Pentylenetetrazole Injection Research Articles

Effects of atorvastatin and metformin on development of pentylenetetrazole-induced seizure in mice

Recent studies have shown that statins and Metformin may have beneficial effects on seizure through different mechanisms. In the current study, we investigated whether Metformin, Atorvastatin, and concomitant uses of them have beneficial effects on pentylenetetrazole (PTZ)-induced kindling. Adult male C57BL/6 mice were randomly divided into four experimental groups with seven mice in each group. Group 1, control group; group 2, received Metformin (200 mg/kg, i.p); group 3, received Atorvastatin (10 mg/kg, i.p.); group 4, received Atorvastatin (10 mg/kg, i.p.) plus Metformin (200 mg/kg, i.p.). Twenty minutes after injection of the mentioned drugs, the experimented mice received 37/5 mg/kg of PTZ intraperitoneally on alternating days. Then the convulsive behavior signs were evaluated for 20 min after each PTZ injection. There were significant differences in the stage 2 latency parameter among group 2 (p = 0.033, F = 8.46)/group 3 (p = 0.032, F = 10.42)/group 4 (p = 0.008, F = 24.57) as compared to the control group, while no significant differences were found comparing only group 2,3, and 4 with eachother excluding the control group. Pretreatment with Atorvastatin (p = 0.002, F = 33), Atorvastatin + Metformin (p = 0.006, F = 20.77), and Metformin alone increased stage 5 latency as compared to the PTZ group, significantly. Also, our results have shown that pretreatment with Atorvastatin (p = 0.013, F = 14.48), Metformin (p = 0.015, F = 16.67), and concomitant usage of them significantly decreased stage 5 duration as compared to the control group. Our findings clearly demonstrate that concomitant use of Metformin and Atorvastatin has no more protective effect against the development of kindling as compare to these drugs alone. Thus, we concluded that, these drugs may inhibit kindling via a similar mechanism and we suggested that it is probably through regulation of autophagy.

Experimental Preeclampsia Causes Persistent Impairment of Hippocampal‐Dependent Memory and Network Function that is Exacerbated by Status Convulsions

Preeclampsia (PE) is a hypertensive disorder of pregnancy involving hyperlipidemia and widespread maternal endothelial dysfunction that can cause spontaneous seizures including status convulsions known as eclampsia. Further, PE increases the risk of cardiovascular disease and cognitive impairment later in life. This study investigated long‐lasting effects of PE without and with status convulsions on the hippocampus, a brain region involved in memory and cognition. Sprague Dawley rats that were either normal pregnant or with experimental PE (ePE) induced by a high cholesterol diet starting d7 of gestation were used. Acute status convulsions were induced on day 19 of a 22‐day gestation via multiple i.p. injections of the chemoconvulsant pentylenetetrazol or saline (no‐seizure controls). Five weeks after status convulsions, an object recognition task was used to quantify the percent of time spent investigating a novel object as a measure of long‐term memory function (n = 8/group). After which, hippocampal network function was assessed by evoking long‐term potentiation (LTP), a well‐accepted cellular model for learning and memory, in the Schaffer Collateral to CA1 (Sch‐CA1) pathway of hippocampal slices. Synaptically evoked field excitatory post‐synaptic potentials (fEPSPs) were collected from the Sch–CA1 area of the hippocampus at a rate of 0.05 Hz. A 20 min stable baseline period was established before delivering a 40 pulse theta burst stimulation (TBS). Increase in fEPSP slope 60 min after TBS was analyzed as a measure of synaptic LTP. Data are mean ± SEM and comparisons made via a two‐way ANOVA to determine the interaction between two independent variables (ePE and status convulsions) with a post‐hoc Tukey test.There were significant interactions between the effects of ePE and status convulsions on memory function (F (1, 18) = 9.469; p = 0.007) as well as LTP (F (1, 19) = 9.991; p = 0.005). Object recognition was reduced in rats that had ePE compared to those that had a normal pregnancy, as formerly ePE rats spent 55 ± 3 % of the time investigating the novel object, much less than the 73 ± 3 % in rats that had a healthy pregnancy (Fig 1). Status convulsions impaired memory in rats that had a normal pregnancy, but not in the ePE group likely due to memory already being impaired (Fig 1). Further, LTP was impaired in rats that had ePE, with the slope of fEPSPs increasing to only 132 ± 7 % of baseline in slices from ePE rats compared to 157 ± 4 % in rats that had a healthy pregnancy (Fig 2). Status convulsions impaired LTP in rats that had ePE and those that had a normal pregnancy, with the slope of fEPSPs increasing to only 114 ± 5 % of baseline in formerly ePE rats and 106 ± 5 % in rats that had seizures during normal pregnancy (Fig 2).Overall, these findings suggest that PE and eclampsia cause permanent memory dysfunction by impairing LTP in the hippocampus, and highlight the importance of seizure prevention to maternal cognitive health. Further, understanding mechanisms of impaired hippocampal plasticity after PE and/or eclampsia may lead to novel therapeutic approaches to minimize the cognitive burden associated with PE and eclampsia later in life.Support or Funding InformationNIH NINDS R01 NS045940NIH NINDS R01 NS108455Long‐term memory as measured via a novel object recognition task. **p<0.01.Figure 1LTP of hippocampal slices. *p<0.05 and **p<0.01.Figure 2

The Reduction of Seizure Intensity and Attenuation of Memory Deficiency and Anxiety-Like Behavior through Aerobic Exercise by Increasing the BDNF in Mice with Chronic Epilepsy

Epilepsy is a disease characterized by recurrent and unprovoked seizures. Cognitive deficiency and anxiety are important comorbidities of the chronic epilepsy. Studies on epilepsy using human and animal models have shown that aerobic exercise (AX) induces beneficial structural and functional changes and reduce the intensity of seizures. The present study seeks to evaluate effects of an AX program on the intensity of seizures, cognitive function and anxiety-like behavior and expression of serum brain-derived neurotrophic factor (BDNF) level in mice with epilepsy. The intensity of seizures was recorded 30 min following pentylenetetrazol (PTZ) injection, and cognitive function and anxiety-like behavior were assessed through novel object recognition task (NORT) and light–dark box test, respectively. Using ELISA, the effects of AX program on the serum BDNF level of epileptic mice was further determined. Mice with epilepsy subjected to AX showed a reduction in the intensity of seizures compared to non-exercised epileptic mice. Memory deficits and increased anxiety-like behavior were attenuated by AX which also restored the Serum BDNF level, reduced in epileptic mice, to control levels. In conclusion, AX reduces seizure intensity and mitigates memory deficits and increased anxiety-like behavior in mice with epilepsy. These AX induced beneficial effects can be ascribed to the changes in BDNF level. Finally, AX might be as a complementary therapeutic strategy for treating epilepsy.

Synthesis, in Vivo and in Silico Studies of N-Aryl-4-(1,3-Dioxoisoindolin-2-Yl)Benzamides as an Anticonvulsant Agent

Background: These days epilepsy is a common neurological disorder, which can affect on quality of life by unpredictable seizure. Thalidomide is one of the drugs to control the epilepsy but side effects such as teratogenicity, made it difficult to use. Methods: Six new analogues of N-aryl-4-(1,3-dioxoisoindolin-2-yl)benzamides were synthesized and tested for anti-seizure activity. To evaluate the anti-seizure activity of these new derivatives, 40 mice in 8 groups were received 10 mg/Kg of each new derivatives 30 min before the injection of pentylenetetrazole (PTZ, 70 mg/kg) to induced seizures. Latency time to first symptom of seizure was measured and compared to vehicle and standard groups. Docking methodology was applied to study on mode of interaction between GABAA receptor and synthetized compounds. Results: Structures of the all synthesized compounds were confirmed by NMR and mass spectroscopy. The latency time and mortality rate were individually measured for an hour after injection of pentylenetetrazole. Docking study revealed that synthesized compounds and thalidomide interact in similar conformation with GABAA receptor. Conclusion: The experimental and docking results were found in good correlation and demonstrated that the most active compound (5a), with 3,4-dimethylphenyl residue increased the duration of seizure inhibition threshold in comparison with thalidomide.

Capsaicin Exerts Anti-convulsant and Neuroprotective Effects in Pentylenetetrazole-Induced Seizures.

The transient receptor potential vanilloid-1 (TRPV1) receptor has been implicated in the development of epileptic seizures. We examined the effect of the TRPV1 agonist capsaicin on epileptic seizures, neuronal injury and oxidative stress in a model of status epilepticus induced in the rat by intraperitoneal (i.p.) injections of pentylenetetrazole (PTZ). Capsaicin was i.p. given at 1 or 2 mg/kg, 30 min before the first PTZ injection. Other groups were i.p. treated with the vehicle or the anti-epileptic drug phenytoin (30 mg/kg) alone or co-administered with capsaicin at 2 mg/kg. Brain levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, and paraoxonase-1 (PON-1) activity, seizure scores, latency time and PTZ dose required to reach status epilepticus were determined. Histopathological assessment of neuronal damage was done. Results showed that brain MDA decreased by treatment with capsaicin, phenytoin or capsaicin/phenytoin. Nitric oxide decreased by capsaicin or capsaicin/phenytoin. GSH and PON-1 activity increased after capsaicin, phenytoin or capsaicin/phenytoin. Mean total seizure score decreased by 48.8% and 66.3% by capsaicin compared with 78.7% for phenytoin and 69.8% for capsaicin/phenytoin treatment. Only phenytoin increased the latency (115.7%) and threshold dose of PTZ (78.3%). Capsaicin did not decrease the anti-convulsive effect of phenytoin but prevented the phenytoin-induced increase in latency time and threshold dose. Neuronal damage decreased by phenytoin or capsaicin at 2 mg/kg but almost completely prevented by capsaicin/phenytoin. Thus in this model of status epilepticus, capsaicin decreased brain oxidative stress, the severity of seizures and neuronal injury and its co-administration with phenytoin afforded neuronal protection.

Proconvulsant effect of trans-cinnamaldehyde in pentylenetetrazole-induced kindling model of epilepsy: The role of TRPA1 channels

The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily, is widely distributed in the central nervous system (CNS) and plays an important role in pain and inflammation. However, no data has been reported regarding the effects of TRPA1 on epileptic seizures. Thus, this study was designed to investigate the sub-chronic effect of trans-cinnamaldehyde (TCA), an agonist of TRPA1, in pentylenetetrazole (PTZ) induced kindling model via electrocorticography (ECoG). Furthermore, the expressions of cAMP response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), and NMDA receptor subunit NR2B were measured using Western blotting. Rats were kindled by intraperitoneal (i.p.) PTZ (35 mg/kg) injections. After electrode implantation and healing period, 10 and 30 mg/kg TCA was given i.p. for 14 consecutive days. On the next day, ECoG recordings were obtained after the injection of PTZ (35 mg/kg, i.p.), and twenty-four hours later, rats were decapitated for molecular analyses. TCA, at a dose of 30 mg/kg, decreased the first myoclonic jerk latency and increased seizure duration and total spike activity. Additionally, both doses of TCA enhanced CREB, BDNF, and NR2B expressions, which were increased by the kindling. The evidence from this study suggests that long term activation of TRPA1 channels causes an exacerbated seizure activity. Moreover, PTZ-induced increases in CREB, BDNF, and NR2B levels were enhanced by the repeated administrations of TCA.

Effect of acute pentylenetetrazol injection induced epileptic seizures on rat dentate gyrus at different postnatal ages.

Epilepsy is one of the most common neurological disorders, its prevalence approximately from 0.5% to 2% of the general population. Generalized seizures could lead to several morphological changes in the brain. This study aimed to investigate the morphological effects of a single convulsive dose of pentylenetetrazol (PTZ) on rat dentate gyrus at different postnatal ages. Thirty-six male Wistar rats were used at the following postnatal ages: P10, P21, and P90 (12 rats per each age). The animals in each age were equally divided into two groups: group I, control and group II, treated with a single intraperitoneal injection of PTZ (55 mg/kg). After confirmation of generalized tonic-clonic seizures, specimens from the right dentate gyrus were processed for light and electron microscopy. In PTZ-treated groups, the number of granule cells significantly decreased. Dark granule cells appeared in the deep layers of the granule cells in P10 and with the progress of age, they significantly increased in number and extended into the superficial layers of the granule cells. The dendritic spines diminished. Glial fibrillary acidic protein and caspase-3 expression increased. Ultrastructurally, granule cells showed irregular shaped nucleus, dilated rough endoplasmic reticulum (RER) cisternae, mitochondria with damaged cristae, large vacuoles, lysosomes, and lipofuscin granules. Dark granule cells characterized by electron-dense nucleus and cytoplasm containing disorganized Golgi bodies, swollen mitochondria with damaged cristae, numerous free ribosomes and few long strands of RER. Astrocytes had hypertrophied cell body. Acute treatment with PTZ-induced epileptic seizures caused toxic effect on the structure of rat dentate gyrus at different postnatal ages.

Effects of aqueous extract of Hyssopus officinalis on seizures induced by pentylenetetrazole and hippocampus mRNA level of iNOS in rats.

We examined the effectiveness of Hyssopus officinalis (hyssop) aqueous extract on pentylenetetrazole (PTZ)-induced acute seizures and the hippocampus iNOS (inducible nitric oxide synthases) gene expression as a potential mediator of the effects. Adult male Wistar rats were used. Tonic-clonic seizures were induced by intraperitoneal (i.p.) injection of PTZ (80 mg/kg) then behavioral profile during 30 min was characterized by stages defined as seizure scores. Hyssop extract were prepared and injected (i.p.) 15 minutes before the seizure induction at three doses 50, 100 and 200 mg/kg. Experimental groups were as below: (1) saline+PTZ (n=5); (2) Hyssop 50mg/kg+PTZ (n=10); (3) Hyssop 100mg/kg+PTZ (n=10); (4) Hyssop 200 mg/kg+PTZ (n=8). Two hours after the experimental procedure, all animals were decapitated, brain was removed and right hippocampus was quickly dissected. After total RNA extraction and cDNA synthesis quantitative PCR were used for gene expression of iNOS. Our results showed significant increase (p<0.05) in latency to reach stages 5 and 6 of tonic-clonic seizure at dose 100 mg/kg hyssop extract. In addition, this dose caused significant increase in the gene expression of iNOS in the hippocampus. It seems a 100 mg/kg dose of hyssop extract might have anticonvulsant effects. However, these anticonvulsant effects might not occur through the iNOS gene expression.

Protective impact of Rosa damascena against neural damage in a rat model of pentylenetetrazole (PTZ)-induced seizure.

Based on the previously-declared anticonvulsant properties of Rosa damascena (R. damascena), this study explored the probable effects of R. damascena on neuronal apoptosis in the hippocampus of a rat model of pentylenetetrazole (PTZ)-induced seizure. 40 male Wistar rats were randomely divided into control (n=8) and experimental (n=32) groups which underwent PTZ injection. A one-week pre-medication with 50 (PTZ-Ext 50) (n=8), 100 (PTZ-Ext 100) (n=8), and 200 (PTZ-Ext 200) (n=8) mg/kg of hydro-alcoholic extract of R . Damascene was performed while one experimental group (PTZ-induced group) (n=8) received only saline during the week before PTZ injection. After provocation of PTZ-induced seizures, the brains underwent tissue processing and TUNEL staining assay for apoptotic cell quantification. Our findings revealed that PTZ-induced seizures led to apoptosis in neuronal cells of all sub-regions of the hippocampus; yet, only at CA1, CA3 and DG sub-regions of the PTZ-induced group, the difference in the number of apoptotic neuronal cells was significant in comparison with the control group. In addition, pre-medication with the plant extract led to a significant drop in the quantity of apoptotic neurons in these sub-regions in comparison with the PTZ-induced group which received no pre-medication . The results of this study showed that R. damascena extract exerts neuro-protective effects on PTZ-induced seizure.

The Effect of Low-Doses of Caffeine and Taurine on Convulsive Seizure Parameters in Rats.

Introduction: Caffeine, an adenosine-receptor blocker, is believed to have neuronal excitatory effects, while Taurine, a mammalian amino acid, was shown to have neuroinhibitory effects. Aim: The aim of this study was to investigate the effects of acute and chronic administration of low doses of Caffeine and Taurine on the seizure threshold in rats. Methods: Six-week-old Sprague-Dawley male rats (n = 280) were divided randomly into five groups (control, acute caffeine intake, acute taurine intake, chronic caffeine intake and chronic taurine intake), with five subgroups per group according to five different doses of Pentylenetetrazole (PTZ) injections. Each subgroup consisted of eight rats. Data was entered and analyzed using Microsoft EXCEL and AddinsoftTM XLSTAT (Version 2012.6.06; New York, NY, USA). p-value = 0.05 was regarded as statistically significant. Results: There was a significant decrease in the latency of PTZ-induced seizures with both acute (p-value < 0.05) and chronic (p-value < 0.01) Caffeine treatment groups. Chronic exposure to Caffeine exhibited an increase in the probability of seizures (p-value < 0.05). However, acute exposure to Caffeine did not show a significant impact on the probability of seizures. Neither acute nor chronic exposures to Taurine had an effect on the probability of seizures, nor on the latency of PTZ-induced seizures. Discussion: Our study found that acute as well as chronic exposure to low doses of Caffeine (50 and 80 mg/kg) reduces the threshold, and hence increases the likelihood for seizures since it favors a state of neuronal hyper excitability through blocking of all adenosine receptors. On the other hand, acute or chronic exposure to Taurine did not show a significant effect on the PTZ-induced seizures parameters.

Cyclosporin A ameliorates eclampsia seizure through reducing systemic inflammation in an eclampsia-like rat model.

Our previous studies have shown that the maternal hyperinflammatory response in pre-eclampsia lowered the eclampsia-like seizure threshold. Cyclosporin A (CsA), which is an effective immunosuppressant, could attenuate the inflammatory responses in LPS-induced pre-eclampsia rats. Here, we hypothesized that CsA may ameliorate seizure severity through reducing systemic inflammation in pre-eclampsia/eclampsia. In the current study, the effects of CsA on pre-eclampsia manifestation, eclampsia-like seizure activities and systemic inflammation were examined in a pre-eclampsia model. Pregnant rats were given an intraperitoneal injection of the epileptogenic drug pentylenetetrazol (PTZ) following a tail vein injection of lipopolysaccharide to establish the eclampsia-like seizure model. CsA (5 mg/kg) was administered intravenously through the tail after LPS infusion. Mean systolic blood pressure and proteinuria in pre-eclampsia were detected. After PTZ injection, seizure activity was assessed, inflammatory responses were determined and pregnancy outcomes were analyzed. The results showed that CsA treatment significantly decreased blood pressure and proteinuria and increased the fetal and placental weight (P < 0.01). Meanwhile, CsA treatment significantly reduced serum IL-1β, TNF-α, and IL-17 levels (P < 0.01), decreased the seizure scores and prolonged the latency to seizure (P < 0.01). CsA effectively attenuated pre-eclampsia manifestation and eclampsia-like seizure severity. In addition, CsA treatment significantly reduced the inflammatory cytokine levels and improved pregnancy outcomes following eclampsia-like seizures. The decreased inflammatory cytokines in pre-eclampsia are coincident with attenuated pre-eclampsia manifestation after CsA treatment, suggesting that CsA treatment might decrease the eclampsia-like seizure severity through decreasing systemic inflammation in pre-eclasmpsia/eclampsia.

Effects of Nigella sativa on Plasma Oxidative Stress, and Some Apoptotic Protein Markers in Cerebrum and Hippocampus in Pentylenetetrazol-Induced Kindling Rats

Objective: This study was designed for investigating the effectiveness of the Nigella sativa (N. sativa) extract on apoptosis in cerebrum and hippocampus and also plasma oxidative stress, in pentylenetetrazol (PTZ)-induced kindling rats. Materials and Methods: The kindling model was induced by subconvulsive doses (35 mg/kg i.p.) of intraperitoneal PTZ injections in N. sativa treated and non-treated PTZ groups (PTZ and PTZ + NS). The PTZ + NS group were also treated with an extract of N. sativa (10 mg/kg) 2 h before each PTZ injection. The total oxidant and antioxidant status, oxidative stress index, paraoxonase, arylesterase, catalase (CAT) and total thiol levels were analyzed in plasma. Brain derived neurotrophic factor (BDNF), cyclin-B1 and B-cell lymphoma 2 (Bcl-2) expressions were investigated in the cerebrum and hippocampus. Results: PTZ decreased the oxidative stress by increasing the activities of CAT, arylesterase, and paraoxonase. N. sativa decreased activities of arylesterase, paraoxonase, while increasing the CAT. It also brought the decreased BDNF and Bcl-2 expression levels to their normal levels in the cerebrum but not in the hippocampus. Conclusion: N. sativa treatment improved the PTZ induced-impairments in BDNF and Bcl-2 expressions, resulting in a neuronal apoptosis in the cerebrum, without affecting blood oxidative stress.

Anticonvulsant Effect of Alcea aucheri on Pentylenetetrazole and Maximal Electroshock Seizures in Mice.

Introduction:This study was designed to investigate the possible anticonvulsant effect of acute administration of an aqueous extract of flowers of Alcea aucheri (EFA) in two in vivo seizure models.Methods:Seizures were induced in male adult Swiss mice by administration of Pentylenetetrazol (PTZ) or Maximal Electroshock (MES). Mice were randomly subjected to receive saline, EFA (8.75–175 mg.kg−1), or diazepam intraperitoneally (i.p.) 15 or 30 min before PTZ injection. In another experiment, mice were treated (i.p.) with saline, EFA (8.75–350 mg.kg−1), or phenytoin 15 or 30 min before the MES test. Diazepam and phenytoin were used as reference drugs.Results:EFA (175 mg.kg−1) significantly increased the PTZ-induced seizure threshold compared with the saline control group 15 min after its administration. In the MES test, the extract (35 mg.kg−1) increased the latency to onset of tonic Hind Limb Extension (HLE) (seizure activity) compared with the saline group 15 min after treatment. Also, 30 min after treatment, EFA (35, 70, and 175 mg.kg−1) increased the latency to onset of the seizure, decreased the duration of the seizure (70 mg.kg−1), and decreased seizure occurrence (350 mg.kg−1) compared with those of the saline group. At both time points, the extract at all doses significantly reduced the mortality rate compared with the saline group.Conclusion:These findings provide evidence of a possible anticonvulsant effect of A. aucheri in PTZ and MES seizure models in mice.

Neuronal injury and death following focal mild brain injury: The role of network excitability and seizure.

Objective(s):While traumatic brain injury (TBI) is a predisposing factor for development of post-traumatic epilepsy (PTE), the occurrence of seizures following brain trauma can infuriate adverse consequences of brain injury. However, the effect of seizures in epileptogenesis after mild TBI cannot yet be accurately confirmed. This study was designed to investigate the histopathological and molecular modifications induced by seizures on traumatized brain. Materials and Methods:Using a new method, head was traumatized and seizures were evoked by sub-convulsive dose of pentylenetetrazole (PTZ) fifteen days after induction of focal mild TBI. Convulsion assessments were performed one hour after PTZ injection and was followed by histopathological and molecular evaluations. Results:A significantly higher score and longer duration of seizure attacks as well as higher number of epileptiform discharges were observed in the TBI+PTZ group compared to sham and TBI groups. An elevated number of apoptotic cells was observed in the TBI+PTZ group compared to sham and TBI rats. Molecular investigations revealed higher levels of Bax/Bcl2 ratio, Caspase 3, and NF-κB in the TBI+PTZ group compared to the other animal groups. The value of Nrf2 did not change after mild TBI compared to sham and PTZ control groups. Occurrence of seizures after TBI, however, significantly decreased the level of Nrf2. Conclusion:Our data indicated that seizure occurrence following mild TBI aggravates cell injury and death via activation of neuroinflammatory processes and may increase the risk of PTE. Additionally, our results suggest a potential protective role of Nrf2 after chemically evoked PTE.

Effect of Wuling powder on the pharmacokinetics of valproic acid in epileptic rats

Purpose: To investigate the effect of Wuling powder (WP) on the pharmacokinetics of valproic acid (VPA) in epileptic rats.Methods: A model of epilepsy was established in SD rats by intraperitoneal injection of pentylenetetrazole (PTZ). Twelve epileptic rats were randomly divided into two groups: control group given oral VPA alone at a dose of 180 mg/kg VPA, and drug combination group orally given VPA (180 mg/kg) co-administered with WP at a dose of 200 mg/kg. Blood sample (0.5 mL) was collected at 15, 30, 60, 120, 240 and 720 min after drug administration for measurement of plasma concentrations of VPA using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).Results: The AUC (0-480min) and maximum plasma concentrations (Cmax) of VPA in the drug combination group were significantly higher than those in the control group (p < 0.01). The half-time (t1/2) and time taken to attain maximum plasma VPA concentration (Tmax) in the combination group were extended, when compared to control group (p < 0.05).Conclusion: These results demonstrate that WP increases the plasma concentration of VPA and affects the pharmacokinetic properties of VPA in epileptic rats. Thus, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing WP to epileptic patients already taking VPA.

Prolonged febrile seizure history exacerbates seizure severity in a pentylenetetrazole rat model of epilepsy

Epilepsy is a debilitating neurological illness that affects all aspect of an individual life. Despite advancement in research there is little reduction in the incidence of this disease. Prolonged febrile seizure (PFS) has been linked to epilepsy however, the pathophysiology of this is still not clear. We therefore looked at the effect of PFS on the development of epilepsy in a pentylenetetrazole (PTZ) rat model of epilepsy.A total of 42 male Sprague–Dawley rats were used for the experiment. On post-natal day (PND) 14, PFS was induced in 14 rats. This was followed by the induction of epilepsy in the 14 PFS animal and 14 animals from the remaining 28 rats by an initial injection of PTZ at a dose of 60 mg/kg on day one followed by 35 mg/kg on alternate day until kindle. We looked at the effect of PFS on the onset and the stage of convulsion at kindle. We also observed it effect on the hippocampal glial fibrillary acidic protein (GFAP), synaptophysin and metabotropic glutamate receptor 3 (mGluR3) expression measured with immunofluorescence, LI Cor Tissue florescence and immunohistochemistry respectively.Our study showed that PFS reduced seizure threshold by decreasing the time it took animals to kindle and also increased the stage of convulsion. The hippocampal GFAP, synaptophysin and mGluR3 expressions where upregulated in PTZ rats with PFS history when compared to PTZ rats alone.These findings indicated that PFS may increase the severity of epilepsy and alter brain expression of GFAP, synaptophysin and mGluR3 proteins.

Effect of vitamin D on apoptosis of hippocampal cells in epileptic rats induced by kainic acid and pentylenetetrazol

Objective To investigate the effect of vitamin D on apoptosis of hippocampal cells in epileptic rats induced by kainic acid and pentylenetetrazol. Methods 48 Sprague Dawley (SD) rats were randomly divided into 6 groups: control group (group A), vitamin D group (group B), kainic acid (KA) group (group C), pentylenetetrazol (PTZ) (group D), vitamin D+ KA group (group E), vitamin D+ PTZ group (group F) with 8 rats in each group. Group B, group E, group F were given vitamin D 3 for two weeks. At the end of the day, when the average body weight of group C, group D, group E and group F reached 220 g, group C and group E. The epileptic animal model was established by intraabdominal injection of pentylenetetrazol into group D and group F. The seizures were observed within 1 hour after intraabdominal injection of the same dose of saline in group A and group B. The time of seizures after administration of kainic acid and pentylenetetrazol, the grade of seizures in the paroxysmal and subsequent stages, the duration of each grade of seizures, and the overall duration of recurrent seizures were recorded. The therapeutic effect of vitamin D on seizures was evaluated by recording the latent time from kainic acid and pentylenetetrazol to the first seizure. Results The TdT-mediated dUTP nick end labeling (TUNEL) positive cell counts in the KA group [(40.6±3.5)%] and the PTZ group [(83.2±3.3)%] were significantly higher than those in the control group [(4.3±2.0)%] and the vitamin D group [(4.5±2.2)%] (P 0.05). Conclusion Vitamin D has protective effects on hippocampal cell apoptosis in rats with epilepsy induced by KA and PTZ. Key words: Vitamin D; Kainic acid; Pentylenetetrazol; Epilepsy; Hippocampus; Apoptosis

Evaluation of the anticonvulsant and anxiolytic-like activities of aqueous leaf extract of Cymbopogon citratus in mice.

Background Anxiety is a common ailment of high co-morbidity with epilepsy, a chronic neurologic disease characterized by recurrent seizures. Current drugs used for these conditions have several limitations such as disabling side effects, relapse, and ineffectiveness in certain population necessitating the search for alternative options. The aqueous leaf extract of Cymbopogon citratus (CYC) is widely used for its various health-promoting effects including relief of seizures and anxiety in ethnomedicine. This present study describes its effects on convulsions, anxiety-like behaviors, and social interaction in mice. Methods Male Swiss mice were pretreated orally with CYC (25, 50, and 100 mg/kg), diazepam (1 mg/kg), or distilled water (10 mL/kg) 60 min before induction of convulsions with intraperitoneal (i.p.) injection of picrotoxin (10 mg/kg), pentylenetetrazole (PTZ; 85 mg/kg), or isoniazid (300 mg/kg). The animals were then observed for the occurrence of seizure for 30 min or 2 h for isoniazid. The effects of CYC on anxiety-like behaviors, social interaction, and spontaneous motor activity (SMA) were evaluated in naive mice. Results CYC (25-100 mg/kg) did not prevent convulsions nor delay the latency to convulsions induced by picrotoxin, PTZ, or isoniazid. Pretreatment with CYC (50 and 100 mg/kg, p.o) produced anxiolytic-like effect, decreased SMA, and also enhanced social interaction behavior in naive mice. Conclusions The results of this study suggest that CYC did not exhibit an anticonvulsant property in mice injected with picrotoxin, PTZ, or isoniazid, but its anxiolytic-like activity and social interaction-promoting effect might be of benefit as an adjuvant in improving the quality of life of epileptic patients.

Home-cage monitoring ascertains signatures of ictal and interictal behavior in mouse models of generalized seizures.

Epilepsy is a significant contributor to worldwide disability. In epilepsy, disability can be broadly divided into two components: ictal (pertaining to the burden of unpredictable seizures and associated medical complications including death) and interictal (pertaining to more pervasive debilitating changes in cognitive and emotional behavior). In this study, we objectively and noninvasively appraise aspects of ictal and interictal behavior in mice using instrumented home-cage chambers designed to assay kinematic and appetitive behavioral measures. Through daily intraperitoneal injections of the chemoconvulsant pentylenetetrazole (PTZ) applied to C57BL/6J mice, we coordinately measure how “behavioral severity” (complex dynamic changes in movement and sheltering behavior) and convulsive severity (latency and occurrence of convulsive seizures) evolve or kindle with repeated injections. By closely studying long epochs between PTZ injections, we identify an interictal syndrome of nocturnal hypoactivity and increased sheltering behavior which remits with the cessation of seizure induction. We observe elements of this interictal behavioral syndrome in seizure-prone DBA/2J mice and in mice with a pathogenic Scn1a mutation (modeling Dravet syndrome). Through analyzing their responses to PTZ, we illustrate how convulsive severity and “behavioral” severity are distinct and independent aspects of the overall severity of a PTZ-induced seizure. Our results illustrate the utility of an ethologically centered automated approach to quantitatively appraise murine expressions of disability in mouse models of seizures and epilepsy. In doing so, this study highlights the very unique psychopharmacological profile of PTZ.

Mild foot electrical stimulation is comparable with phenytoin in inhibiting pentylenetetrazol-induced kindling in rats.

Increasing evidence demonstrates that electric stimulation has anticonvulsant effects. The present study was undertaken to investigate the effects of mild foot electrical stimulation (MFES) on the development of pentylenetetrazol (PTZ) kindling and compare its effectiveness with the more commonly used treatment, phenytoin. Kindling was induced in rats by repeated injections (every 24h) of PTZ (37.5mg/kg). The rats were subjected to either MFES (0.2mA in intensity for a 160ms duration with a 160ms interval for 20min) or phenytoin (30mg/kg) before PTZ injections. Following this treatment, rats received MFES every other day for 10days or 26days after establishment of PTZ kindling. The data showed that MFES significantly inhibited development of chemical kindling induced by PTZ in rats (p = 0.001, as compared to PTZ-treated animals). This inhibitory effect is comparable with the effect of 30mg/kg doses of phenytoin (P = 0.99, as compared to phenytoin group). However, 10days or 26days durations of MFES had no effect on established kindled seizures (P = 0.58 as compared to PTZ-treated animals). Our data demonstrate that although MFES significantly inhibited the development of chemical kindling, this experimental paradigm had no effect on established kindled seizures.