Experimental Models Of Epilepsy Research Articles

Vortioxetine increases absence-like seizures in WAG/Rij rats but decreases penicillin- and pentylenetetrazole-induced seizures in Wistar rats

AimDepression is the major psychiatric disorder in patients with epilepsy. Vortioxetine is a novel antidepressant drug for the treatment of major depressive disorders. In the present study, effects of vortioxetine were evaluated in different experimental epilepsy models of rats. Materials and methodsFifty-six adult male Wistar rats and 28 WAG/Rij rats were divided into 12 groups of 7 rats each. Experiments were conducted with penicillin (500 IU, i.c.) and pentylenetetrazole models (50 mg/kg, intraperitoneally (i.p.)) in Wistar rats and genetic absence epileptic WAG/Rij rats. The vortioxetine (1, 5, or 10 mg/kg, i.p.) was evaluated in these three models. All groups were compared with their control groups. ResultsIn the penicillin-induced seizure model, 1, 5, or 10 mg/kg vortioxetine administration significantly decreased mean spike frequency. In the pentylenetetrazole-induced seizure model, 1, 5, or 10 mg/kg vortioxetine demonstrated a significant dose-dependent decrease in mean spike frequency, an increase in the latency to minor and major seizures, and a decrease in total duration of major seizure and convulsion stage. In genetic absence epileptic WAG/Rij rats, 1 mg/kg vortioxetine caused no significant alteration in the number and duration of SWDs compared to the controls, while 5 and 10 mg/kg doses of vortioxetine increased the number and duration of SWDs. Amplitude of the epileptiform activity did not change in any of the experimental epilepsy models. ConclusionThe results of this study suggested that vortioxetine has anticonvulsant activity in penicillin- and pentylenetetrazole-induced seizure models. However, it exhibited proconvulsant activity in the absence epileptic WAG/Rij rats.

Дисфункція гематоенцефалічного бар’єру та розвиток епілептичних нападів (за матеріалами наукового повідомлення на засіданні Президії НАН України 23 грудня 2020 р.)

Blood-brain barrier dysfunction (BBB) is an important factor to the development of epilepsy and its behavioral comorbidities. Disruption of its integrity is accompanied by the ingress of blood components, including thrombin, into the cerebrospinal fluid. The effect of thrombin is mediated mainly through its major receptor, protease-activated receptors 1 (PAR1). Using lithium-pilocarpine model of seizures, we show that downregulation of PAR1 activity reduces anxiety and aggressive behavior in epileptic rats and restores distinct forms of hippocampal synaptic plasticity in experimental model of temporal-lobe epilepsy. Taken together, our data suggest that PAR1-signaling promotes the development of acquired epilepsy. PAR1 may be a new potential target for the treatment of this disorder and associated behavioral pathologies.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats

Ethnopharmacological relevanceCentella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. Aim of the studyThe present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. Materials and methodsWistar rats (175–200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. ResultsThe VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. ConclusionThe results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.

Selected flavonoids and their role in the treatment of epilepsy – a review of the latest reports from experimental studies

Epilepsy is a chronic neurological disease characterized by recurrent seizures that affects about 70 million people worldwide. Antiepileptic drugs are the most commonly used medications in the treatment of epilepsy. They help control seizures in about 60‑70% of people. The remaining percentage of patients suffer from drug‑resistant epilepsy, prompting scientists to look for natural substances that would prevent seizures or support the effects of drugs in add‑on therapy while reducing side effects. Currently, there is a lot of emphasis on natural product. Flavonoids are included in this group, and their use in the treatment of epilepsy could support the effect of other drugs. Due to very good results of preclinical studies, flavonoids are a promising candidate for epilepsy related clinical trials related. The article is an overview of literature reports from the past 10 years including mainly in vivo preclinical research on various models of experimental epilepsy with the use of selected flavonoids.

Effect of thiamazole on kainic acid-induced seizures in mice.

Kainic acid (KA) induced epileptic seizures in mice is a commonly used experimental model of epilepsy. Previous studies have suggested the roles of various neurotransmitters and oxidative stress in KA-induced seizures. An important role of hypothyroidism has also been suggested in epilepsy. Thiamazole (TZ) is an anti-hyperthyroid drug with antioxidant property. This study reports the effect of TZ on KA-induced epileptic seizures in mice, produced by intraperitoneal (IP) injection of KA (18 mg/kg). Prior to KA injection, the animals were treated with TZ (12.5, 25 and 50 mg/kg IP). Our results showed that in KA alone group, about half of the animals developed seizures. Pre-treatment of mice with TZ significantly increased the frequency of seizures in dose-dependent manner. Administration of TZ significantly reduced the latency time and aggravated the severity of seizures. TZ also increased the mortality in KA-treated mice. Striatal dopamine and serotonin levels were markedly increased in KA alone treated mice, which were not significantly affected by TZ treatment. Among the indices of oxidative stress, we observed a significant reduction in cerebral vitamin E whereas the levels of cerebral malondialdehyde and conjugated dienes were significantly increased in animals with high severity of seizures. In conclusion, TZ potentiated the frequency and severity of experimental seizure in mice. There is a possibility of altered metabolism of KA in presence of TZ that might have potentiated the toxicity of KA. These findings suggest a caution while administering anti-hyperthyroid drugs in epileptic seizures.

Not Part of the Temporal Lobe, but Still of Importance? Substantia Nigra and Subthalamic Nucleus in Epilepsy.

The most researched brain region in epilepsy research is the temporal lobe, and more specifically, the hippocampus. However, numerous other brain regions play a pivotal role in seizure circuitry and secondary generalization of epileptic activity: The substantia nigra pars reticulata (SNr) and its direct input structure, the subthalamic nucleus (STN), are considered seizure gating nuclei. There is ample evidence that direct inhibition of the SNr is capable of suppressing various seizure types in experimental models. Similarly, inhibition via its monosynaptic glutamatergic input, the STN, can decrease seizure susceptibility as well. This review will focus on therapeutic interventions such as electrical stimulation and targeted drug delivery to SNr and STN in human patients and experimental animal models of epilepsy, highlighting the opportunities for overcoming pharmacoresistance in epilepsy by investigating these promising target structures.

Extraction, GC-MS Evaluation and Anti-epileptic Potential of Seeds Ethanolic Extract of Putranjiva roxburghii Wall.

Putranjiva roxburghii Wall is traditionally known to cure many pathological conditions including epilepsy. The present study is aimed at determining bioactive compounds in ethanolic extract of Putranjiva roxburghii test extract (PRTE) seeds by GCMS analysis and to assess its antiepileptic potential using various experimental models of epilepsy. The ethanolic extract of seeds of Putranjiva roxburghii was subjected to GC-MS analysis to detect the bioactive phytoconstituents. Acute oral toxicity of the extract was performed using OCED guideline 420. Pentylenetetrazol (PTZ) kindling model of epilepsy and Maximal electroshock epilepsy (MES) model of epilepsy were used to determine anti-epileptic potential. The GC-MS analysis of the extract revealed the presence of 20 phytoconstituents. The major phytoconstituents included n-Propyl heptyl ether (25.25%), 5-Ethyl hydantoin (8%), octadec- 9-enoic acid (16.25%) and 1, 2-Benzene dicarboxylic acid (11.86%). The PRTE (50 mg/kg and 100 mg/kg) afforded a significant and dose-dependent protection against PTZ-induced kindling epilepsy and MES induced epilepsy (p<0.001 and p<0.01). Based on the above findings, it is evident that Putranjiva roxburghii seeds contain biologically active compounds. It can also be concluded that the extract possesses anti-epileptic potential.

Impact of predictive, preventive and precision medicine strategies in epilepsy.

Over the last decade, advances in genetics, neuroimaging and EEG have enabled the aetiology of epilepsy to be identified earlier in the disease course than ever before. At the same time, progress in the study of experimental models of epilepsy has provided a better understanding of the mechanisms underlying the condition and has enabled the identification of therapies that target specific aetiologies. We are now witnessing the impact of these advances in our daily clinical practice. Thus, now is the time for a paradigm shift in epilepsy treatment from a reactive attitude, treating patients after the onset of epilepsy and the initiation of seizures, to a proactive attitude that is more broadly integrated into a 'P4 medicine' approach. This P4 approach, which is personalized, predictive, preventive and participatory, puts patients at the centre of their own care and, ultimately, aims to prevent the onset of epilepsy. This aim will be achieved by adapting epilepsy treatments not only to a given syndrome but also to a given patient and moving from the usual anti-seizure treatments to personalized treatments designed to target specific aetiologies. In this Review, we present the current state of this ongoing revolution, emphasizing the impact on clinical practice.

Functional Genomics of Epileptogenesis in Animal Models and Humans.

It has been estimated that epilepsies are among the top five neurological diseases with the highest burden of disease. In recent years, genome-wide expression studies (GWES) have been carried out in experimental models of epilepsy and in samples from human patients. In this study, I carried out meta-analyses and analyses of convergence for available GWES for epileptogenesis in humans and in mouse, rat, zebrafish and fruit fly models. Multiple lines of evidence (such as genome-wide association data and known druggable genes) were integrated to prioritize top candidate genes for epileptogenesis and a functional enrichment analysis was carried out. Several top candidate genes, which are supported by multiple lines of genomic evidence, such as GRIN1, KCNAB1 and STX1B, were identified. Druggable genes of potential interest (such as GABRA2, GRIK1, KCNAB1 and STX4) were also identified. An enrichment of genes regulated by the MEF2 and SOX5 transcription factors and the miR-106b-5p and miR-101-3p miRNAs was found. The current work is the first meta-analysis and convergent analysis of GWES for epileptogenesis in humans and in multiple animal models, integrating results from several genomic studies. Novel candidate genes and pathways for epileptogenesis were identified in this analysis.

Alterations of the Hippocampal Neurogenic Niche in a Mouse Model of Dravet Syndrome.

Hippocampal neurogenesis, the process by which neural stem cells (NSCs) continuously generate new neurons in the dentate gyrus (DG) of most mammals including humans, is chiefly regulated by neuronal activity. Thus, severe alterations have been found in samples from epilepsy patients and in the hippocampal neurogenic niche in mouse models of epilepsy. Reactive-like and gliogenic NSCs plus aberrant newborn neurons with altered migration, morphology, and functional properties are induced by seizures in experimental models of temporal lobe epilepsy. Hippocampal neurogenesis participates in memory and learning and in the control of anxiety and stress. It has been therefore hypothesized that part of the cognitive symptoms associated with epilepsy could be promoted by impaired hippocampal neurogenesis. We here analyze for the first time the alterations of the neurogenic niche in a novel mouse model of Dravet syndrome (DS), a genetic encephalopathy with severe epilepsy in infancy and multiple neurological comorbidities. Scn1aWT/A1783V mice, hereafter referred to as DS, carrying a heterozygous and clinically relevant SCN1A mutation (A1783V) recapitulate the disease at the genetic and phenotypic levels. We demonstrate that in the neurogenic niche of young adult DS mice there are fewer NSCs, they have impaired cell division and bear reactive-like morphology. In addition, there is significant aberrant neurogenesis. Newborn immature neurons migrate abnormally, and several morphological features are drastically changed. Thus, this study shows for the first time important modifications in hippocampal neurogenesis in DS and opens venues for further research on this topic.

Alpha-pinene and dizocilpine (MK-801) attenuate kindling development and astrocytosis in an experimental mouse model of epilepsy

Understanding the molecular and cellular mechanisms involved during the onset of epilepsy is crucial for elucidating the overall mechanism of epileptogenesis and therapeutic strategies. Previous studies, using a pentylenetetrazole (PTZ)-induced kindling mouse model, showed that astrocyte activation and an increase in perineuronal nets (PNNs) and extracellular matrix (ECM) molecules occurred within the hippocampus. However, the mechanisms of initiation and suppression of these changes, remain unclear.Herein, we analyzed the attenuation of astrocyte activation caused by dizocilpine (MK-801) administration, as well as the anticonvulsant effect of α-pinene on seizures and production of ECM molecules. Our results showed that MK-801 significantly reduced kindling acquisition, while α-pinene treatment prevented an increase in seizures incidences. Both MK-801 and α-pinene administration attenuated astrocyte activation by PTZ and significantly attenuated the increase in ECM molecules.Our results indicate that astrocyte activation and an increase in ECM may contribute to epileptogenesis and suggest that MK-801 and α-pinene may prevent epileptic seizures by suppressing astrocyte activation and ECM molecule production.

Genome-wide microRNA profiling in brain and blood samples in a mouse model of epileptogenesis

ObjectivesThis study profiled circulating and hippocampal microRNAs (miRNAs) to identify alterations associated with the risk of epileptogenesis in a mouse temporal lobe epilepsy model. MethodsNext-generation sequencing was performed to examine the changes in miRNA expression 24 h after pilocarpine-induced status epilepticus (SE) in C57BL/6NCrl mice using both blood and hippocampus samples. Differentially expressed miRNAs were identified from SE animals and matched controls that failed to develop SE after receiving equal doses of pilocarpine (NS animals). Blood and brain miRNA profiles were then compared to identify circulating miRNA alterations reflecting the changes in the brain. ResultsWe identified 3 miRNAs that were significantly up-regulated and 4 miRNAs that were significantly down-regulated in the blood of SE animals compared with NS animals. When hippocampal miRNAs of SE animals and NS animals were compared, 5 miRNAs were up-regulated and 4 were down-regulated. Of these, miR-434-3p and miR-133a-3p were observed to have greatest changes in both blood and brain of SE animals. SignificanceThis study extends current knowledge of changes in miRNAs associated with epileptogenesis by profiling miRNAs in SE and NS animals in an experimental temporal lobe epilepsy model. The study was designed to allow non-specific changes due to the activation of muscarinic cholinergic receptors in peripheral organs by pilocarpine to be ruled out. Significantly altered circulating miRNAs that reflect changes in the brain during epileptogenesis after SE have the potential to be developed as prognostic biomarkers for epileptogenesis.

The effect of agonist and antagonist of Nociceptine/Orphanin FQ receptor on seizure and cognitive dysfunction in experimental model of temporal lobe epilepsy in male rat

The effect of agonist and antagonist of Nociceptine/Orphanin FQ receptor on seizure and cognitive dysfunction in experimental model of temporal lobe epilepsy in male rat

Pilocarpine-induced status epilepticus reduces chemosensory control of breathing

One of the possible causes of death in epilepsy is breathing disorders, especially apneas, which lead to an increase in CO2 levels (hypercapnia) and/or a decrease in O2 levels in arterial blood (hypoxemia). The respiratory neurons located in the ventral brainstem respiratory column are the main groups responsible for controlling breathing. Recent data from our group demonstrated respiratory changes in two experimental models of epilepsy, i.e. audiogenic epilepsy, and amygdala rapid kindling. Here, we aimed to evaluate respiratory changes in the classic model of temporal lobe epilepsy induced by intra-hippocampal injection of pilocarpine. Adult Wistar rats with stainless-steel cannulas implanted in the hippocampus region were used. The animals were submitted to pilocarpine injection (2.4 mg/μL, N = 12–15) or saline (N = 9) into the hippocampus. The respiratory parameters analyzed by whole-body plethysmography were respiratory rate (fR), tidal volume (VT) and ventilation (VE). Respiratory mechanics such as Newtonian airway resistance (Rn), viscance of the pulmonary parenchyma (G) and the elastance of the pulmonary parenchyma (H) were also investigated. No changes in baseline breathing were detected 15 or 30 days after pilocarpine-induced status epilepticus (SE). However, 30 days after pilocarpine-induced SE, a significant reduction in VE was observed during hypercapnic (7% CO2) stimulation, without affecting the hypoxia (8% O2) ventilatory response. We also did not observe changes in respiratory mechanics. The present results suggest that the impairment of the hypercapnia ventilatory response in pilocarpine-induced SE could be related to a presumable degeneration of brainstem respiratory neurons but not to peripheral mechanisms.

The Influence of Palmatine Isolated from Berberis sibiricaRadix on Pentylenetetrazole-Induced Seizures in Zebrafish.

Palmatine (PALM) and berberine (BERB) are widely identified isoquinoline alkaloids among the representatives of the Berberidaceae botanical family. The antiseizure activity of BERB was shown previously in experimental epilepsy models. We assessed the effect of PALM in a pentylenetetrazole (PTZ)-induced seizure assay in zebrafish, with BERB as an active reference compound. Both alkaloids were isolated from the methanolic root extract of Berberis sibirica by counter-current chromatography, and their ability to cross the blood–brain barrier was determined via quantitative structure–activity relationship assay. PALM exerted antiseizure activity, as confirmed by electroencephalographic analysis, and decreased c-fos and bdnf levels in PTZ-treated larvae. In a behavioral assay, PALM dose-dependently decreased PTZ-induced hyperlocomotion. The combination of PALM and BERB in ED16 doses revealed hyperadditive activity towards PTZ-induced hyperlocomotion. Notably, we have indicated that both alkaloids may exert their anticonvulsant activity through different mechanisms of action. Additionally, the combination of both alkaloids in a 1:2.17 ratio (PALM: BERB) mimicked the activity of the pure extract, which indicates that these two active compounds are responsible for its anticonvulsive activity. In conclusion, our study reveals for the first time the anticonvulsant activity of PALM and suggests the combination of PALM and BERB may have higher therapeutic value than separate usage of these compounds.

The intrinsic cell type-specific excitatory connectivity of the developing mouse subiculum is sufficient to generate synchronous epileptiform activity.

The activity of local excitatory circuits of the subiculum has been suggested to be involved in the initiation of pathological activity in epileptic patients and experimental animal models of temporal lobe epilepsy. We have taken advantage of multimodal techniques to classify subicular cells in distinct subclasses and have investigated their morphofunctional properties and connectivity in vitro. Our results indicate that local subicular excitatory circuits are connected in a cell type-specific fashion and that synapses are preferentially established on basal vs. apical dendrites. We show that local excitatory circuits, isolated from extrasubicular inputs and pharmacologically disinhibited, are sufficient to initiate synchronous epileptiform activity in vitro. In conclusion, this work provides a high-resolution description of local excitatory circuits of the subiculum and highlights their mechanistic involvement in the generation of pathological activity. The subiculum has been suggested to be involved in the initiation of pathological discharges in human patients and animal models of temporal lobe epilepsy. Although converging evidence has revealed the existence of functional diversity within its principal neurons, much less attention has been devoted to its intrinsic connectivity and whether its local excitatory circuits are sufficient to generate epileptiform activity. Here, we have directly addressed these two key points in mouse subicular slices. First, using multivariate techniques, we have distinguished two groups of principal cells, which we have termed type1 and type2. These subgroups roughly overlap with what were classically indicated as regular and bursting cells, and showed differences in the extension and complexity of their apical dendrites. Functional connectivity was found both between similar (homotypic) and different (heterotypic) types of cells, with a marked asymmetry within heterotypic pairs. Unitary excitatory postsynaptic potentials (uEPSPs) revealed a high degree of variability both in amplitude, failure rate, rise time and half-width. Post hoc analysis of functionally connected pairs suggested that the observed uEPSPs were mediated by few contact sites, predominantly located on the basal dendrites. When surgically isolated from extrasubicular excitatory afferents, pharmacologically disinhibited subicular slices generated hyper-synchronous discharges. Thus, we conclude that local subicular excitatory circuits, connected according to cell type-specific rules, are sufficient to promote epileptiform activity. This conclusion fits well with a previous suggestion that local subicular events, purely mediated by excitatory connections, may underlie the pre-ictal discharges that govern interictal-ictal transitions.

Seizure-induced neuroinflammation contributes to ectopic neurogenesis and aggressive behavior in pilocarpine-induced status epilepticus mice

Epilepsy is a chronic neurological disorder often associated with recurrent seizures. A growing body of evidence suggests that seizures cause structural and functional alterations of the brain. It is reported that behavioral abnormalities frequently occur in patients with epilepsy and experimental epilepsy models. However, the precise pathological mechanisms associated with these epilepsy comorbidities remain largely unknown. Neurogenesis persists throughout life in the hippocampal dentate gyrus (DG) to maintain proper brain function. However, aberrant neurogenesis usually generates abnormal neural circuits and consequently causes neuronal dysfunction. Neuroinflammatory responses are well known to affect neurogenesis and lead to aberrant reorganization of neural networks in the hippocampal DG. Here, in this study, we observed a significant increase in neuroinflammation and in the proliferation and survival of newborn granular cells in the hippocampus of pilocarpine-induced status epilepticus (SE) mice. More importantly, these proliferating and surviving newborn granular cells are largely ectopically located in the hippocampal DG hilus region. Our behavior test demonstrated that SE mice displayed severe aggressive behavior. Pharmacological inhibition of neuroinflammation, however, suppressed the ectopic neurogenesis and countered the enhanced aggressive behavior in SE mice, indicating that seizure-induced neuroinflammation may contribute to ectopic neurogenesis and aggressive behavior in SE mice. These findings establish a key role for neuroinflammation in seizure-induced aberrant neurogenesis and aggressive behavior. Suppressing neuroinflammation in the epileptic brain may reduce ectopic neurogenesis and effectively block the pathophysiological process that leads to aggressive behavior in TLE mice.

Complement in the Development of Post-Traumatic Epilepsy: Prospects for Drug Repurposing.

Targeting neuroinflammation is a novel frontier in the prevention and treatment of epilepsy. A substantial body of evidence supports a key role for neuroinflammation in epileptogenesis, the pathological process that leads to the development and progression of spontaneous recurrent epileptic seizures. It is also well recognized that traumatic brain injury (TBI) induces a vigorous neuroinflammatory response and that a significant proportion of patients with TBI suffer from debilitating post-traumatic epilepsy. The complement system is a potent effector of innate immunity and a significant contributor to secondary tissue damage and to epileptogenesis following central nervous system injury. Several therapeutic agents targeting the complement system are already on the market to treat other central nervous system disorders or are well advanced in their development. The purpose of this review is to summarize findings on complement activation in experimental TBI and epilepsy models, highlighting the potential of drug repurposing in the development of therapeutics to ameliorate post-traumatic epileptogenesis.

Study on the antiepyleptic activity of the new amide derivative of valproic acid and 1,3,4-thiadiazole

Aim – experimental evaluation of the antiepileptic activity of a new amide derivative of valproic acid and 1,3,4-thiadiazole. Materials and Methods : The antiepileptic activity of valprazolamide (N- (5-ethyl-1,3,4-thiadiazol-2-yl) -2-propylpentanamide) was tested in mice using the model of maximal electroshock and also the antagonism model with pentylenetetrazole. Neurotoxicity was assessed with the rotating rod test and the probit analysis. The therapeutic and protective index and the ED50 values were calculated for each experimental model of epilepsy. Results : The ED50 values of valprazolamide (intraperitoneally) in mice with seizures induced by pentylenetetrazole or maximal electroshock were 74.5 (46.8-106.4) mg/kg or 138.4 (97.2-197.2) mg/kg, respectively. Conclusion : The new amide derivative of valproic acid and 1,3,4-thiadiazole (valprazolamide) has an antiepileptic activity. The author declares no financial support or conflict of interest with respect to this publication.

Effect of tadalafil and nitric oxide agonist sodium nitroprusside on penicillin-induced epileptiform activity

ABSTRACTObjective: Comorbidity of erectile dysfunction (ED) and epilepsy is not rare. Tadalafil is widely used in the treatment of ED and shows its effect by increasing nitric oxide (NO) level. Previous studies demonstrated that ED treatment drugs increased epileptiform activity in clinical studies and various experimental epilepsy models. Therefore, it is important to know whether an ED treatment drug has proconvulsion or anticonvulsant properties. This study was designed to demonstrate the effect of tadalafil and NO agonist sodium nitroprusside during penicillin-induced seizures in rats. The experimental penicillin epilepsy model is preferred in clinical studies of partial epilepsy.Methods: A single dose of penicillin (500 units) intracortical (i.c.) injection into the left sensorimotor cortex induced epileptiform activity. In the first set of experiments, tadalafil (20 mg/kg/intraperitoneal [i.p.]) and sodium nitroprusside (50 µg/intracerebroventricular [μg/i.c.v]) were administered 30 min after penicillin injection.In the second set of experiments, tadalafil (i.p) was administered 30 min after penicillin injection and sodium nitroprusside was administered simultaneously with the tadalafil injection.Results: Tadalafil, sodium nitroprusside and tadalafil+sodium nitroprusside groups decreased the frequency and amplitude of epileptiform activity in rats. Spike frequency of all groups decreased significantly 10 min after the administration and this decrease continued for 180 min. The mean amplitude of epileptiform activity significantly decreased 120 min after penicillin application in tadalafil or sodium nitroprusside applications. But this decrease was observed 110 min after tadalafil+sodium nitroprusside combined application.Conclusion: Data from the present study indicate that tadalafil has an anticonvulsion effect against penicillin-induced epileptiform activity in rats.