Chimney Test Research Articles

Muscular Injection of Botox Exacerbates Seizures Through TNF-alpha and Oxidative Stress in Mice

Background: Recent research has revealed the central adverse effects of Botox after intramuscular injection. The aim of this study was to examine the role of brain oxidative stress factors and circulatory cytokines as indicators of the severity of seizures following acute intramuscular (IM) injection of Botox in mice. Methods: Botox (1, 5 and 30 U, IM) was injected 60 minutes before inducing maximal electroshock (MES) seizures. Nitric oxide (NO), malondialdehyde (MDA) and glutathione (GSH) levels were measured in the brain. Tumor necrosis factor-alpha (TNF-α) levels were also determined in the serum. The motor coordination was assessed after Botox administration by using the chimney test. Results: Botox (5 and 10 U/kg, IM) significantly reduced the duration of hindlimb extension (HLE) and elevated levels of NO and MDA in the brain compared to the seizure group. Additionally, the administration of Botox (1 and 5 U, IM) increased the level of GSH in the brain, while 30 U decreased it. All Botox dosages demonstrated an enhancing effect on serum TNF-α levels compared to the seizure group. Botox at 5 and 30 U induced locomotor incoordination in mice. Conclusion: Our results showed that IM injection of Botox can lead to the exacerbation of tonic-clonic seizures by stimulating oxidative stress in the brain and increasing circulating TNF-α levels in mice.

Chronic Treatment with Oxcarbazepine Attenuates Its Anticonvulsant Effect in the Maximal Electroshock Model in Mice.

The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.

Muscle relaxant and antipyretic effects of pentacyclic triterpenes isolated from the roots of Diospyros lotus L

The present article describes the muscle relaxant and antipyretic effects of pentacyclic triterpenes, oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) isolated from roots of Diospyros lotus in animal models. The muscle relaxant effects of isolated pentacyclic triterpenes were determined by chimney and inclined plane tests. In the chimney test, pretreatment of pentacyclic triterpenes evoked significant dose dependent influence on muscle coordination. When administered intraperitoneally (i.p.) to mice at 10 mg/kg for 90 min, OA, UA, and BA exhibited muscle relaxant effects of 66.72 %, 60.21 %, and 50.77 %, respectively. Similarly, OA, UA, and BA (at 10 mg/kg) illustrated 65.74 %, 59.84 % and 51.40 % muscle relaxant effects in the inclined plane test. In the antipyretic test, significant amelioration was caused by pretreatment of all compounds in dose dependent manner. OA, UA, and BA (at 5 mg/kg) showed 39.32 %, 34.32 % and 29.99 % anti-hyperthermic effects, respectively 4 h post-treatment, while at 10 mg/kg, OA, UA, and BA exhibited 71.59 %, 60.99 % and 52.44 % impact, respectively. The muscle relaxant effect of benzodiazepines is well known for enhancement of GABA receptors. There may exist a similar mechanism for muscle relaxant effect of pentacyclic triterpenes. The in-silico predicted binding pattern of all the compounds reflects good affinity of compounds with GABAA receptor and COX-2. These results indicate that the muscle relaxant and antipyretic activities of these molecules can be further improved by structural optimization.

Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis.

Trimetozine is used to be indicated for the treatment of mental illnesses, particularly anxiety. The present study provides data on the pharmacological profile of trimetozine derivative morpholine (3,5-di-tert-butyl-4-hydroxyphenyl) methanone (LQFM289) which was designed from molecular hybridization of trimetozine lead compound and 2,6-di-tert-butyl-hydroxytoluene to develop new anxiolytic drugs. Here, we conduct molecular dynamics simulations, docking studies, receptor binding assays, andin silicoADMET profiling of LQFM289 before its behavioral and biochemical assessment in mice within the dose range of 5-20mg/kg. The docking of LQFM289 showed strong interactions with the benzodiazepine binding sites and matched well with receptor binding data. With the ADMET profile of this trimetozine derivative that predicts a high intestinal absorption and permeability to blood-brain barrier without being inhibited by the permeability glycoprotein, the oral administration of LQFM289 10mg/kg consistently induced anxiolytic-like behavior of the mice exposed to the open field and light-dark box apparatus without eliciting motor incoordination in the wire, rotarod, and chimney tests. A decrease in the wire and rotarod´s fall latency coupled with an increase in the chimney test´s climbing time and a decrease in the number of crossings in the open field apparatus at the dose of 20mg/kg of this trimetozine derivative suggest sedative or motor coordination impairment at this highest dose. The attenuation of the anxiolytic-like effects of LQFM289 (10mg/kg) by flumazenil pretreatment implicates the participation of benzodiazepine binding sites. The lowering of corticosterone and tumor necrosis factor alpha (cytokine) in LQFM289-treated mice at a single oral (acute) dose of 10mg/kg suggests that the anxiolytic-like effect of this compound also involves the recruitment of non-benzodiazepine binding sites/GABAergic molecular machinery.

Evaluation of CNS Depressant and Anti-anxiety Activities of Leaves of Convolvulus pluricaulis.

Convolvulus pluricaulis is a native plant that is commonly mentioned in Ayurveda as a Rasayana and is primarily recommended for use in mental stimulation and rejuvenation therapy. Convolvulus pluricaulis is used as a brain tonic. The plant is reported to be a prominent memory-improving drug. It is used as a psychostimulant and tranquilizer. It is reported to reduce mental tension. The present study aimed to explore the protective effect of hydroalcoholic extract from the leaves of Convolvulus pluricaulis along with CNS depressant and anti-anxiety activities, in models of mice. The extract from leaves of Convolvulus pluricaulis were sequentially isolated with a mixture of water and alcohol solution in the soxhlet apparatus. An acute toxicity study was conducted as per OECD guidelines no. 423, in which 18 Albino male mice were treated with different doses (1, 10, 100, 500, 1000, and 2000 mg/kg) of hydroalcoholic extract of Convolvulus pluricaulis and assessed for toxicity parameters for 14 days. Various psychomotor activities of hydroalcoholic extract from leaves of Convolvulus pluricaulis for 100, 200, and 300 mg/kg doses were performed in mice by using various tests like actophotometer, open field, rota-rod, grip strength tests, elevated plus maze, hole board test, inclined plane, chimney test. The hydroalcoholic extract from leaves of Convolvulus pluricaulis was found to fall under category 4 in the acute toxicity study. Therefore, 100, 200, and 300 mg/kg doses of hydroalcoholic extract of leaves of Convolvulus pluricaulis were selected for the further pharmacological study. The results of psychomotor tests (actophotometer, open field, rota-rod, grip strength, hole board test, inclined plane, chimney test, elevated plus maze, light-dark model) for test doses 100, 200, and 300 in mice showed CNS depressant and anti-anxiety effects. Hydroalcoholic extract from leaves of Convolvulus pluricaulis at the 100, 200, and 300 mg/kg doses has shown CNS depressant and anti-anxiety effects in mice models.

Ranolazine Interacts Antagonistically with Some Classical Antiepileptic Drugs-An Isobolographic Analysis.

Ranolazine, an antianginal and antiarrhythmic drug blocking slow inactivating persistent sodium currents, is described as a compound with anticonvulsant potential. Since arrhythmia often accompanies seizures, patients suffering from epilepsy are frequently co-treated with antiepileptic and antiarrhythmic drugs. The aim of this study was to evaluate the effect of ranolazine on maximal-electroshock (MES)-induced seizures in mice as well as interactions between ranolazine and classical antiepileptic drugs in this model of epilepsy. Types of pharmacodynamic interactions were established by isobolographic analysis of obtained data. The main findings of the study were that ranolazine behaves like an antiseizure drug in the MES test. Moreover, ranolazine interacted antagonistically with carbamazepine, phenytoin, and phenobarbital in the proportions of 1:3 and 1:1. These interactions occurred pharmacodynamic, since ranolazine did not change the brain levels of antiepileptic drugs measured in the fluorescence polarization immunoassay. Ranolazine and its combinations with carbamazepine, phenytoin, and phenobarbital did not impair motor coordination evaluated in the chimney test. Unfortunately, an attempt to conduct a passive avoidance task (evaluating long-term memory) resulted in ranolazine-induced delayed lethality. In conclusion, ranolazine exhibits clear-cut anticonvulsant properties in the MES test but interacts antagonistically with some antiepileptic drugs. The obtained results need confirmation in clinical studies. The mechanisms of ranolazine-induced toxicity require specific explanation.

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

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

Trimetazidine, an Anti-Ischemic Drug, Reduces the Antielectroshock Effects of Certain First-Generation Antiepileptic Drugs.

Trimetazidine (TMZ), an anti-ischemic drug for improving cellular metabolism, is mostly administered to patients with poorly controlled ischemic heart disease (IHD). Since IHD is considered the most frequent causative factor of cardiac arrhythmias, and these often coexist with seizure disorders, we decided to investigate the effect of TMZ in the electroconvulsive threshold test (ECT) and its influence on the action of four first-generation antiepileptic drugs in the maximal electroshock test (MES) in mice. The TMZ (up to 120 mg/kg) did not affect the ECT, but applied at doses of 20–120 mg/kg it decreased the antielectroshock action of phenobarbital. The TMZ (50–120 mg/kg) reduced the effect of phenytoin, and, when administered at a dose of 120 mg/kg, it diminished the action of carbamazepine. All of these revealed interactions seem to be pharmacodynamic, since the TMZ did not affect the brain levels of antiepileptic drugs. Furthermore, the combination of TMZ with valproate (but not with other antiepileptic drugs) significantly impaired motor coordination, evaluated using the chimney test. Long-term memory, assessed with a passive-avoidance task, was not affected by either the TMZ or its combinations with antiepileptic drugs. The obtained results suggest that TMZ may not be beneficial as an add-on therapy in patients with IHD and epilepsy.

Influence of methadone on the anticonvulsant efficacy of valproate sodium gabapentin against maximal electroshock seizure in mice by regulation of brain MDA TNF-α.

Methadone is the most frequently used opioid therapy worldwide, with controversial effects on oxidative stress homeostasis. This study investigated the effects of intraperitoneal (i.p.) co-administration of methadone (0.1, 0.3, 1, and 3 mg/kg) and valproate sodium (300 mg/kg) or gabapentin (50 mg/kg) in the mice maximal electroshock (MES)-induced seizure model. The adverse effect of drugs was assessed using the chimney test. The levels of tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA) contents were measured in mice brains after a single seizure. Administration of methadone alone resulted in a significant reduction in the duration of hind limb extension (HLE) than that in the control group. Methadone pretreatment at doses of 0.1 and 0.3 mg/kg i.p. decreased, and at doses of 1 and 3 mg/kg i.p. had an increasing effect on anticonvulsant efficacy of gabapentin. Pretreatment with all doses of methadone significantly decreased the valproate anticonvulsive efficacy. At doses of 1 and 3 mg/kg i.p. methadone per se increased brain MDA levels after MES-induced seizure. Administration of methadone (0.3 mg/kg i.p.) enhanced and at 3 mg/kg decreased gabapentin effect on brain MDA level, but their co-treatment did not lead to further increase in MDA. Methadone at 0.3–3 mg/kg enhanced the effect of sodium valproate on MDA levels in the brain, but at all doses significantly potentiated its effect on brain TNF-α levels. The drugs did not produce any side effects on motor coordination in experimental animals. In conclusion, methadone showed different effects on anticonvulsant actions of gabapentin and valproate through regulation of brain levels of MDA and TNF-α.

Anticonvulsant like Activity of Silybin Correlates Blood Glucose Levels in PTZ induced Chemo-convulsive Rats

The objective of this study is to observe the impact of Silybin (SIB) on the link between blood glucose and seizure prevention in chemo-convulsive rats. To produce seizures, adult male rats were administered with pentylenetetrazol (PTZ-105 mg/kg i.p.) at the CD97 dose. SIB (100 mg/kg.p.o.) was administered for two weeks. The animals were subjected to chemo convulsions on the 14th day, and the effectiveness of SIB to reduce clonus-type chemo convulsions (CC) was recorded, as well as blood glucose levels measured with a one-touch glucometer.Morphometric analysis and chimney tests were evaluated to know the neurotoxic profile of SIB, while actophotometer, rota rod, and hole board tests were used for behavioural analysis.Pre-treatment with SIB (100 mg/kg p.o) resulted in a significant delay in the onset of CC (*p<0.05) and a significant reduction in the duration of CC (**p<0.01) as compared to controls. The acute dose of SIB significantly reduced blood glucose levels. In addition, acute administration of SIB considerably lowered blood glucose levels and promoted body weight of animals whereas chimney tests, indicating that, non-neurotoxic profile of silybin to animals. Additionally, behavioural tests revealed that no significant alterations in muscular coordination, locomotion, or anxious behaviour were noticed in animals. In summary; results reveal that the NDH + PTZ groups had considerably greater hyperglycemia levels, which is reflected in the early onset and longer duration of chemo convulsions in rat. SIB treatment, However, there was a significant reduction in elevated glucose levels, as well as a considerable delay in the onset and duration of seizures, demonstrating the relationship between blood glucose and Anticonvulsant like activity against chemo convulsive episodes. Keywords: Silybin, Hyperglycaemia, Pentylenetetrazol, chemo convulsions, seizure protection

Effect of caffeine on the anticonvulsant action of pregabalin against electroconvulsions in mice.

Experimental data indicate that caffeine (CAF) can reduce the anticonvulsant activity of antiepileptic drugs (AEDs) in animal models of seizures. The purpose of the current study was to examine the effect of CAF on the protective action of pregabalin (PGB) against electroconvulsions in mice. Maximal electroshock seizure (MES) test was used in the current study. In addition, the combined treatment with CAF and PGB was assessed in the passive avoidance task (long-term memory) and the chimney test (motor coordination). Drugs were injected intraperitoneally (ip) as single injections. CAF was administered at doses reported to compromise the anticonvulsant action of AEDs in mice. CAF at a dose of 23.1mg/kg reduced the anticonvulsant action of PGB in the MES test. The brain concentration of PGB was not significantly changed by CAF and vice versa. In the chimney test, CAF (23.1mg/kg) protected mice against PGB-induced motor coordination impairment. Regarding seizure control, it might be suggested that patients with epilepsy treated with PGB should avoid taking CAF. The estimated total brain concentration of PGB and CAF does not suggest a pharmacokinetic interaction as an explanation for these results.

Evaluation of Anti-depressant, Anti-anxiety and Muscle Relaxant Activity of Hydroalcoholic Extract of Aerva javanica Roots

Aims: To evaluate anti-depressant, anti-anxiety and muscle relaxant activity of hydroalcoholic extract of Aerva javanica roots in various experimental animal models.
 Study Design: Animal study.
 Place and Duration of Study: The study was conducted in Bilwal Medchem and Research Laboratory, Jaipur from July 2021-August 2021.
 Methodology: The root powder of Aerva javanica was extracted with hydroalcoholic solvent (70% ethanol). The hydroalcoholic extract at three doses 100 mg/kg, 200 mg/kg, and 400 mg/kg was checked for anti-depressant and skeletal muscle relaxant activity in the experimental animal models. To determine the anti-depressant activity tail suspension test, locomotor activity, open field test, and MAO inhibitor assay were done; to determine the anti-anxiety activity hole board test was used; and to determine the skeletal muscle relaxant activity rotarod test, grip strength test, and chimney test were done.
 Results: In the tail suspension test, the extract at 200 mg/kg and 400 mg/kg significantly reduced the duration of immobility compared to normal control (p<0.0001). The extract at dose 400 mg/kg significantly reduced MAO-A and MAO-B activity compared to the normal control group (p<0.01 and p<0.05, respectively). The extract at 200 mg/kg and 400 mg/kg were able to decrease locomotor activity in actophotomoter and increased time spent in centre square in open field test revealing the sedative effect of the extract. In hole board test, the extract at dose 400 mg/kg and 200 mg/kg significantly increased number of head dip count (p<0.0001 and p<0.001) respectively. In the rotarod test, the extract at dose 200 and 400 mg/kg decreased the time spent on the rotating rod (p<0.0001), compared to normal control. Similarly, in the grip strength test the extract at dose 200 and 400 mg/kg decreased the time spend on suspended wire revealing the skeletal muscle relaxant property of the test extract.
 Conclusion: Based on the result, it can be concluded that the extract exert anti-depressant, anti-anxiety and skeletal muscle relaxant like activity in the experimental rat which was hypothesized to be attributed to the flavonoids present in the hydroalcoholic root extract of Aerva javanica.

Preliminary phytochemical screening, acute toxicity and effect of Albuca amoena extracts on the central nervous system

Introduction: Albuca amoena is a Moroccan-Algerian endemic medicinal plant with various implications. The aim of this study is to identify phytochemical compounds of the plant, check its acute toxicity, and test its anti-depressive, anxiolytic, and analgesic effects on the central nervous system (CNS). Methods: The estimation of chemical compounds was carried out according to coloring and precipitation reactions. The Organization of Economic Cooperation and Development guidelines 423 and 402 made it possible to verify the acute toxicity of the plant orally and dermally. The sedative activity was performed according to 4 tests: rotarod, hole-board, traction, and chimney tests. The anti-depressive, anxiolytic, and analgesic effects were evaluated by forced swimming, light/dark, and writhing tests, respectively. Results: The phytochemical analysis showed that A. amoena contained a mixture of phytochemical compounds like terpenes, alkaloids, and polyphenols. According to the acute toxicity tests, the lethal dose of 50% (LD50) of A. amoena hydroalcoholic extract was between 300 and 2000 mg/kg orally and higher than 2000 mg/kg dermally. Moreover, the result of the behaviour tests of sedative and analgesic activities revealed that A. amoena hydroalcoholic extract exerted positive effects on the CNS. Conclusion: These results show the anti-depressive, anxiolytic, and analgesic effects of the bioactive substances present in A. amoena on the CNS and provide access to further investigations to highlight the main compounds of this plant and their mechanisms of actions.

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

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

Potential benefits of gallic acid as skeletal muscle relaxant in animal experimental models.

Background and ObjectiveMany natural bioactive chemicals have been shown to have functional activity, suggesting that they could be useful in the treatment and management of a wide range of chronic conditions. Flavonoids, which include gallic acid (GA), are the most abundant polyphenols found in nature. Skeletal muscle relaxants are drugs that reduce undesired spasms while maintaining awareness and reflexes unaffected. The purpose of this investigation was to determine if GA has any skeletal muscle relaxant properties in experimental animal models.Materials and MethodsThe muscle relaxant activity of three dosages of GA (5, 10, and 20 mg/kg) was compared to that of normal diazepam (5 mg/kg) utilizing climbing, chimney, and modified Kondziela's inverted tests. An analysis of variance (ANOVA) and a post-ANOVA Tukey multiple comparisons test were used to assess the data.ResultsAnimals given 10 and 20 mg/kg of GA had a great deal of trouble climbing up the chain, presumably because their muscles were relaxed. Similarly, rats given a high dose of GA (20 mg/kg) had a significantly (P < 0.05) longer response time in the chimney test, indicating a lack of attention and slowed muscle tone, resulting in problems with motor coordination. In inverted testing, animals given a high dose of GA had a significantly (P < 0.01) reduced holding capacity on the mesh for a longer period of time. A decrease in holding time is caused by a decrease in muscular contraction. The low dose of GA, on the other hand, failed to show muscle relaxant effect in any of the three models.ConclusionsAs a conclusion, our data show that GA has a dose-dependent skeletal muscle relaxant effect when administered orally to mice.

Effect of Ellagic Acid on Seizure Threshold in Two Acute Seizure Tests in Mice.

Ellagic acid (EA) is a natural dietary polyphenol that has many beneficial properties, including anti-inflammatory, antioxidant, antiviral, antibacterial, and neuroprotective effects. Studies have revealed that EA may modulate seizure activity in chemically induced animal models of seizures. Therefore, the aim of the present study was to investigate the effect of EA on the seizure threshold in two acute seizure tests in male mice, i.e., in the intravenous (i.v.) pentylenetetrazole (PTZ) seizure test and in the maximal electroshock seizure threshold (MEST) test. The obtained results showed that EA (100 mg/kg) significantly elevated the threshold for both the first myoclonic twitch and generalized clonic seizure in the i.v. PTZ seizure test. At the highest dose tested (200 mg/kg), EA increased the threshold for tonic hindlimb extension in the MEST test. EA did not produce any significant changes in motor coordination (assessed in the chimney test) or muscular strength (investigated in the grip-strength test). The plasma and total brain concentration-time profiles of EA after intraperitoneal and oral administration were also determined. Although further studies are necessary to confirm the anticonvulsant activity of EA, our findings suggest that it may modulate seizure susceptibility in animal models.

Anti-depressant, Anxiolytic, and the Muscle Relaxant Activity of Hydroalcoholic Extract of Cissampelos pareira Linn. Leaves.

The ethnopharmacological relevance suggests that the ethnic minorities of India use leaves of Cissampelos pareira L. as a traditional medicine for curing various psychopharmacological disorders. To evaluate anti-depressant, anxiolytic, and muscle relaxant activity of hydro-alcoholic extract of Cissampelos pareira. Leaves of Cissampelos pareira were extracted using a hydro-alcoholic solvent. The safety of hydro-alcoholic extract of Cissampelos pareira was assessed by acute oral toxicity (OECD 423). The anti-depressant activity was measured using open field test, locomotor test, despair swim test, tail suspension test. The anxiolytic activity was assessed using elevated plus maze and hole board test, and skeletal muscle relaxant activity was assessed using rotarod, grip strength, chimney, and inclined plane test. No moribund status or mortality was observed in experimental mice up to 2000 mg/kg dose of Cissampelos pareira hydro-alcoholic extract (CPHE). In the open field and actophotometer tests, CPHE 200 and 400 mg/kg treated mice significantly abridged ambulation, number of central squares crossed, total locomotion, and depicted less coordinated movements, and in despair swim and tail suspension tests, CPHE 400 mg/kg treated mice significantly decreased duration of immobility and increased number of climbing, confirming its anti-depressant effect. In an elevated plus-maze test, CPHE 200 and 400 mg/kg increased the open arm exploration, while in the hole board test, CPHE 400 mg/kg treated rats augmented the number of head dips, depicting its anxiolytic effect. In rotarod, grip strength, and inclined plane test, CPHE 400 mg/kg treated mice decreased the fall-off time on a rotating rod, suspended wire, or inclined plane. Furthermore, in the chimney test, treatment with CPHE 400 depicted less coordinated movements in mice; the mice of this group took more time to leave the cylinder, depicting its skeletal muscle relaxant effect. Based on the results, of this study, it can be concluded that CPHE 400 mg/kg exhibits strong anti-depressant, anxiolytic, and muscle relaxant effects, justifying its traditional uses.

Effect of acute and chronic exposure to lovastatin on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Numerous studies indicate neuroprotective activity of statins, commonly used cholesterol lowering drugs in epilepsy and several other neurological diseases. Promising anti-convulsant and neuroprotective effects of statins, attributed to their anti-excitotoxic and anti-inflammatory action were reported in several animals’ seizure models.To determine the effects of acute (single) and chronic (once daily for 7 consecutive days) administration of lovastatin on the protective activity of four classical antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin and valproate in the mouse maximal electroshock seizure model.Seizure activity (maximal electroconvulsions) in mice were generated by alternating current delivered via ear-clip electrodes. Adverse-effect profile of lovastatin combinations with the tested antiepileptic drugs was assessed in the chimney test (motor performance). Total brain concentrations of antiepileptic drugs were evaluated with the fluorescence polarization immunoassay technique as a measure of the pharmacokinetic interaction between drugs.Lovastatin administered acutely or chronically (5–20 mg/kg) did not significantly affect the threshold for electroconvulsions in mice. Acute lovastatin (10 mg/kg) significantly enhanced the anticonvulsant effect of valproate, which was accompanied with a 34% significant increase in total brain concentration of valproate. Acute lovastatin in combination with phenytoin impaired motor performance by notably decreasing the TD50 value of phenytoin. Chronic lovastatin (10 mg/kg) markedly enhanced the anticonvulsant potential of phenytoin.Acute lovastatin increased anticonvulsant action of valproate but also significantly raised level of valproate in brain after combined administration suggesting pharmacokinetic nature of interaction. The combinations of chronic lovastatin combined with phenytoin can potentially enhance the anticonvulsant potency of phenytoin.

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

BackgroundDue to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice.Materials and methodsAs a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry.ResultsSotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study.ConclusionSotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

Acute and chronic treatment with moclobemide, a reversible MAO-inhibitor, potentiates the antielectroshock activity of conventional antiepileptic drugs in mice

BackgroundDue to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin. MethodsThe effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. ResultsGiven acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5‐75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment. ConclusionsAcute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards.