabinoid CB1 receptor agonist changes neurogenesis in mouse brain
2019, Neuroscience Letters
Citation Excerpt :
It is a unique antiepileptic drug in that is ineffective in classic seizure models which screen potential compounds for antiseizure efficacy such as maximal electroshock and pentylenetetrazol in rodents [2–5]. On the other hand it was proven that during preclinical evaluations, it increased the threshold for electroconvulsions and suppressed seizures in kindled and genetically epileptic animals [6–11]. Levetiracetam has also shown protective activity against acute seizures induced by 6 Hz electrical stimulation - a model of psychomotor seizures [12–14].
The aim of the study was to evaluate the impact of second generation antiepileptic drug levetiracetam (LEV) with arachidonyl-2′-chloroethylamide (ACEA) on proliferating neural precursor cells in mouse brain. Additionally, we established the relationship between treatment with ACEA in combination with LEV and hippocampal neurogenesis in mouse brain. All experiments were performed on male CB57/BL mice injected i.p. with LEV (10 mg/kg), ACEA (10 mg/kg) and PMSF (30 mg/kg) for 10 days. Experiments were provided in two stages: stage 1- an acute response of proliferating neural precursor cells to ACEA and LEV administration (Ki-67 staining), stage 2 – a long term response to ACEA and LEV administration (BrDU, NeuN, GFAP staining). Results indicate that ACEA + PMSF and ACEA + PMSF + LEV significantly increased the total number of Ki-67 positive cells comparing to the control group. PMSF and LEV administered alone and in combination had no significant impact on cell proliferation compared to the control group. Results from neurogenesis study indicated that ACEA + PMSF administered alone and in combination with LEV increased the total number of BrDU cells compared to the control group, although LEV on its own decreased the number of BrDU cells. Moreover, the combination of ACEA + PMSF + LEV significantly increased the total number of newborn neurons compared to the control group. In turn, LEV significantly decreased the process of neurogenesis. Astrocytes were considerably reduced in all treated groups as compare to the control mice. These data provide substantial evidence that LEV administered chronically decreases the proliferation and differentiation of newly born cells while combination of LEV + ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.
Neuroprotective effects of levetiracetam, both alone and combined with propylparaben, in the long-term consequences induced by lithium-pilocarpine status epilepticus
2018, Neurochemistry International
Citation Excerpt :
LEV is used as monotherapy and adjunctive therapy for the treatment of refractory partial seizures, juvenile myoclonic epilepsy and generalized idiopathic tonic-clonic seizures (Aiguabella et al., 2011; Lyseng-Williamson, 2011). Using experimental models, it has been described that LEV diminishes audiogenic seizures and delays the epileptogenesis process induced by amygdala-kindling (Gower et al., 1992; Löscher et al., 1998). The administration of LEV during status epilepticus (SE) reduces the duration of seizure activity (Itoh et al., 2015; Lee et al., 2013; Mazarati et al., 2004; Oliveira et al., 2005; Zheng et al., 2010).
Status epilepticus (SE) is a neurological condition that frequently induces severe neuronal injury in the hippocampus, subsequent epileptogenesis and pharmacoresistant spontaneous recurrent seizures (SRS). The repeated administration of LEV (a broad-spectrum antiepileptic drug) during the post-SE period does not prevent the subsequent development of SRS. However, this treatment reduces SE-induced neurodegeneration in the hippocampus. Conversely, propylparaben (PPB) is a widely used antimicrobial that blocks voltage-dependent Na⁺ channels, induces neuroprotection and reduces epileptiform activity in vitro. The present study attempted to determine if the neuroprotective effects induced by LEV are augmented when combined with a sub-effective dose of PPB. Long-term SE-induced consequences (hyperexcitability, high glutamate release, neuronal injury and volume loss) were evaluated in the hippocampus of rats. LEV alone, as well as combined with PPB, did not prevent the occurrence of SRS. However, animals treated with LEV plus PPB showed high prevalence of low frequency oscillations (0.1–4 Hz and 8–90 bands, p < 0.001) and low prevalence of high frequency activity (90–250 bands, p < 0.001) during the interictal period. In addition, these animals presented lower extracellular levels of glutamate, decreased rate of neurodegeneration and a similar hippocampal volume compared to the control conditions. This study's results suggest that LEV associated with PPB could represent a new therapeutic strategy to reduce long-term consequences induced by SE that facilitate pharmacoresistant SRS.
Dose-dependent effects of levetiracetam after hypoxia and hypothermia in the neonatal mouse brain
2016, Brain Research
Perinatal asphyxia to the developing brain remains a major cause of morbidity. Hypothermia is currently the only established neuroprotective treatment available for term born infants with hypoxic-ischemic encephalopathy, saving one in seven to eight infants from developing severe neurological deficits. Therefore, additional treatments with clinically applicable drugs are indispensable. This study investigates a potential additive neuroprotective effect of levetiracetam combined with hypothermia after hypoxia-induced brain injury in neonatal mice.
9-day-old C57BL/6-mice (P9) were subjected either to acute hypoxia or room-air. After 90 min of systemic hypoxia (6% O₂), pups were randomized into six groups: 1) vehicle, 2) low-dose levetiracetam (LEV), 3) high-dose LEV, 4) hypothermia (HT), 5) HT combined with low-dose LEV and 6) HT combined with high-dose LEV. Pro-apoptotic factors, neuronal structures, and myelination were analysed by histology and on protein level at appropriate time points. On P28 to P37 long-term outcome was assessed by neurobehavioral testing.
Hypothermia confers acute and long-term neuroprotection by reducing apoptosis and preservation of myelinating oligodendrocytes and neurons in a model of acute hypoxia in the neonatal mouse brain. Low-dose LEV caused no adverse effects after neonatal hypoxic brain damage treated with hypothermia whereas administration of high-dose LEV alone or in combination with hypothermia increased neuronal apoptosis after hypoxic brain injury. LEV in low- dosage had no additive neuroprotective effect following acute hypoxic brain injury.

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ucb L059, a novel anti-convulsant drug: pharmacological profile in animais

Abstract

Pharmacol. Biochem. Behav.

Brain Res. Rev.

Epilepsy Res.

A statistically precise and relatively simple method of estimating the bioassay with quantal response based on the logistic function

Am. Stat. Assoc. J. Sept.

The effectiveness of Piracetam in cortical myoclonus

J. Movement Disorders

Evaluation of anticonvulsant drugs in DBA/2 mice with sound-induced seizures

Arzneim. Forsch. Drug Res.

Accurate freehand injection into the lateral hrain ventricle of the conscious mouse

J. Appl. Physiol.

GABA antagonists: their use and mechanisms of action

Probit Analysis: A Statistical Treatment of the Response Curve

Epilepsy Towards Tomorrow

Comprehensive observational assessment: la. A systematic quantitative procedure for assessing the behavioural and physiologic state of the mouse

Psychopharmacologica (Berlin)

Antiepileptic drug development program: a cooperative effort of Government and industry

Epilepsia

A model of chronic sponlancous peta mal-like seizures in the rat: comparison with pentylenetrazol-induced seizures

Epilepsia