Dose Of Pentylenetetrazole Research Articles

Sida corymbosa prevents seizures and memory deficit via inhibition of oxidative stress and neuronal loss in the hippocampus

Mesiotemporal lobe epilepsy is the most refractory form of epilepsy. The management of this condition relies on the use of antiepileptic drugs known to provide symptomatic relief. Herbal remedies are therefore an alternative to finding a cure for epilepsy. The present study aimed to assess the antiepileptic and anti-amnesic effects of Sida corymbosa aqueous extract using the pentylenetetrazole (PTZ) kindling model in rats. For this, 48 rats were divided into 6 groups of 8 animals each and treated as follows: normal and negative controls received per os (p.o) distilled water (10 mL/kg); experimental groups received S. corymbosa extract (17.14, 34.28, and 68.56 mg/kg, p.o); and positive control group received levetiracetam (250 mg/kg, p.o). One hour after the treatments, animals intraperitoneally (i.p) received a subconvulsive dose of PTZ (25 mg/kg), except the normal control group. The animals were treated once daily until the onset of the first tonic-clonic seizure (stage 5) in the negative control group. Twenty-four hours following the onset of the first seizure, memory impairment was assessed. Twenty-four hours later, the animals were sacrificed, and the hippocampus and prefrontal cortex were collected for biochemical analyses. The extract (68.56 mg/kg) prevented (p < 0.001) seizures from day 1 to day 12 compared to the negative control group. The extract (17.14 and 34.28 mg/kg) increased the recognition index by 80 % (p < 0.05) and 60 % (p < 0.01), respectively, compared with the negative control group. Moreover, the extract (17.14 mg/kg) increased by 68 % (p < 0.001) the concentration of GABA in the hippocampus. The extract (17.14 and 34.28 mg/kg) increased the acetylcholine level by 51 % (p < 0.001) and 69 % (p < 0.001) in the hippocampus, respectively. The extract at a dose of 17.14 mg/kg decreased the concentration of MDA in the hippocampus by 43 % (p < 0.001). These findings suggest that the extract has antiepileptic and anti-amnesic potentials that could justify its empirical use.

Antiepileptic and anti-inflammatory effects of Lippia multiflora moldenke (Verbenaceae) in mice model of chronic temporal lobe epilepsy induced by pilocarpine

Lippia multiflora Moldenke (Verbenaceae) is an aromatic plant used as a popular medicine with antidepressant, antispasmodic, antifungal, anti-inflammatory, and antioxidant properties. In this study, we explored the effects of L. multiflora in mice chronic model of temporal lobe epilepsy induced by pilocarpine and kindled with pentylenetetrazol. Mice were divided into 7 groups of 10 animals, and received a single dose of pilocarpine (360 mg/kg, i.p.), 20 min after the administration of N-methyl-scopolamine (1 mg/kg, i.p). Thirty days after the induction of status epilepticus, animals were daily treated for 60 days with distilled water (10 mL/kg, per os) for the negative control group, extract (23.07, 57.69, 115.39 and 230.78 mg/kg, per os) for the test groups, and sodium valproate (300 mg/kg, i.p) for the positive control group. On every 10th day, animals were injected with a sub-convulsive dose of pentylenetetrazol (15 mg/kg, i.p) 1 h after the administration of the various treatments to assess the susceptibility of animals to seizures. At the end of behavioural tests, animals were sacrificed and the level of inflammatory cytokines was assessed in the hippocampus. The plant extract reduced (p < 0.001) the occurrence of seizures and the number of spontaneous recurrent seizures induced by pilocarpine in mice. It ameliorated the levels of inflammatory cytokines (TNF-α, INF- γ, IL-1β, IL-6, and IL-10) in the hippocampus. The in vitro studies show that L. multiflora have a high amount of total phenolic content, flavonoids and tannins and also have some good antioxidant properties. These results suggest that L. multiflora aqueous extracts has the potential to be a promising complementary and alternative medicine for the treatment of epilepsy, due to its antiepileptic, anti-inflammatory and antioxidant effects.

Long‑term effects of vitexin against development of pentylenetetrazole‑induced kindling in rats.

Evidence is provided that the glycosylated flavonoid vitexin (apigenin‑8‑C‑beta‑D‑glucopyranoside) attenuates pentylenetetrazole (PTZ)‑induced acute tonic‑clonic seizures in rats. However, the effects of chronic and systemic vitexin in PTZ‑kindled rats remain unknown. The aim of this work was to investigate the effect of long‑term treatment with vitexin in the PTZ‑kindling model of epilepsy. Male Wistar rats received intraperitoneal injections of PTZ at a subconvulsive dose of 35 mg/kg every other day for 29 days. Either saline containing dimethyl sulfoxide - DMSO 1% (vehicle), diazepam (2 mg/kg; positive control) or vitexin (2.5 mg/kg) was administered intraperitoneally 30 min before each PTZ injection. The behavioral reactions were recorded by 30 min immediately after each PTZ injection. Furthermore, on the 31st day, that is, 48 h after the latter dose of PTZ, the animals were euthanized and renal and hepatic biochemical markers were evaluated in blood serum. Chronic treatment with either diazepam or vitexin attenuated the seizures provoked by PTZ injections. Neither diazepam nor vitexin caused changes in renal levels of creatinine and urea and in hepatic levels of aspartate aminotransferase and alanine aminotransferase. Our findings suggest that chronic administration of vitexin attenuates the progression of PTZ‑induced kindling without causing side effects on kidneys and liver.

Saccharomyces Boulardii alleviates neuroinflammation and oxidative stress in PTZ-kindled seizure rat model.

Previous research have reported that modulating the gut microbiome composition by fecal microbiota transplantation and probiotic administration can alleviate seizure occurrence and severity. Saccharomyces boulardii (SB) is a yeast probiotic that has demonstrated ameliorating effects on anxiety, memory and cognitive deficit, and brain amyloidogenesis. In this research, our goal was to examine the anti-seizure effects of SB on the pentylenetetrazole (PTZ)-kindled male Wistar rats. The animals were randomly categorized into four test groups. The rats were orally administered with saline (control and PTZ groups) or S. boulardii (SB + PTZ and SB groups) for 57days. From the 29th day of the experiment, the animals received intraperitoneally saline (control and SB groups) or PTZ (PTZ and SB + PTZ groups) on alternate days for 30 days. The administration dose of SB and PTZ was 1010 CFU/ml/day and 35mg/kg, respectively. We assessed animal seizure behavior, neuroinflammation, oxidative stress, and the levels of matrix metalloproteinase-9 (MMP-9) and brain-derived neurotrophic factor (BDNF) in the hippocampus tissue. S. boulardii hindered the PTZ-induced kindling development. SB treatment elevated glutathione (GSH) and total antioxidant capacity (TAC) and reduced malondialdehyde (MDA) levels. SB also lessened the hippocampal levels of BDNF and MMP-9. Following SB supplementation, proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-6 were lowered, and anti-inflammatory cytokine IL-10 was enhanced. Overall, our data indicated, for the first time, the positive impact of SB on the PTZ-kindled seizure rat model. The anti-seizure activity of SB was mediated by modulating oxidative stress, neuroinflammation, and MMP-9 and BDNF levels.

Altered Hippocampal Activation in Seizure-Prone CACNA2D2 Knock-out Mice.

The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c-fos and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out (CACNA2D2 KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-fos and ΔFosB expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 h after handling-associated convulsions, KO mice had fewer c-fos-positive cells but dramatically increased ΔFosB expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c-fos expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.

The effect of valproate on the amino acids, monoamines, and kynurenic acid concentrations in brain structures involved in epileptogenesis in the pentylenetetrazol-kindled rats.

The study aimed to assess the influence of a single valproate (VPA) administration on inhibitory and excitatory neurotransmitter concentrations in the brain structures involved in epileptogenesis in pentylenetetrazol (PTZ)-kindled rats. Adult, male Wistar rats were kindled by repeated intraperitoneal (ip) injections of PTZ at a subconvulsive dose (30mg/kg, three times a week). Due to the different times required to kindle the rats (18-22 injections of PTZ), a booster dose of PTZ was administrated 7days after the last rats were kindled. Then rats were divided into two groups: acute administration of VPA (400mg/kg) or saline given ip. The concentration of amino acids, kynurenic acid (KYNA), monoamines, and their metabolites in the prefrontal cortex, hippocampus, amygdala, and striatum was assessed by high-pressure liquid chromatography (HPLC). It was found that a single administration of VPA increased the gamma-aminobutyric acid (GABA), tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and KYNA concentrations and decreased aspartate (ASP) levels in PTZ-kindled rats in the prefrontal cortex, hippocampus, amygdala and striatum. Our results indicate that a single administration of VPA in the PTZ-kindled rats restored proper balance between excitatory (decreasing the level of ASP) and inhibitory neurotransmission (increased concentration GABA, KYNA) and affecting serotoninergic neurotransmission in the prefrontal cortex, hippocampus, amygdala, and striatum.

Saikosaponin a alleviates pentylenetetrazol-induced acute epileptic seizures in mouse models of depression by suppressing microglia activation-mediated inflammation

To explore the inhibitory effect of saikosonin a (SSa) on pentylenetetrazol-induced acute epilepsy seizures in a mouse model of depression and explore the mechanism mediating this effect. Male C57BL/6J mouse models of depression was established by oral administration of corticosterone via drinking water for 3 weeks, and acute epileptic seizures were induced by intraperitoneal injection of a single dose of pentylenetetrazole. The effect of intraperitoneal injection of SSa prior to the treatment on depressive symptoms and epileptic seizures were assessed using behavioral tests, epileptic seizure grading and hippocampal morphology observation. ELISA was used to detect blood corticosterone levels of the mice, and RTqPCR was performed to detect the pro- and anti-inflammatory factors. Microglia activation in the mice was observed using immunofluorescence staining. The mouse model of corticosterone-induced depression showed body weight loss and obvious depressive behaviors with significantly increased serum corticosterone level (all P < 0.05). Compared with those with pentylenetetrazole-induced epilepsy alone, the epileptic mice with comorbid depression showed significantly shorter latency of epileptic seizures, increased number, grade and duration of of seizures, reduced Nissl bodies in hippocampal CA1 and CA3 neurons, increased number of Iba1-positive cells, and significantly enhanced hippocampal expressions of IL-1β, IL-10, TNF-α and IFN-γ. Pretreatment of the epileptic mice with SSa significantly prolonged the latency of epileptic seizures, reduced the number, duration, and severity of seizures, increased the number of Nissl bodies, decreased the number of Iba1-positive cells, and reduced the expression levels of IL-1β, IL-10, TNF-α, and IFN-γ in the hippocampus (P < 0.05). Depressive state aggravates epileptic seizures, increases microglia activation, and elevates inflammation levels. SSA treatment can alleviate acute epileptic seizures in mouse models of depression possibly by suppressing microglia activation-mediated inflammation.

Quercetin Exerts Anticonvulsant Effect through Mitigation of Neuroinflammatory Response in Pentylenetetrazole-induced Seizure in Mice.

Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions. Therefore, there is need for new therapeutic intervention that will prevent epileptogenesis with greater therapeutic success. Quercetin (QT) is a flavonoid with known neuroprotective and anti-inflammatory properties. The study aimed to investigate its effects against pentylenetetrazole (PTZ)-induced seizures. Animals were divided into four groups (n = 10). Group 1(control) only received vehicle (10 mL/kg), group 2 received vehicle, groups 3 and 4 received QT 12.5 mg/kg and 25 mg/kg respectively. Sixty minutes after treatments, animals in groups 2 to 4 were injected with sub-convulsive dose of pentylenetetrazole (35 mg/kg, i.p.) on every alternate day (48±2h) for 21 days. The mice were observed for 30 minutes after each PTZ injection for seizure activity. Brain samples were collected for biochemical assays. Administration of PTZ caused significant increase in the intensity of seizures, neuronal degeneration and level of proinflammatory cytokines in animals compared to control. These behavioural alterations were attenuated significantly by QT (12.5 and 25 mg/kg). The PTZ-induced increase in IL-12, TNF-α and IFN-ɣ were significantly reduced by pre-treatment with the QT (12.5 and 25 mg/kg, p.o). Quercetin also reduced neuronal loss compared to control. Quercetin attenuates seizures in kindled mice and reduces neuroinflammation and neurodegeneration. This neuroprotective effect may be attributed to its ability to inhibit inflammatory mediators in the brain.

Interference of Seizure Disorders on Motor Functions, Coordination and Balance in Wistar Rats

Chronic recurrent seizures is a characteristic feature of epilepsy. It is a chronic neurological condition, usually resulting in unpredictable, unprovoked recurrent seizures that affect a variety of mental and physical functions. Some motor functions appear vulnerable to these seizure disorders. This study investigated the neurobehavioural analysis of pentylenetetrazole (PTZ) induced seizure on motor balance, coordination in Wistar rats. The study was done in two phases: acute (14days) and chronic (28days). A total of twenty adult Wistar rats weighing between 90-120g were used for each phase of study. The rats were divided into four (4) groups (1-4, n=5). PTZ was administered intraperitoneally to the PTZ treated groups one (1) week before the neurobehavioral experiments commenced. Group 1 (control) received distilled water; groups 2, 3 and 4 were administered with subconvulsive doses of PTZ (25mg/kg, 30mg/kg and 35mg/kg) respectively at alternate days (48 hourly) until kindling was achieved. The study evaluated neurobehavioural parameters using Rotarod test (RT) and Handgrip test (HT). In both tests, the time latencies were significantly (P&lt;0.05) reduced and worsened with time, when test groups were compared to control either in acute or chronic phase study. The results from the current study on the effects of the chemoculvosant seizures on motor functions, coordination and balance shows that severity and chronicity of seizures caused a deficit in motor coordination and balance. In conclusion, seizure disorder disrupts motor activities.

Levetiracetam ameliorates epileptogenesis by modulating the adenosinergic pathway in a kindling model of epilepsy in mice.

Levetiracetam (LEV) has been found to have an antihyperalgesic effect via acting on the adenosine system. However, the effects of LEV on the modulation of the adenosine system in the brain have not been elucidated in the prevention of seizures and epilepsy. The present study aimed to explore the possible LEV mechanisms of action in the adenosine signaling systems in an animal model of epilepsy. A docking study was initially performed to determine the possible interaction of LEV with adenosine A1 receptors (A1Rs) and equilibrative nucleoside transporters-1 (ENT1). The experimental study was divided into an acute seizure test (32 mice distributed into 4 groups) and a chronic kindling model study (40 mice distributed into 5 groups), followed by gene expression analysis and immunohistochemistry. The kindling model lasted 26 days and took 13 subconvulsive doses of pentylenetetrazole (PTZ) to completely kindle the mice in the PTZ control group. Gene expression changes in the A1Rs, potassium inwardly-rectifying channel 3.2 (Kir3.2), and ENT1 in the brain tissue samples of the mice following treatment with LEV were analyzed using reverse transcription-quantitative polymerase chain reaction, and immunohistochemistry was performed for the A1R protein expression. Docking studies predicted a significant interaction of LEV with A1Rs and ENT1 proteins. Results from the acute testing revealed that caffeine (100 mg/kg) and 8-cyclopentyl-1,3-dipropylxanthine (25 mg/kg) significantly reversed the antiseizure effects of LEV by reversing the percent protection and shortening the onset of the first myoclonic jerk (FMJ) and generalized clonic seizures (GCSs). In the PTZ-induced kindling, LEV demonstrated an increased gene expression of A1Rs and Kir3.2 in the brain. LEV also significantly reduced the gene expression of ENT1. Furthermore, the immunohistochemical analysis showed that LEV increased the protein expression of A1Rs in the brain. Based on these results, it can be concluded that LEV modulates epileptogenesis by acting on the adenosine pathway in the central nervous system.

Acute and Chronic Study of PTZ –Induced Seizure Effects on Visuo-Spatial Functions in Wistar Rats

Epilepsy is one of the chronic neurological conditions affecting people of all ages globally. Educational progress have been affected negatively by some abnormalities associated with epilepsy. This study employed neurobehavioural analysis of pentylenetetrazole (PTZ) induced seizure on some visual spatial functions in Wistar rats. The study was done in two phases: acute (14days) and chronic (28days). A total of twenty adult Wistar rats weighing between 90-120g were used. The rats were divided into four (4) groups (1-4, n=5). PTZ was administered intraperitoneally to the PTZ treated groups one (1) week before the neurobehavioral experiments commenced. Group 1 (control) received distilled water, group 2, 3and 4 were administered with doses of PTZ (25mg/kg, 30mg/kg and 35mg/kg) respectively at alternate days (48 hourly) until kindling was achieved. The study evaluated neurobehavioural parameters using Barnes maze (BM), navigational box test (NBT). The results from neurobehavioural evaluations on effects of the chemo-convulsant seizures on visual spatial functions, suggests that severity of seizures caused a deficit in learning and visual spatial memory which was worsened by chronicity. In conclusion, PTZ-induced seizure negatively interferes with visual spatial functions.

Neuroprotective Effect of Chlorogenic Acid against Pentylenetetrazol Induced Kindled Epilepsy in Mice

Background: Epilepsy is a group of chronic neurological disorders characterized by seizures. Kindling, a chronic epileptic mouse model that was used to explore the epileptogenic mechanism and seeking new anti-epileptics. In kindling, sub-convulsive (chemical/ electrical) stimuli are delivered repeatedly and erratically, eventually causes massive convulsions. The aim of this study was to investigate the neuroprotective effects of chlorogenic acid, a phenolic acid derived from coffee, on seizure severity and kindling progression. Memory impairment inflammation due to oxidative stress by pentylenetetrazol (PTZ). Objective: This study was used to investigate the neuroprotective effect of chlorogenic acid against pentylenetetrazol induced kindled epilepsy in mice. Methods: Kindling was provoked by subsequent (one-day-gap) injections of PTZ (subconvulsive; 35 mg/kg; s.c.) for 29 days in mice. The experimental protocol included six groups (n=6) receiving proconvulsant doses of PTZ (35 mg/kg i.p.) every other day for 31 days. Alternating subcutaneous injections of PTZ induced priming with 15 injections of PTZ. Compared with the PTZ group, pre-treatment with chlorogenic acid (5 and 10 mg/kg) 1 h before PTZ administration reduced seizure score, reduced metastasis latency due to increased normal maze, and decreased metastasis latency extension at FST. PTZ-induced biochemical changes were enhanced in chlorogenic acid-treated animals, as indicated by decreased lipid peroxidation (MDA), nitric oxide and AChE levels, and increased SOD, GSH, catalase level. Following PTZ injection, convulsive behaviours were noted for 30 minutes. Open-field-test (locomotor activity), force swimming test (depressive behaviors), elevated plus-maze and passive avoidance tests were employed to evaluate cognition. Brain homogenate was used to estimate oxidative stress (glutathione,superoxide-dismutase, lipid-peroxidation), and acetylcholinesterase activity. Results: This result suggest the neuroprotective potential of chlorogenic acid. This may be correlated with its ability to inhibit oxidative damage and reduce the occurrence of seizures and other related damage. It may be a promising candidate for mitigating the consequences of events. Conclusion: Our findings suggest effect of chlorogenic acid against pentylenetetrazol-induced kindled epilepsy in mice which were established by behavioral and biochemical paradigms

Tetramethylpyrazine contributes to the neuroprotection in a rodent epileptic model of pentylenetetrazole-induced kindling.

In this study, tetramethylpyrazine (TMP) was evaluated for its therapeutic potential as an alternative therapy for epileptogenesis and its associated comorbidities in rats. The sub-convulsant dose of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneally) was injected on alternative days to produce kindling for 32 days and observed for seizure score percent of kindled animals in each group. After kindling, the animals were evaluated in models of anxiety, memory and predictive of depression. The neuroprotective effect of TMP was assessed by estimating the biochemical parameters in the cortex and hippocampus of the brain. Histopathological alterations were also observed in the cortex and hippocampus (CA1, CA3 and DG). The administration of TMP reduced the seizure score and percentage of kindled animals dose-dependently. Furthermore, TMP significantly improved the behavioural parameters measured in the predictive models of depression but not in the anxiety and cognitive performances of the animals. The oxidative-nitrosative stress, excitotoxicity, neuroinflammation and histological alterations in the brain induced by PTZ were significantly mitigated by administering the TMP high dose of 60 mg/kg. In conclusion, the TMP attenuated the depression behaviour in the PTZ-induced kindled rats, and reduced the oxidative-nitrosative stress, excitotoxicity, neuroinflammation and histological alterations of the brain.

The Aqueous Lyophilisate of Alchemilla Kiwuensis Engl. (Rosaceae) Displays Antiepileptogenic and Antiepileptic Effects on PTZ-induced Kindling in rats: Evidence of Modulation of Glutamatergic and GABAergic Pathways Coupled to Antioxidant Properties.

Alchemilla kiwuensis Engl. (Rosaceae) (A. kiwuensis) is an herbaceous plant traditionally used by Cameroonians to treat epilepsy and other central nervous system disorders. The present study evaluated the antiepileptogenic and antiepileptic effects of A. kiwuensis (40mg/kg, 80mg/kg) following Pentylenetetrazole (PTZ)-induced kindling as well as its sub-chronic toxicity. Following an initial i.p administration of a challenge dose (70mg/kg), Wistar rats of both sexes received sub convulsive doses (35mg/kg) of PTZ every other day, one hour after the oral gavage of animals with treatments, until two consecutive stage 4, in all animals of negative control. Seizure progression, latency, duration, and repetition were noted. Twenty-four hours later, animals were dissected to extract their hippocampi. The resulting homogenates were used to evaluate Malondialdehyde, reduced glutathione, catalase activity, GABA, GABA-Transaminase, glutamate, glutamate transporter 2, IL-1β and TGF-1 β. Sub-chronic toxicity was conducted according to OECD 407 guidelines. The lyophilisate of A. kiwuensis significantly increased the latency of seizure appearance, delayed seizure progression and decreased seizure repetition and duration. Biochemical analysis revealed that the lyophilisate significantly increased the catalase activity, reduced glutathione, GABA, glutamate transporter 2 and TGF-1B levels. The lyophilisate equally caused a significant decreased in the GABA-Transaminase activity, malondialdehyde, and IL-1 β levels. There was no noticeable sign of toxicity. A. kiwuensis possesses antiepileptic and antiepiletogenic effects by enhancing GABAergic neurotransmission and antioxidant properties, coupled to modulation of glutamatergic and neuroinflammatory pathways and is innocuous in a sub-chronic model. These justifies its local use for the treatment of epilepsy.

The anxiolytic and antidepressant effect of Stachys Lavandulifolia in the experimental pentylenetetrazole-induced rat model of acute seizure

Objective: In traditional medicine, Stachys lavandulifolia or mountain tea has been used in the treatment of arthritis and rheumatoid arthritis. A leaf extract from this plant is also thought to be effective in treating epilepsy as well as other neurological ailments. To assess the effect of S. lavandulifolia extract (SLE), rats were exposed to a stress and anxiety model caused by seizures. Materials and Methods: A challenge dose of pentylenetetrazole (PTZ) (60 mg/kg) was used to induce seizures in male Wistar rats (200–250 g). Animal treated with an intraperitoneal injection of either SLE (50 mg/kg) or sodium valproate (100 mg/kg) alone or in combination 30 min before PTZ challenge. The effect of stress and anxiety was assessed using an open field test (OFT), forced swim test (FST), and elevated plus maze (EPM). At the end of the experiment, anesthesia was used to euthanize rats, and their blood serum was collected for measurements of glutathione (GSH), malondialdehyde (MDA), and GSH peroxidase (GPx). Results: In contrast to the control group, those treated with PTZ exhibited depressive behavior. At 50 mg/kg, SLE provided protection against seizures induced by PTZ. SLE also reduced seizure-induced stress and anxiety, significantly improving FST, EPM, and OFT compared with the PTZ-treated group. By decreasing MDA levels and restoring the antioxidant enzymes GSH and GPx, SLE treatment protects against seizure-induced anxiety and stress. Conclusions: SLE inhibits oxidative stress damage and seizure-induced stress by inhibiting seizures' inhibitory effects.

Anticonvulsant Role of Adenosine is Blunted During Alcohol Withdrawal Syndrome in an Adult Zebrafish Model.

Alcohol (ethanol) dependence and related disorders are life-threatening conditions and source of suffering for the user, family members and society. Alcohol withdrawal syndrome (AWS) is a little-known dynamic process associated with a high frequency of relapses. A state of hyperglutamatergic neurotransmission and imbalanced GABAergic function is related to an increased susceptibility to seizures during alcohol withdrawal. Adenosine signaling display an important role in endogenous response to decrease seizure and related damages. Here, an intermittent alcohol exposure regimen (1h daily of 0.5% ethanol solution) for 16 days or 8 days of the same ethanol exposure regimen followed by 1 or 8 days of ethanol withdrawal was used to assess adenosine signaling in the context of seizure susceptibility using adult zebrafish. In both abstainer groups, a sub-convulsant dose of pentylenetetrazol (2.5 mM) was able to increase the frequency of animals reaching a clonic seizure-like state, while continuous-treated animals had no seizure, as did control animals. The total brain mRNA expression of A1 adenosine receptor was decreased in animals with 1day of ethanol withdrawal. The agonism of A1 adenosine receptor induced an anticonvulsant effect in animals with 1day of ethanol withdrawal after the injection of the specific agonist (N6-cyclopentyladenosine, 10mg.Kg- 1; i.p.). These findings reinforce A1 adenosine receptor as a key target in acute alcohol withdrawal syndrome and zebrafish as an excellent platform to study biological mechanism of AWS.

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes.

Complement system plays an important role in the immune defense against pathogens; however, recent studies demonstrated an important role of complement subunits C1q, C4, and C3 in normal functions of the central nervous system (CNS) such as non-functional synapse elimination (synapse pruning), and during various neurologic pathologies. Humans have two forms of C4 protein encoded by C4A and C4B genes that share 99.5% homology, while mice have only one C4B gene that is functionally active in the complement cascade. Overexpression of the human C4A gene was shown to contribute to the development of schizophrenia by mediating extensive synapse pruning through the activation C1q-C4-C3 pathway, while C4B deficiency or low levels of C4B expression were shown to relate to the development of schizophrenia and autism spectrum disorders possibly via other mechanisms not related to synapse elimination. To investigate the potential role of C4B in neuronal functions not related to synapse pruning, we compared wildtype (WT) mice with C3- and C4B- deficient animals for their susceptibility to pentylenetetrazole (PTZ)- induced epileptic seizures. We found that C4B (but not C3)-deficient mice were highly susceptible to convulsant and subconvulsant doses of PTZ when compared to WT controls. Further gene expression analysis revealed that in contrast to WT or C3-deficient animals, C4B-deficient mice failed to upregulate expressions of multiple immediate early genes (IEGs) Egrs1-4, c-Fos, c-Jus, FosB, Npas4, and Nur77 during epileptic seizures. Moreover, C4B-deficient mice had low levels of baseline expression of Egr1 on mRNA and protein levels, which was correlated with the cognitive problems of these animals. C4-deficient animals also failed to upregulate several genes downstream of IEGs such as BDNF and pro-inflammatory cytokines IL-1β, IL-6, and TNF. Taken together, our study demonstrates a new role of C4B in the regulation of expression of IEGs and their downstream targets during CNS insults such as epileptic seizures.

The electrophysiological and behavioral evaluation of the peptide hemopressin and cannabinoid CB1 receptor agonist and antagonist in pentylenetetrazol model of epilepsy in rats.

This study endeavoured to assess the effect of hemopressin (Hp), a nano peptide obtained from the alpha chain of hemoglobin, on chronic epileptic activity and its potential correlation with cannabinoid receptor type 1 (CB1). Male Wistar albino rats (230-260g) were used. The kindling process was conducted by administering a sub-convulsant dose of pentylenetetrazol (PTZ) (35mg/kg, i.p) three times a week for a maximum of 10weeks. Tripolar electrodes and external cannula guides for intracerebroventricular (i.c.v) injections were surgically implanted in the skulls of kindled rats. On the day of the experiment, doses of Hp, AM-251, and ACEA were administered prior to the PTZ injections. Electroencephalography recordings and behavioural observations were conducted simultaneously for 30min after the PTZ injection. The administration of Hp (0.6μg, i.c.v) resulted in a decrease in epileptic activity. The CB1 receptor agonist ACEA (7.5μg, i.c.v) showed an anticonvulsant effect, but the CB1 receptor antagonist AM-251 (0.5μg, i.c.v) displayed a proconvulsant effect. The co-administration of Hp (0.6μg, i.c.v) and ACEA (7.5μg, i.c.v) and of Hp (0.6μg, i.c.v) and AM-251 (0.5μg, i.c.v) produced an anticonvulsant effect. However, when AM-251 was administered prior to Hp, it produced a proconvulsant impact that overrode Hp's intended anticonvulsant effect. Interestingly, the co-administration of Hp (0.03μg) + AM-251 (0.125μg) unexpectedly exhibited an anticonvulsant effect. Electrophysiological and behavioural evaluations demonstrated the anticonvulsant effect of Hp in the present model, highlighting the possibility that Hp may act as an agonist for the CB1 receptor.

The Protection by Vitamin E Against Tramadol-Induced Proconvulsant Effects and Brain Damage in Pentylenetetrazole-Induced Status Epilepticus in Rats

We investigated the effect of the opioid analgesic tramadol on the development of epileptic seizures and neuronal injury and the possible modulatory effect of vitamin E (Vit E) in rats with pentylenetetrazole (PTZ)-induced status epilepticus. Rats received repeated intraperitoneal (i.p.) injections of PTZ till the development of status epilepticus and were pretreated once with tramadol (30, 60 or 90 mg/kg), vitamin E (Vit E, 70 mg/kg) or both tramadol (90 mg/kg) and Vit E (70 mg/kg) prior to starting PTZ injections. Seizure scores, the latency time and the PTZ dose for each group required to reach status epilepticus were determined and histopathological examination of the brain tissue was done. Results indicated that tramadol produced both anticonvulsant and proconvulsant effects. The anticonvulsant effects of tramadol were observed for facial twitching (stage 1), convulsive body waves (stage 2), and myoclonic jerks and rearing (stage 3) and turn over onto one side position (stage 4) that were significantly inhibited by tramadol. In contrast, tonic-clonic convulsions (stage 5) were significantly increased by 60 or 90 mg/kg of tramadol as compared to PTZ control group. The mean latency and PTZ threshold dose for status epilepticus were markedly decreased after tramadol. The administration of Vit E exerted beneficial effects in decreasing epilepsy scores and increasing both the latency time and threshold dose of PTZ for reaching status epilepticus. Meanwhile, rats treated with both tramadol and Vit E exhibited significant increase in tonic-clonic convulsions and markedly shortened latency time to reach status epilepticus compared to those treated with only Vit E. In cerebral cortex and hippocampus, PTZ resulted in apoptotic cells, darkly stained degenerated and vacuolated neurons and gliosis. These pathological changes increased after tramadol but were markedly reduced by Vit E treatment. Collectively, these results suggest that: (i) tramadol exerts both anticonvulsant and proconvulsant effects; (ii) tramadol shortened the latency time and decreased the threshold dose of PTZ for evoking status epilepticus; (iii) PTZ-induced seizures and brain damage can be inhibited by Vit E; (iv) tramadol at high doses interferes with the effect of Vit E in inhibiting tonic-clonic convulsions and in reducing brain damage.

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimer's Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Dysfunction of cortical pyramidal function was also reflected in a reduction of basal theta oscillations and enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol in rTg4510 mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as biomarker candidates in early stages of neurodegenerative tauopathies.