Convulsive Threshold Research Articles

Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy.

Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress. Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed. Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4-5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult. Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.

Effects of the uremic toxin indoxyl sulfate on seizure activity, learning and brain oxidative stress parameters in mice

Patients with end-stage renal disease often have neurological disorders, with a higher incidence of memory impairment or epilepsy than in the general population. Patients undergoing hemodialysis are particularly exposed to the biological effects of uremic toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins; however, its possible effects on seizure susceptibility or memory functions have yet to be elucidated. In the current study, we focused on investigating the possible convulsant and amnesic effects of IS in recognized animal models. The study was performed on adult male Swiss mice. IS and scopolamine (SCO) were administered intraperitoneally (i.p.), and pentylenetetrazole (PTZ) was injected subcutaneously (s.c.). All substances were given as single injections. Acute IS administration (400 mg/kg) led to its accumulation in the brain. IS at doses of 200 and 400 mg/kg decreased the PTZ convulsive threshold, and at the same doses, it did not significantly affect the threshold for electroconvulsions. IS (200 and 400 mg/kg) did not impair learning in the passive avoidance test and did not increase the SCO-induced memory impairment in this test. IS increased lipid peroxidation, decreased the level of reduced glutathione, and reduced the activity of superoxide dismutase and catalase in mouse brains. Exposure to IS did not significantly change the activity of acetylcholinesterase in the brain tissue.This study shows that acute exposure to IS induces oxidative stress in the brain and potentiates PTZ-induced seizures in mice. Further studies are needed to find out whether IS-induced oxidative stress may affect epileptic seizures and/or epileptogenesis.

Specificity of seizure genesis during electroconvulsive therapy and modified pentylenetetrazole kindling

Comparison of the development of chemically induced seizures in the experiment with the change in convulsive thresholds during electroconvulsive therapy (ECT) has demonstrated that repeated ‘chemical’ seizures can initiate the development of the kindling phenomenon, but regular ECT from the first to the 14th session most likely cause an increase in convulsive thresholds. However, the repeated ECT over 15 sessions is associated with a rapid decrease in the threshold current dose and probable dysregulation of endogenous anticonvulsant mechanisms, with the risk of the development of uncontrolled paroxysmal conditions and the risk of organic CNS lesions. The mechanisms of the convulsive action of ECT and pentylenetetrazolinduced kindling are fundamentally different. Differences in the pathogenesis of systemic convulsive reactions determine the divergent change in seizure thresholds during ECT and pentylenetetrazol stimulations.

Effect of synthetic folic acid surplus on neurological symptoms in offspring

Background. It has long been known about the need for folic acid for the vital activity of both macro-and microorganisms. It is necessary for the processes of methylation, nucleotide synthesis and also the formation of methionine and reducing the toxic effect of homocysteine. The addition of synthetic folic acid to the diet of pregnant women, as well as at the stage of pre-pregnancy preparation, significantly reduces the risks of fetal neural tube defects, heart defects, and possibly other organs and systems of the body. In addition, folic acid can help improve fertility potential. However, there is evidence of adverse effects of folic acid proficite on the health of older adults (hiding B12-deficient status) and the offspring of mothers taking high doses prescribed by medical specialists like a risks of infectious-inflammatory and allergic diseases of the upper respiratory tract in children, eczema, also disorders of psychomotor development and insulin resistance. In 1980, the direct excitatory effect of folic acid on synaptic transmission in the central nervous system was proved. This is due to the molecular structure, it contains L-glutamate.
 Therefore, the aim of the work was trying to prove the existing correlation data on probable neuropathologies, including a reduced threshold of seizures, a high risk of epilepsy in a model of offspring of Wistar rats with an increased dosage of folate throughout gestation and including at the stage of pre-gravidar preparation.
 Methods. We have determined the ability to the first convulsive act by introducing a 20% solution of caffeine at the rate of 100 mg/kg of weight intraperitoneally.
 Results. In the control group, the average clonus time was 1779.6 seconds, in the experimental group with a 1 mg/kg folic acid per diet dosage of 797.3 seconds, and in the second group with a 5 mg/kg folic acid per diet 439.7 seconds (p 0,01).
 Conclusion. The obtained results of the difference in the convulsive threshold may be due to changes in synaptic density as a result of an excess of synthetic folic acid during the formation of NT and subsequently during the differentiation of nervous tissue in the central nervous system (in particular, in the 3rd trimester with a massive appearance of glutamatergic receptors), which can affect the processes of neurogenesis and the formation of neural networks.

Neuropharmacological assessment of the methanolic stem back extract of Anopyxis klaineana (Pierre) Engl. (Rhizophoraceae) in mice

BackgroundMedicinal plants have recently attracted attention on a global scale for therapeutic interventions in the field of neuroscience. Anopyxis klaineana, a medicinal plant widely used in West Africa, has been studied extensively for its anti-inflammatory effects. However, studies on its neuropharmacological effects are quite limited. This study therefore assessed the neuropharmacological potential of the methanolic stem bark extract of Anopyxis klaineana (EAK) in murine models. Materials and methodsMice were treated orally with a methanolic stem back extract of Anopyxis klaineana (EAK) at 10, 30 or 100 mg/kg followed by testing in the elevated plus-maze (EPM) and open field (OF) tests for anxiolytic-like effects. EAK's antidepressant-like potential was also evaluated in the tail suspension test (TST), while anticonvulsant and central analgesic effects were evaluated with the pentylenetetrazol (PTZ)-induced convulsion threshold and tail withdrawal tests respectively at 30, 100 or 300 mg/kg. The extract was additionally subjected to chromatographic analyses using high resolution HPLC-MS. ResultsTotal ion current chromatogram of EAK revealed several peaks suggestive of secondary metabolites of the plant extract. EAK significantly (p<0.05) reduced depression-like behaviours in the TST although not as potent as fluoxetine (ED50: EAK=43.39±2.5; fluoxetine=1.16±1.6) (F3,20=9.663, p = 0.0004). It also showed significant anticonvulsive effect by reducing the frequency and duration of PTZ-induced convulsions (ED50=48.53±2.5 mg/kg) (F3,19=5.136, p = 0.0091). This anticonvulsant effect was seen in both clonic and tonic convulsions at 30 and 300 mg/kg. Additionally, EAK-treated mice showed higher latency to tail withdrawal in the analgesia test. We also observed significant (p<0.05) dose-dependent increase in anxiolytic-like effects in EAK-treated animals in the EPM (F3,20=10.77, p = 0.0002) and OF tests (F3,22=5.079, p = 0.008). ConclusionsThe methanolic Anopyxis klaineana stem back extract exhibits anxiolytic-like, antidepressant-like, analgesic and anticonvulsant effects in murine models for assessing neuropharmacological activity and is a good source for novel neuroactive compounds.

Zinc Water Prevents Autism-Like Behaviors in the BTBR Mice

This study aims to explore the effects of zinc water on autism-like behavior, convulsion threshold, and neurogenesis in ASD model animals. This study used the young BTBR ASD mouse model to explore the effect of a 6-week zinc water supplementation on ASD-like behaviors such as repetitive behavior and social communication disorder, seizure threshold, and the correlation with excitability regulation. The mice were divided into four groups of normal controls (B6) and models (BTBR) who did and did not receive zinc supplementation in water (B6, B6 + zinc, BTBR, and BTBR + zinc). For morphological changes in the hippocampus, we selected two indicators: hippocampal mossy fiber sprouting and neurogenesis. ASD-like behavior testing, seizure threshold determination, Timm staining, and neurogenesis-related assays—represented by Ki67 and DCX—were performed after 6 weeks of zinc supplementation. Our results show that zinc water can prevent autism-like behavior, reduce susceptibility to convulsions, and increase the proliferation of hippocampal progenitor cells in BTBR mice but has less effect on mossy fiber sprouting and neural progenitor cell differentiation. Zinc water reduces autism-like behavior in a partially inherited autism model mice—BTBR—which may be associated with hippocampal neural precursor cell proliferation and reversed hyperexcitability.

Caffeine impairs anticonvulsant effects of levetiracetam in the maximal electroshock seizure threshold test in mice.

Caffeine is the most widely used psychoactive substance in the world. Animal studies indicate that acute caffeine exposure at high doses may induce seizures anddiminish the anticonvulsant activity of antiepileptic drugs (AEDs) at much lower doses. The aim of the current study was to assess the effect of caffeine on the anticonvulsant action of levetiracetam (LEV) and vigabatrin (VGB). The anticonvulsant activity of LEV and VGB was examined in the maximal electroshock seizure threshold test in mice (MEST test). All drugs were administered intraperitoneally by single injections, and caffeine was applied at doses capable of interfering with AEDs. Effects of caffeine exposure on AEDs were also investigated in tests of memory and motor performance. Caffeine reduced the protective effect of LEV against electroconvulsions. Total brain concentration of LEV was unaffected by caffeine as well as inversely; LEVhad no significant impact on the brain caffeine concentration, suggesting a pharmacodynamic nature of theinteraction between LEV and caffeine in the MEST test.VGB at applied doses did not affect the convulsive threshold. Administration of VGB, but not LEV, alone orincombination with caffeine, impaired memory retention. In the chimney test, the combined treatment with AEDs and caffeine did not cause motor coordination impairment. It is suggested that caffeine may negatively affect the anticonvulsant action of LEV in patients with epilepsy.

Comorbid epilepsy and depression-pharmacokinetic and pharmacodynamic drug interactions.

Background: Major depressive disorder may be encountered in 17% of patients with epilepsy and in patients with drug-resistant epilepsy its prevalence may reach 30%. This indicates that patients with epilepsy may require antidepressant treatment. Purpose: Both pharmacodynamic and pharmacokinetic interactions between antiepileptic (antiseizure) and antidepressant drugs have been reviewed. Also, data on the adverse effects of co-administration of antiepileptic with antidepressant drugs have been added. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. Methods: The review of relevant literature was confined to English-language publications in PUBMED databases. Table data show effects of antidepressants on the seizure susceptibility in experimental animals, results of pharmacodynamic interactions between antiepileptic and antidepressant drugs mainly derived from electroconvulsions in mice, as well as results concerning pharmacokinetic interactions between these drugs in clinical conditions. Conclusion: Antidepressant drugs may exert differentiated effects upon the convulsive threshold which may differ in their acute and chronic administration. Animal data indicate that chronic administration of antidepressants could reduce (mianserin, trazodone) or potentiate the anticonvulsant activity of some antiepileptics (fluoxetine, reboxetine, venlafaxine). There are also examples of neutral interactions (milnacipran).

Scorpion Envenomation of Lactating Rats Decreases the Seizure Threshold in Offspring.

Few data are available in the literature describing the long-term effects of envenoming in the perinatal period. In this study, the relationship between envenoming of lactating rats and possible behavioral changes in the mother and in her offspring were investigated. Lactating Wistar rats received a single dose of T. serrulatus crude venom on postnatal days 2 (V2), 10 (V10) or 16 (V16), and had their maternal behavior evaluated. The seizure threshold was evaluated in adulthood offspring. A decrease in maternal care during envenoming was observed in V2 and V10 groups. The retrieval behavior was absent in the V2 group, and a lower seizure threshold in the adult offspring of all groups was observed. During envenoming, mothers stayed away from their offspring for a relatively long time. Maternal deprivation during the early postnatal period is one of the most potent stressors for pups and could be responsible, at least in part, for the decrease in the convulsive threshold of the offspring since stress is pointed to as a risk factor for epileptogenesis. Furthermore, the scorpionic accident generates an intense immune response, and inflammation in neonates increases the susceptibility to seizures in adulthood. Therefore, maternal envenoming during lactation can have adverse effects on offspring in adulthood.

Assessment of drug-drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice.

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I1 -imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.

Decreased convulsive threshold and memory loss after anti-NMDAR positive CSF injection in zebrafish

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis initially promotes memory deficits, behavioral changes, and epileptic seizures. We developed a new animal model of anti-NMDAR encephalitis using a single cerebroventricular injection of CSF from patients in adult zebrafish. We observed a reduction of the seizure threshold and recent memory deficits in those animals injected with CSF from patients with anti-NMDAR encephalitis. The locomotor activity was similar in the CSF and control groups. This zebrafish model consistently recapitulates symptoms seen in patients with anti-NMDAR encephalitis. It may provide a reliable, fast and cost-effective platform to investigate new therapeutic strategies to anti-NMDAR encephalitis.

Neuropharmacological Assessment of the Hydroethanolic Leaf Extract of Calotropis procera (Ait). R. Br. (Apocynaceae) in Mice.

Background Calotropis procera has been widely used traditionally for its analgesic and anti-inflammatory effects. It is also reportedly used in ethnomedicine for mental health disorders including epilepsy even in the absence of supporting scientific data. Thus, the potential of the plant to affect neurological functions was evaluated. Methods Irwin's test was performed to determine the effect of the oral administration of the extract (30–3000 mg kg−1) on gross behaviour and physiological function. The activity meter, rotarod, pentylenetetrazol- (PTZ-) induced convulsion, pentobarbitone-induced sleep test, and the tail immersion tests were used to evaluate the spontaneous activity, neuromuscular function, convulsive threshold, sedation, and analgesic effects of the Calotropis procera extract (30–1000 mg/kg), respectively, in mice. Results Calotropis procera extract (CPE) exhibited significant (p < 0.0001) anticonvulsant and analgesic effects. There was a significant increase in withdrawal latency of the CPE-treated animals in the tail immersion test for analgesia (p < 0.0001), while latency and duration of PTZ-induced convulsions were positively modulated. Calotropis procera extract showed significant (p < 0.0001) central nervous system depressant effects in pentobarbitone-induced hypnosis at 100–1000 mg/kg and spontaneous activity test (30–1000 mg/kg). The extract also depicted impaired motor coordination at 100–1000 mg/kg dose levels. LD50 was estimated to be above 1000 mg kg−1. Conclusions Calotropis procera extract has significant central nervous system depressant and analgesic effects in mice.

Secondary psychosis after a temporal lobe resection in a patient with refractory epilepsy. A case report

IntroductionWe present the case of a 34-year-old female patient with no prior psychiatric record who was treated in our outpatient department due to persecutory delusions of recent onset. The patient had a history of refractory temporal epilepsy since adolescence and underwent a temporal lobe resection 4 month prior to the appearance of her symptoms.ObjectivesTemporal lobe resection is a well-established technique to treat refractory temporal lobe epilepsy in which psychotic symptoms are an infrequent complication; the most frequent being cognitive sequelae, visual field defects and depression. According to several sources, this symptomatology may be underdiagnosed and undereportend and there have been a number of case reports and series of cases which describe the aforementioned entity.MethodsA case report is presented alongside a review of the relevant literature regarding cases of secondary psychosis after brain surgery.ResultsDuring her treatment we administered olanzapine up to doses of 7.5mg per day because of the risk of reducing the convulsive threshold. We observed a marked improvement and the disappearance of the delusions. The dose of olanzapine has been maintained for a year with no important side-effects and without a relapse in symptoms.ConclusionsPsychotic symptoms as a complication of temporal lobe resection may be more frequent than what was thought in the past. It is important to study this phenomenon more in-depth because the symptoms may remain undetected and present worse outcomes given that there are effective treatments which could ameliorate the condition.DisclosureNo significant relationships.

A desirable convulsive threshold. Some reflections about electroconvulsive therapy (ect)

Long-standing psychiatric practice confirms the pervasive use of pharmacological therapies for treating severe mental disorders. In many circumstances, drugs constitute the best allies of psychotherapeutic interventions. A robust scientific literature is oriented on finding the best strategies to improve therapeutic efficacy through different modes and timing of combined interventions. Nevertheless, we are far from triumphal therapeutic success. Despite the advances made by neuropsychiatry, this medical discipline remains lacking in terms of diagnostic and prognostic capabilities when compared to other branches of medicine. An ethical principle remains as the guidance of therapeutic interventions: improving the quality of life for patients. Unfortunately, psychotropic drugs and psychotherapies do not always result in an efficient remission of symptoms. In this paper I corroborate the idea that therapists should provide drug-resistant patients with every effective and available treatment, even if some of such interventions could be invasive, like Electroconvulsive Therapy (ECT). ECT carries upon its shoulders a long and dramatic history that should be better investigated to provide new insights. In fact, ECT has attracted renewed interest in recent years. This is due to the fact that antidepressant drugs in younger patients show often scarce effectiveness and unpleasant side-effects. Moreover, I show that, thanks to modern advances, ECT may work as a successful form of treatment for specific and rare cases, such as severe depression (with suicide attempts) and catatonia.

Effect of aliskiren on the anticonvulsant activity of antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice

Drug-drug interactions should be considered during the pharmacological treatment in patients with epilepsy and coexisting hypertension. Experimental studies in rodents showed that antihypertensive drugs which block the renin-angiotensin system (RAS) are able to decrease seizure severity. The anticonvulsant efficacy of several antiepileptic drugs (AEDs) was enhanced in different seizure models following concomitant treatment with RAS inhibitors. The current study examined the combined treatment with AEDs (carbamazepine, valproate, phenobarbital, clonazepam, ethosuximide, levetiracetam) and aliskiren, the first inhibitor of renin for treating hypertension, in the mouse 6 Hz psychomotor seizure model. The convulsive threshold was not affected by the renin inhibitor up to a dose of 75 mg/kg i.p. However, aliskiren (75 mg/kg) enhanced the anticonvulsant action of valproate reducing its ED50 value from 96.7 to 25.6 mg/kg (P < 0.01). The anticonvulsant potency of other AEDs was unaffected by aliskiren treatment. The combinations of aliskiren with AEDs did not cause adverse effects in mice evaluated in the rota-rod or passive avoidance task. Administration of the renin inhibitor did not significantly alter either plasma or brain concentration of valproate. The obtained results confirm earlier findings from other seizure tests (maximal electroshock and pentylenetetrazole-induced seizure test) that aliskiren has a neutral or positive effect on the anticonvulsant efficacy of AEDs, which suggest its safe use for the treatment of high blood pressure in patients with epilepsy. The beneficial anticonvulsant effect of the concomitant treatment with aliskiren and valproate is worthy of recommendation to further both preclinical and clinical studies.

Geroprotective effects of ethylmethylhydroxypyridine succinate in an experimental study

To study an effect of mexidol on the life expectancy, weight, seizure response thresholds, and impaired cognitive and motor functions during aging in male Wistar rats. In a long-term experiment, male Wistar rats, aged 3-26 months, were assessed for impaired cognitive functions (passive avoidance conditioned reflex test), convulsive threshold (test with pentylenetetrazole), motor deficits (tests of rotating rod and pulling on the crossbar), and life expectancy. The rats received mexidol in the form of 0,15% solution, which replaced drinking water, during two 2 month courses at the age of 18-20 and 22-24 month. A dose of mexidol consumed by the rat was 40-75 mg/kg/day. In old male Wistar rats, the long-term treatment with mexidol increases the life expectancy, improves learning, preservation and reproduction of the memory trace in the passive avoidance conditioned reflex test, increases the convulsive threshold and improves muscle tone and coordination of movements that are impaired during aging. Mexidol increases the threshold of convulsive reaction, restores cognitive and neurological deficits that occur during aging in male Wistar rats and increases the by its ability to influence mitochondriogenesis and antioxidant properties.

Persistent alterations in seizure susceptibility, drug responsiveness and comorbidities associated with chemical kindling after neonatal exposure to an organophosphate

Developmental exposure to organophosphates (OPs), at doses that do not cause cholinergic crisis, induces profound and lasting alterations in different neurotransmitter systems, which contribute to several behavioral outcomes. The present work examines whether neonatal exposure to low dose of chlorpyrifos (CPF), a widely used OP insecticide, alters the general excitability of the adult brain, its responsiveness to drugs with antiepileptic properties, the process of chemical kindling and the kindling-induced behavioral outcomes. Neonatal rats were exposed to daily doses of CPF (1 mg/kg) or dimethyl sulfoxide (DMSO, vehicle) on postnatal days (PND) 1–4. On PND 60, a subgroup of animals from both CPF and DMSO groups were injected with additive doses of pentylenetetrazole (PTZ) to evaluate the latency time to the first seizure, the threshold of PTZ-induced convulsion, and to determine the anticonvulsive action of phenobarbital (20 mg/kg), ethosuximide (100 mg/kg) and scopolamine (0.6 mg/kg) when used as pretreatment. Rats in the other subgroups were kindled by repeated intraperitoneal injections of an initially subconvulsive dose of PTZ (37.5 mg/kg) at 48-h intervals for 4 weeks. Kindled rats were then subjected to radial arm maze, sweet taste preference and forced swim test. Neonatal exposure to CPF shortened the latency time to the first seizure after pretreatment with scopolamine in female rats and decreased the threshold for PTZ-induced clonic convulsions after phenobarbital pretreatment in male rats. Neonatal CPF exposure also decreased the rate of kindling progression in female rats during early stages of PTZ kindling. On the other hand, CPF exposure sex-selectively reduced the number of working memory errors after kindling only in male rats. Drug challenge with MK-801 induced more impairment in the working memory of female kindled rats, indicating more dependence of working memory on NMDA receptor activity in these animals. Female kindled rats from CPF exposed group also showed longer time of immobility in forced swim test, showing an increase in the depressive-like behavior. This difference was also observed in the second session of forced swim test, after treating with fluoxetine, a selective inhibitor of serotonin reuptake. The recent finding, together with lack of difference in the sweet taste preference, suggests that mechanism beyond the reduction of serotonergic activity underlie the increased depressive-like behavior in this animals. To our knowledge, this is the first report describing the potential contribution of developmental exposure to an OP in susceptibility to antiepileptic drug resistance and alteration of seizure-induced behavioral deficits.

Sex differences in diurnal cortisol, testosterone and DHEA functioning in incarcerated adolescents

This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg−1) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg−1) failed to change the threshold. AND at a subthreshold dose of 40 mg kg−1 significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED50) values ± SEM from 8.59 ± 0.76 to 6.05 ± 0.81 mg kg−1 (p = 0.0308) for carbamazepine, from 419.9 ± 120.6 to 111.5 ± 41.1 mg kg−1 (p = 0.0405) for gabapentin, and from 20.86 ± 1.64 to 10.0 ± 1.21 mg kg−1 (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg−1) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg−1 failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens.

Associations between biological variables involved in estrogen signaling in pre- and post- menopausal women – Findings from the women 40+ healthy aging study

This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg−1) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg−1) failed to change the threshold. AND at a subthreshold dose of 40 mg kg−1 significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED50) values ± SEM from 8.59 ± 0.76 to 6.05 ± 0.81 mg kg−1 (p = 0.0308) for carbamazepine, from 419.9 ± 120.6 to 111.5 ± 41.1 mg kg−1 (p = 0.0405) for gabapentin, and from 20.86 ± 1.64 to 10.0 ± 1.21 mg kg−1 (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg−1) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg−1 failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens.

Effects of androsterone on the protective action of various antiepileptic drugs against maximal electroshock-induced seizures in mice

This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg−1) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg−1) failed to change the threshold. AND at a subthreshold dose of 40 mg kg−1 significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED50) values ± SEM from 8.59 ± 0.76 to 6.05 ± 0.81 mg kg−1 (p = 0.0308) for carbamazepine, from 419.9 ± 120.6 to 111.5 ± 41.1 mg kg−1 (p = 0.0405) for gabapentin, and from 20.86 ± 1.64 to 10.0 ± 1.21 mg kg−1 (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg−1) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg−1 failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens.