Administration Of Pentylenetetrazol Research Articles

Effects of metformin on apoptosis and α-synuclein in a rat model of pentylenetetrazole-induced epilepsy.

The present study was designed to examine the possible neuroprotective and antiepileptic effects of metformin (Metf) in a rat model of pentylenetetrazole (PTZ)-induced epilepsy and its possible underlying mechanisms. Forty male albino rats were assigned to 4 groups of equal size: (1) normal control (NC) group, (2) Metf group: daily treatment with Metf (200 mg/kg, i.p.) for 2 weeks, (3) PTZ group: treatment with PTZ (50 mg/kg, i.p.) every other day for 2 weeks, and (4) Metf + PTZ group: daily treatment with PTZ and metformin (200 mg/kg, i.p.) for 2 weeks. Administration of PTZ caused a significant increase in seizure score and duration, induced a state of oxidative stress (high malondialdehyde, low reduced glutathione and catalase activity), and led to the upregulation of β-catenin, caspase-3, and its cleavage products, Hsp70 and α-synuclein, in hippocampal regions as well as a significant reduction in seizure latency. While Metf treatment significantly ameliorated PTZ-induced seizures, attenuated oxidative stress, and upregulated α-synuclein and β-catenin expression, it also inhibited caspase-3 activation and the release of the cleavage product and caused more upregulation in Hsp70 expression in hippocampal regions (p < 0.05). In conclusion, the antiepileptic and neuroprotective effects of Metf in PTZ-induced epilepsy might be due to the inhibition of apoptosis, attenuation of oxidative stress and α-synuclein expression, and upregulation of Hsp70.

Effects of Prenatal Seizures on Cognitive and Motor Performance in Mice Offspring (with Emphasis on BDNF and GDNF Levels)

Prenatal seizures in a mother’s organism exert adverse effects on offspring. We investigated the effects of exposure to prenatal seizures in utero on the motor coordination and cognitive performance of mice offspring. Considering that brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) play important roles in providing motor and learning abilities, the levels of these factors in serum of the offspring were measured. Adult female ICR mice were randomly separated into two groups and injected i.p. with either pentylenetetrazole (PTZ) or saline for 30 days. Then fully kindled mice and control animals were allowed to mate; PTZ administration was continued until delivery, while the control group received saline at the same time. The motor coordination and cognitive performance shown by male offspring of the groups were evaluated using the raised-beam task and novel object recognition task (NORT), respectively .The serum BDNF and GDNF levels in offspring were measured 24 h after the completion of the behavioral tests. Prenatal exposure to maternal seizures induced by PTZ led to a motor coordination deficiency, significant cognitive impairment, a decrease in the serum BDNF level, and an increase in the GDNF level in adult male offspring (P < 0.05 in all cases). These findings suggest that seizures during mother’s pregnancy cause strong cognitive deficiency and disorders of motor coordination mostly due to alteration of the BDNF and GDNF level in adult male offspring.

140. A novel pre-eclampsia model induced by renal artery clipping

Background Pre-eclampsia affects approximately 2–8% of pregnant women, causing proteinuria and blood pressure above 140 × 90 mmHg after the 20th week of gestation. If left untreated, PE can lead to the occurrence of self-sustained seizures (Eclampsia) that could eventually evolve to coma, and death of the mother and fetus. In the present study, an experimental model of hypertension was induced in pregnant rats that, later, received a seizure-trigger injection of pentylenetetrazol (PTZ) aiming to mimetize the eclampsia clinical picture. Methods Wistar rats were divided into four groups: non-pregnant (NP), pregnant (P), hypertensive (H) and pregnant hypertensive (HP). Hypertension (H and HP) was induced via clipping of the left renal artery. Subsequently, all animals were injected with PTZ and behavioral and electroencephalographic (EEG) changes were recorded. Results In opposition to control animals (NP and P), those from the H and HP groups presented a steady increase in BP that was first noticed two weeks after the renal artery clipping. PTZ injection at pregnancy days 18, 19 and 20 was able to induce behavioral and electrographic seizures in all groups although the number and the duration of each fit were higher in HP animals when compared to other groups. Besides, EEG analysis revealed that signal power and amplitude during the seizure events were significantly higher in the HP group. Conclusion Renal artery clipping in pregnant female rats was able to induce signs similar to those observed in preeclampsia. Besides, PTZ administration was able to induce behavioral and electrographic seizures significantly more intense in the HP group than those observed in the control groups (NP, P, H).

Cannabis sativa Increases Seizure Severity and Brain Lipid Peroxidation in Pentylenetetrazole-Induced Kindling in Rats

The effect of Cannabis sativa extract on chemical kindling induced in rats by the repeated intraperitoneal (ip) injections of pentylenetetrazole (PTZ) was studied. Rats were treated with PTZ (35 mg/kg) once every 48 hours for 12 times alone or with ip Cannabis sativa (20 mg/kg expressed as Δ9-THC content) 30 min prior to PTZ injection. Seizures were recorded for 20 minutes. Control rats received ip saline. Cannabis treatment caused significant elevation of mean seizure score as compared to PTZ only group after the 5th, 6th and 7th PTZ repeated injections during seizure development. In particular, cannabis caused significant elevation in the frequency of myoclonic jerks, rearing (stage 3), turn over onto one side position and back position (stage 4), and generalized tonic-clonic seizures (stage 5) compared with the PTZ only group. PTZ caused significant elevations in brain lipid peroxidation (malondialdehyde), and nitric oxide along with deceased reduced glutathione level. In addition, brain acetylcholinesterase (AChE) activity significantly decreased compared to control value after PTZ treatment. Cannabis given to PTZ treated rats caused significant increase in brain malondialdehyde and AChE activity compared to PTZ only group. Reduced glutathione level was restored by cannabis. Histopathological studies indicated the presence of spongiform changes, degenerated and necrotic neurons, inflammatory cells, and gliosis in cerebral cortex and degeneration of some Purkinje cells in the cerebellum in both PTZ- and cannabis-PTZ-treated groups. It is concluded that in an epilepsy model induced by repeated PTZ administration, cannabis increased lipid peroxidation and mean seizure score.

A gain-of-function study of amelioration of pentylenetetrazole-induced seizures by endogenous prostaglandin D2

We previously showed that knockout mice of hematopoietic prostaglandin (PG) D synthase (H-PGDS) produce less PGD2 to exacerbate pentylenetetrazole (PTZ)-induced seizures. Here, we adopted a gain-of-function strategy and used transgenic mice that over-express human H-PGDS enzyme, to elucidate the role of overproduction of endogenous PGD2 in PTZ-induced seizures. H-PGDS-transgenic mice showed the elevated level of a urinary metabolite of PGD2, tetranor-PGDM, 3.3- and 2.8-fold higher than the wild-type littermates under the basal condition and after the PTZ administration, respectively, without significantly changing the urinary concentration of a PGE2-metabolite, tetranor-PGE2. The intensity of PTZ-induced seizures was decreased in H-PGDS-transgenic mice as evident by the increased seizure onset latency, and a decrease in total duration of generalized tonic-clonic seizures and a total number of EEG seizure spikes during the postictal period (84 s, 17 s, and 5.3/min, respectively), as compared to wild-type mice (53 s, 24 s, and 12.6/min, respectively). These results indicate that overproduction of endogenous PGD2 decreased PTZ-induces seizures.

Pentylenetetrazole-Induced Kindling Mouse Model.

Pentylenetetrazole (PTZ) is a GABA-A receptor antagonist. An intraperitoneal injection of PTZ into an animal induces an acute, severe seizure at a high dose, whereas sequential injections of a subconvulsive dose have been used for the development of chemical kindling, an epilepsy model. A single low-dose injection of PTZ induces a mild seizure without convulsion. However, repetitive low-dose injections of PTZ decrease the threshold to evoke a convulsive seizure. Finally, continuous low-dose administration of PTZ induces a severe tonic-clonic seizure. This method is simple and widely applicable to investigate the pathophysiology of epilepsy, which is defined as a chronic disease that involves repetitive seizures. This chemical kindling protocol causes repetitive seizures in animals. With this method, vulnerability to PTZ-mediated seizures or the degree of aggravation of epileptic seizures was estimated. These advantages have led to the use of this method for screening anti-epileptic drugs and epilepsy-related genes. In addition, this method has been used to investigate neuronal damage after epileptic seizures because the histological changes observed in the brains of epileptic patients also appear in the brains of chemical-kindled animals. Thus, this protocol is useful for conveniently producing animal models of epilepsy.

Elevation of MMP-9 Levels Promotes Epileptogenesis After Traumatic Brain Injury

Posttraumatic epilepsy (PTE) is a recurrent seizure disorder that often develops secondary to traumatic brain injury (TBI) that is caused by an external mechanical force. Recent evidence shows that the brain extracellular matrix plays a major role in the remodeling of neuronal connections after injury. One of the proteases that is presumably responsible for this process is matrix metalloproteinase-9 (MMP-9). The levels of MMP-9 are elevated in rodent brain tissue and human blood samples after TBI. However, no studies have described the influence of MMP-9 on the development of PTE. The present study used controlled cortical impact (CCI) as a mouse model of TBI. We examined the detailed kinetics of MMP-9 levels for 1 month after TBI and observed two peaks after injury (30 min and 6 h after injury). We tested the hypothesis that high levels of MMP-9 predispose individuals to the development of PTE, and MMP-9 inhibition would protect against PTE. We used transgenic animals with either MMP-9 knockout or MMP-9 overexpression. MMP-9 overexpression increased the number of mice that exhibited TBI-induced spontaneous seizures, and MMP-9 knockout decreased the appearance of seizures. We also evaluated changes in responsiveness to a single dose of the chemoconvulsant pentylenetetrazol. MMP-9-overexpressing mice exhibited a significantly shorter latency between pentylenetetrazol administration and the first epileptiform spike. MMP-9 knockout mice exhibited the opposite response profile. Finally, we found that the occurrence of PTE was correlated with the size of the lesion after injury. Overall, our data emphasize the contribution of MMP-9 to TBI-induced structural and physiological alterations in brain circuitry that may lead to the development of PTE.

Anticonvulsant effect of minocycline on pentylenetetrazole-induced seizure in mice: involvement of nitric oxide and N-methyl-d-aspartate receptor.

Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole-induced seizures in mouse considering the possible role of the nitric oxide/N-methyl-d-aspartate (NMDA) pathway. We induced seizure using intravenous administration of pentylenetetrazole. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of subeffective doses of the nonselective nitric oxide synthase (NOS) inhibitor NG-l-arginine methyl ester (10 mg/kg) and the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of subeffective doses of minocycline (40 mg/kg). We found that inducible NOS inhibitor aminoguanidine (100 mg/kg) had no effect on the antiseizure effect of minocycline. Moreover, l-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with the NMDA receptor antagonists ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of subeffective doses of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of a neuronal NOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to a decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors.

Baicalein administration protects against pentylenetetrazole-induced chronic epilepsy in rats

Purpose: To investigate the protective effect of baicalein against chronic seizures in pentylenetetrazole induced epilepsy in a rat model.Methods: A rat model of chronic epilepsy was prepared by administration of pentylenetetrazole at a dose of 35 mg/kg to Sprague-Dawley rats. The animals were divided into 6 groups (5 rats/group): normal control, model (untreated epilepsy) and four treatment groups that received separately, intraperitoneal injection of 20, 30, 40 and 50 mg/kg baicalein, respectively, on alternate days for 30 days. On each day following baicalein treatment, behavioural alterations in the rats were assessed.Results: Analyses of behavioural changes revealed significant (p &lt; 0.05) decrease in pentylenetetrazole-induced convulsions by baicalein treatment at a dose of 50 mg/kg. Immunohistochemical studies revealed that treatment with baicalein caused significant (p &lt; 0.05) dosedependent reductions in the levels of inducible nitric oxide synthase (iNOS). Baicalein treatment inhibited alterations in cell morphology, and also inhibited pentylenetetrazole-induced increase in the proportion of glial fibrillary acidic protein (GFAP)-positive cells in a dose-dependent manner (p &lt; 0.05). Real-time polymerase chain reaction (RT-PCR) analysis showed that baicalein significantly inhibited the expression of mRNA of NR1 subunit N methyl D aspartic acid (NMDA) receptor, without any effect on the expression of the NR2b (N-methyl D-aspartate receptor subtype 2B ) subunit mRNA (p &lt; 0.05).Conclusion: These results indicate that baicalein inhibits pentylenetetrazole-induced chronic seizures in rats via reduction in astrocytes, inhibition of neuronal death and reduction of NR1 mRNA expression. Thus, baicalein has a potential for development into a new drug for the treatment of chronic epilepsy.Keywords: Pentylenetetrazole, Epilepsy, Baicalein, Convulsion, Inhibition, behavioural changes, Hippocampus

The Effects of Aqueous Extract of Apium Graveolens on Brain Tissues Oxidative Damage in Pentylenetetrazole-induced Seizures Model in Rat

Introduction: An important role for oxidative stress both as a consequence and as a cause of epileptic seizures has been suggested. Regarding the antioxidant and central nervous system depressant effects of Apium graveolens, the effects of aqueous extract of the plant on the brain tissues oxidative damage in pentylenetetrazole (PTZ)-induced seizures model was investigated. Materials & methods: Male Wistar rats were divided into 5 groups and treated: Control (saline), PTZ and three doses of the Apium graveolens extract (100, 500 and 1000 mg/kg) before PTZ. Latency to the first minimal clonic seizure (MCS) and the first generalized tonic-clonic seizures (GTCS) were recorded. The brain tissues were then removed for biochemical measurements. Results: MCS and GTCS latencies in extract treated groups were significantly higher than that of PTZ group (P < 0.05-P< 0.01). The malondialdehyde (MDA) levels in the brain tissues of PTZ group were significantly higher than that of control animals (P < 0.01-P< 0.001). Pretreatment with the extract resulted in a significant reduction in the MDA levels (P < 0.05-P< 0.001). Following PTZ administration, a significant reduction in total thiol content was observed in the brain tissues (P < 0.05- P < 0.01). Pretreatment with the extract was not effective to prevent from the lowering effects of PTZ- induced seizures on total thiol concentrations in the brain tissues. Conclusion: The present study showed that aqueous extract of Apium graveolens aerial parts possess anticonvulsant activity. This activity is accompanied by an antioxidant effect in the brain.

Elucidation of the molecular mechanism of tempol in pentylenetetrazol-induced epilepsy in mice: Role of gamma-aminobutyric acid, tumor necrosis factor-alpha, interleukin-1β and c-Fos

Background: Epilepsy is a chronic neurological disorder occurred due to periodic neuronal discharge and imbalance in brain electrical activity. 4-Hydroxy-TEMPO (Tempol) is a membrane-permeable radical scavenger moiety. Aim: The aim of this study is to evaluate the anticonvulsant potential of tempol against pentylenetetrazol (PTZ)-induced seizures in mice. Materials and Methods: Convulsion was produced in the male Swiss albino mice by administration of PTZ (90 mg/kg, i.p.). Mice were pretreated with either vehicle, tempol (50, 100 and 200 mg/kg, i.p.) or diazepam (5 mg/kg). Various behavioral, biochemical, molecular, and histological parameters were evaluated. Results: Mice pretreated with tempol (100 and 200 mg/kg) showed significantly (P Abbreviations used: GABA: Gamma-aminobutyric acid; PTZ: Pentylenetetrazol; TNF-α: Tumor necrosis factor-alpha; 4-HT: 4-Hydroxy-TEMPO; DZP: Diazepam; GSH: Reduced glutathione; NO: Nitric oxide; MDA: Malondialdehyde; SOD: Superoxide dismutase; ROS: Reactive oxygen species; IL-1β: Interleukin-1 beta.

Anti-epileptic effect of morin against experimental pentylenetetrazol-induced seizures via modulating brain monoamines and oxidative stress

Objective: To evaluate the protective effect of morin against pentylenetetrazol (PTZ)-induced tonic-clonic convulsions in mice. Methods: Swiss albino mice (18-22 g) was used to induce convulsions by intraperitoneal (i.p.) administration of PTZ (90 mg/kg). Mice were either pretreated with morin (10, 20 and 40 mg/kg) or vehicle (distilled water, 10 mg/kg) 45 min before PTZ administration. Various behavioral and biochemical parameters were assessed. Results: PTZ administration resulted in significant production (P

AMELIORATIVE EFFECT OF SODIUM VALPROATE IN COMBINATION WITH JUGLANS REGIA FRUIT EXTRACT AGAINST PENTYLENETETRAZOLE INDUCED CONVULSIONS IN MICE

Epilepsy is a complex neurological disorder characterized by hypersecretion of excitatory neurotransmitters in the brain. Level ofantioxidant enzymes in the brain changes during seizure. There are many herbal supplements that posses antioxidant potential and might help inprevention and recovery of seizures when used as an adjunct with modern antiepileptic drugs. Objective: The present work was undertaken toevaluate the Ameliorative effect of Sodium valproate in combination with Juglans regia extract against Pentylenetetrazole (PTZ) inducedconvulsions in mice. Materials and Methods: Juglans regia ethanolic extract (JREE) were administered at doses of (200mg/kg and 400 mg/kgp.o) and Sodium Valproate (500mg/kg p.o.) one hour before the administration of PTZ (80mg/kg i.p.). Brain tissues were screened for MDA,Catalase, GSH and protein estimation. Result and Discussion: Administration of JREE in the low and high dose prolongs the onset of myoclonicjerks dose-dependently and also showed protection against PTZ-induced convulsions. PTZ induced seizures caused a significant increase in MDAlevels and a significant decrease in GSH and catalase levels in PTZ group as compared to the vehicle control group. Juglans regia pre-treatmentprevented the oxidative stress as indicated by significant decrease in MDA levels and significant increase in GSH and catalse levels incomparison to PTZ group. Conclusion: The present study showed ameliorative effect of combination of Sodium Valproate in anticonvulsantactivity of ethanolic extract of Juglans regia fruit against PTZ induced seizures and also its protective effect against seizure induced oxidativestress.

Anticonvulsant and Antioxidant Effects of Musa sapientum Stem Extract on Acute and Chronic Experimental Models of Epilepsy.

Background:Musa sapientum (banana) plant extract has been shown to possess antioxidant activity in previous studies. Neuronal injury resulting from oxidative stress is an important factor involved in pathogenesis of epilepsy.Objective:The present study aimed to evaluate the anticonvulsant activity of M. sapientum stem extract (MSSE) in acute and chronic experimental models in mice and its effects on various markers of oxidative stress in the brain of pentylenetetrazole (PTZ)-kindled animals.Material and Methods:Maximal electroshock seizures (MES) and PTZ-induced convulsion models were used for acute studies. For the chronic study, the effect of MSSE on the development of kindling was studied. For the evaluation of the effects of MSSE on oxidative stress in brain, malondialdehyde (MDA) and reduced glutathione (GSH) levels were estimated in the brains of the kindled animals.Results:MSSE significantly increased the latency to onset of myoclonic jerks and the duration of clonic convulsions following PTZ administration. The MSSE pretreated group showed significantly reduced mean seizure score on PTZ-induced kindling. There was a significant increase in the brain MDA levels and decrease in GSH levels in response to PTZ-induced kindling. On MSSE pretreatment, there was a significant decrease in the MDA levels in the brains, though the increase in the GSH levels was not significant.Conclusion:The results from this study suggest the presence of significant anticonvulsant activity in MSSE, in both acute and chronic PTZ-induced seizure models, which could be due to its antioxidant activity, as is reflected by the change in oxidative stress markers in brain.SUMMARY Evaluation of the anticonvulsant activity of Musa sapientum and its effects on various markers of oxidative stress in the brain has not been done previously to the best of our knowledgeM. sapientum stem extract (MSSE) significantly increased the latency to onset of myoclonic jerks and the duration of clonic convulsions in the experimental modelsThe MSSE pretreated group showed significantly reduced mean seizure score on pentylenetetrazole (PTZ)-induced kindlingThere was significant increase in the brain malondialdehyde (MDA) levels and decrease in glutathione (GSH) levels in response to PTZ-induced kindlingOn MSSE pretreatment, there was a significant decrease in the MDA levels in the brain, though the increase in the GSH levels was not significant. Abbreviations Used: MSSE: Musa sapientum stem extract, PTZ: Pentylenetetrazole, MES: Maximal electroshock seizures, MDA: Malondialdehyde, GSH: Glutathione, SOD: Superoxide dismutase, THLE: Tonic hindlimb extension

Anticonvulsant effects of acetaminophen in mice: Comparison with the effects of nonsteroidal anti-inflammatory drugs

ObjectiveThe appropriate use of analgesic drugs based on their degree of analgesia and adverse effects is important for pain management. Although it has been reported that AM404, a metabolite of acetaminophen, has anticonvulsant effects in several animal seizure models, little is known about the relation between acetaminophen and seizures. We therefore investigated the effects of acetaminophen on seizure susceptibility in several mouse seizure and epilepsy models and compared the effects with those of nonsteroidal anti-inflammatory drugs (NSAIDs). MethodsAnticonvulsant activity was evaluated in ICR mice using maximum electroshock-induced seizure tests and acute pentylenetetrazol-induced seizure tests. Electrical kindling via corneal stimulation and pentylenetetrazol administration were used to establish animal kindling epilepsy models. Proconvulsive activity was examined using an electroconvulsive shock test with low-stimulus currents. ResultsAcetaminophen showed slight, but not statistically significant, anticonvulsant activity in both the maximum electroshock-induced seizure test (300–600mg/kg i.p.) and acute pentylenetetrazol-induced seizure test (100–600mg/kg i.p.). In contrast, acetaminophen exhibited significant anticonvulsant effects in corneal electroshock-kindled and pentylenetetrazol-kindled mice (ED50 values: 251 and 310mg/kg i.p., respectively). When the proconvulsive effects of NSAIDs were examined in the low-current electroconvulsive shock-induced seizure model, the nonselective cyclooxygenase (COX)-1 and COX-2 inhibitors indomethacin, diclofenac, and loxoprofen induced dose-dependent proconvulsant activity. Celecoxib, a COX-2 selective inhibitor, had no proconvulsant activity. ConclusionThese findings suggest that acetaminophen has a significant anticonvulsant effect and that its profile is completely different from that of NSAIDs.

Lacosamide Reduces Seizure Severity but Increases Seizure Frequency in PTZ-Kindled Rats

Abstract Objective: This study evaluated the anticonvulsant action of lacosamide (LCS), a novel drug that was recently approved for the treatment of partial or secondarily generalized seizures, using an animal model of generalized epilepsy induced by repetitive pentylenetetrazole (PTZ) administration in rats. The main goal was to evaluate the behavioral pattern of lacosamide action by classifying seizures according to a modi Racine-scale. Furthermore, the reproducibility of the win-PTZ kindling model of epilepsy, a recently described variant of the standard PTZ-kindling model, was also assessed. Methods: Adult male Wistar rats (n=16) were divided into two groups and underwent the win-PTZ-kindling protocol in two independent trials. After finishing the kindling procedure, all animals, which presented stage 5 seizures were tested for the anticonvulsant action of lacosamide at three different doses (3, 10, and 30 mg/kg). Results: The maximal severity of seizures decreased and the latency to stage 3-5 seizures increased when the animals were treated with lacosamide at a single dose of 10 mg/kg compared to saline pretreatment (p &lt; 0.05), both parameter reflecting an anticonvulsant action of the drug. Unfortunately, the number of stage 3-5 seizures also increased, but not significantly. The win-PTZ kindling model showed an adequate reproducibility between different trials, however, the number of fully kindled rats was lower than previously reported. Conclusions: Lacosamide showed a convincing anticonvulsant action in the win-PTZ kindling model of epilepsy by preventing the generalization of seizures. The win-PTZ kindling model was proved to be useful for studying epileptogenesis and the anticonvulsant action of drugs.

PROTECTIVE EFFECT OF MONTELUKAST AGAINST PENTYLENETETRAZOLE-INDUCED ACUTE SEIZURES AND KINDLING IN MICE

Montelukast, a selective reversible cysteinyl leukotriene1 (CysLT1) receptor antagonist, is used in treatment of asthma, exercise induced-bronchospasm, allergic rhinitis and urticaria. It was shown to protect against cerebral ischemia/reperfusion injury. Objectives: To examine the possible anticonvulsant effect of montelukast, either alone or in combination with a known antiepileptic drug against pentylenetetrazole (PTZ)-induced seizures. Methods: 112 adult male Swiss albino mice were used in the study and divided into two main groups, each containing 5 subgroups (Gp). The first main PTZ model (PTZ-a) contains: Gp1 vehicle-treated group was injected with saline (10 ml/kg, intraperitoneally i.p. in a single dose ), Gp2 PTZ-control injected with a single dose of PTZ (60 mg/kg, i.p.), Gp3 injected with valproate (50 mg/kg, i.p.) 30 minutes before PTZ, Gp4 injected with a single dose of montelukast (10 mg/kg, i.p.) 30 minutes before PTZ and Gp5 injected with both montelukast and valproate 30 minutes before PTZ administration. The second main kindling model (PTZ-k) contains: Gp1 was injected with saline (i.p.) every other day for 17 days, Gp2 PTZ-kindled received 9 PTZ injections in a dose of (40 mg/kg, i.p.) on alternate days for 17 days, Gp3 injected with valproate (50 mg/kg, i.p.) for 17 days, 30 minutes before PTZ, Gp4 daily injected with montelukast (10 mg/kg, i.p.) for 17 days 30 minutes before PTZ and Gp5 received both montelukast (10 mg/kg, i.p.) and valproate (50 mg/kg, i.p.) daily for 17 days, 30 minutes before administration of PTZ. Results: Single and repeated PTZ administration produced stage 4 seizures associated with a significant reduction in the brain level of reduced glutathione (GSH), concomittent with significant elevation in the brain levels of malondialdehyde (MDA), inteleukin1β (IL1β), tumor necrosis factor α (TNFα) and leukotriene D4 (LtD4). The use of valproate alone and its combination with montelukast suppressed the incidence of stage 4 seizures in acute PTZ induced convulsion while montelukast, valproate and their combination decreased the percentage of animals reaching stage 4 seizures in kindled mice. In both PTZ acute and kindled models, montelukast, valproate and their combined administration significantly elevated brain level of GSH and significantly decreased brain levels of MDA, IL1β, TNFα and LtD4 as compared to PTZ control groups. Interestingly, co-administration of valproate and montelukast resulted in a significant elevation in the brain level of GSH concomitant with a significant reduction in the brain levels of MDA, IL1β, TNFα and LtD4 as compared to each of the valproate and the montelukast groups in both models. Conclusion: Montelukast, either alone or in combination with valproate protects against PTZ induced seizures via blockade of leukotreine receptors & amelioration of oxidative stress and inflammatory cascades.

Effects of genistein on pentylenetetrazole-induced behavioral and neurochemical deficits in ovariectomized rats.

Estrogenic compounds have been documented in literature to exert neuroprotective effects. This study investigated the potential neuroprotective effect of genistein; a phytoestrogen at doses of 5, 10, 20, and 40mg/kg p.o. in ovariectomized rats challenged with pentylenetetrazole (PTZ) 90mg/kg i.p. Systemic acute administration of PTZ induced seizures, increased oxidative stress, and caused apoptosis and histological abnormalities. Pretreatment with genistein delayed seizure onset, reduced the seizure duration, improved oxidative stress profile, decreased estrogen receptor expression, reduced apoptosis, and improved the histopathological pattern. Overall, the genistein doses (10 and 20mg/kg) showed the strongest protective effects. In conclusion, the current study suggests that genistein exhibits neuroprotective effects against PTZ-induced seizures. Such effects might be attributed to its estrogenic, antioxidant, and/or anti-apoptotic properties.

Quinine and carbenoxolone enhance the anticonvulsant activity of some classical antiepileptic drugs

ObjectiveQuinine (QUIN) and carbenoxolone (CNX) elicit anticonvulsant effects typically characterized by the reduction of the epileptiform activity as well as changes in behavioral parameters related to seizures. Therefore, the aim of this study was to analyze the effects of these molecules on the anticonvulsant activity of some classical antiepileptic drugs.MethodsMale Wistar rats were used. Valproate (VPA), phenytoin (PHT), or carbamazepine (CBZ) was administered at sub-therapeutic doses for intraperitoneal via. Subsequently, animals were administered with a single dose of QUIN or CNX. The anticonvulsant activity was evaluated with the maximal electroshock (MES) test and pentylenetetrazole (PTZ) administration. Additionally, the plasma levels of CBZ were determined using an HPLC method.ResultsAll the control rats presented generalized tonic–clonic seizures after the MES test or the administration of PTZ. For the MES test, all of the antiepileptic drugs increased their anticonvulsant activity when were co-administered with QUIN. For the PTZ test, only the combination CBZ plus QUIN significantly increased the percentage of protection against the generalized tonic–clonic seizures. The co-administration of CBZ plus QUIN resulted in an augmented concentration of CBZ in plasma.DiscussionThe present study shows that QUIN and CNX enhance the anticonvulsant activity of some classical antiepileptic drugs. However, only the combination CBZ/QUIN had significant effects on both MES and PTZ models. Such anticonvulsant activity could be attributed to increased levels of CBZ in plasma. We propose that these molecules could improve the pharmacological actions of antiepileptic drugs administered at sub-therapeutic doses.

Protective effect of naringin on pentylenetetrazole (PTZ)-induced kindling; possible mechanisms of antikindling, memory improvement, and neuroprotection

The present study investigated the effects of Naringin on seizure severity, progress of kindling, memory impairment, oxidative stress, neurochemicals, and neural damage in Pentylenetetrazole (PTZ)-induced kindling. Alternate intra-peritoneal injections of PTZ induced kindling at 22 injections of PTZ. In comparison with the PTZ group, pretreatment with Naringin 30 min prior to PTZ administration and on a PTZ-free day was found to lead to a decreased seizure score, a mitigated progress of kindling, decreased transfer latency, and increased total number of arm entries, % alternation behavior in Y maze, and % conditioned avoidance response in a pole climbing apparatus. Biochemical analysis of the frontal and temporal cortexes and the hippocampus of the brain showed that Naringin attenuated the level of lipid peroxidation (MDA) and augmented the reduced glutathione, superoxide dismutase, catalase, and total thiol results in decreased oxidative stress compared with the PTZ group and control group. Investigation of neurochemicals revealed a minute change in gamma amino butyric acid (GABA), glutamate and dopamine, and decreased AChE in the three regions. Increased CA1 neuronal density in the hippocampus and increased cell density in the frontal and temporal regions indicate the potential of naringin to act against PTZ-induced kindling, memory impairment, oxidative stress, neurochemical changes, and histological aberrations.