Convulsions In Mice Research Articles

The impact of piperazine and antipsychotic co-exposures and CB1 blockade on the effects elicited by AMB-FUBINACA, a synthetic cannabinoid, in mice

Background & purposeThe constant emergence and broad toxicological effects of synthetic cannabinoids create a discernible public health threat. The synthetic cannabinoid AMB-FUBINACA (AMB-FUB) is a potent agonist at the CB1 receptor and has been associated with numerous fatalities. Synthetic cannabinoids are commonly abused alongside other drugs and medications, including a "party pill" drug, para-fluorophenylpiperazine (pFPP), and the antipsychotic risperidone. This research aimed to investigate the mechanisms underpinning AMB-FUB toxicity and the impact of clinically relevant co-exposures in vivo. Experimental approachMale and female C57Bl/6 mice received a single dose of AMB-FUB (3 or 6 mg kg−1), pFPP (10 or 20 mg kg−1) or vehicle intraperitoneally. Mice were co-exposed to AMB-FUB (3 mg kg−1) and pFPP (10 mg kg−1) or risperidone (0.5 mg kg−1) to investigate these drug combinations. To study receptor-dependency and potential rescue of AMB-FUB toxicity, rimonabant (3 mg kg−1) was administered both pre- and post-AMB-FUB. Adverse effects caused by drug administration, including hypothermia and convulsions, were recorded. Key resultsAMB-FUB induced CB1-dependent hypothermia and convulsions in mice. The combination of AMB-FUB and pFPP significantly potentiated hypothermia, as did risperidone pre-treatment. Interestingly, risperidone provided significant protection from AMB-FUB-induced convulsions in female mice. Pre- and post-treatment with rimonabant was able to significantly attenuate both hypothermia and convulsions in mice administered AMB-FUB. Conclusion & implicationsFactors such as dose, CB1 signalling, and substance co-exposure significantly contribute to the toxicity of AMB-FUBINACA. Mechanistic understanding of synthetic cannabinoid toxicity and fatality can help inform overdose treatment strategies and identify vulnerable populations of synthetic cannabinoid users.

PEG300 Protects Mitochondrial Function By Upregulating PGC-1α to Delay Central Nervous System Oxygen Toxicity in Mice.

Central nervous system oxygen toxicity (CNS-OT) is a complication of hyperbaric oxygen (HBO) treatment, with limited prevention and treatment options available. In this study, we aimed to explore the effect of polyethylene glycol 300 (PEG300) on CNS-OT and underlying mechanisms. Motor and cognitive functions of mice in normobaric conditions were evaluated by Morris water maze, passive active avoidance, and rotarod tests. HBO was applied at 6 atmospheres absolute (ATA) for 30min after drug administration. The latency period of convulsion in mice was recorded, and hippocampal tissues were extracted for biochemical experiments. Our experimental results showed that PEG300 extended the convulsion latencies in CNS-OT mice, reduced oxidative stress and inflammation levels in hippocampal tissues. Furthermore, PEG300 preserved mitochondrial integrity and maintained mitochondrial membrane potential in hippocampal tissue by upregulating Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α). This protective effect was enhanced following the administration of ZLN005, an agonist of PGC-1a. Hence, our study suggests that PEG300 might exert protective effects by upregulating PGC-1α expression and preserving mitochondrial health, offering promising prospects for CNS-OT treatment.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

The neutral CB1 antagonist AM6527 reduces ethanol seeking, binge-like consumption, reinforcing, and withdrawal effects in male and female mice.

Alcohol use disorder (AUD) is a debilitating physiological and psychiatric disorder which affects individuals globally. The current pharmacological interventions to treat AUD are limited, and hence there is an urgent need for a novel pharmacological therapy which can be effective and safe across the population. We aimed to investigate a novel neutral cannabinoid receptor-1 (CB1R) antagonist, AM6527, in several preclinical models of ethanol consumption using male and female C57BL6/J mice. Independent groups of male and female mice were subjected to repeated cycles of drinking in the dark (DID), or intermittent access to alcohol (IAA) procedures. Twenty minutes prior to ethanol access in each procedure, animals were treated with intraperitoneal injections of either 1, 3, and 10 mg/kg of AM6527 or its respective vehicle. Acamprosate (100, 200, 300, and 400 mg/kg) or its respective vehicle was used as a positive control. Separate groups of male mice were subjected to a chain schedule of ethanol reinforcement to gain access to ethanol wherein completion of a fixed interval (FI; 5 min) schedule (link 1: "Seeking") was reinforced with continuous access to ethanol (fixed ratio; FR1) for up to 1.8 g/kg (link 2: "consumption"). All the animals were treated with 1, 3, and 10 mg/kg of AM6527 or its respective vehicle 20 mins prior to the start of the FI chain of the procedure. Separately, AM6527 was also evaluated in male and female mice undergoing acute ethanol withdrawal following 8 weeks of intermittent or continuous access to 20% ethanol drinking. In both DID and IAA procedures, AM6527 reduced ethanol consumption in a dose-related manner in both male and female mice. AM6527 produced no tolerance in the DID procedure; mice treated with 3 mg/kg of AM6527 for 3 weeks continuously drank significantly smaller amounts of ethanol as compared to vehicle-treated mice over a period of three DID cycles. Moreover, in the IAA procedure, AM6527 caused an increase in water intake over the 24-h period. Acamprosate transiently reduced ethanol intake in male mice in both the DID and the IAA procedures but failed to produce any significant effect in female mice. AM6527 also produced a decrease in the FI responding ("ethanol seeking") in animals trained to self-administer ethanol. Lastly, AM6527 mitigated neurological withdrawal signs, i.e., handling induced convulsions(HIC) in mice undergoing acute ethanol withdrawal. Current findings support previous studies with CB1R neutral antagonist in reducing voluntary ethanol intake and seeking behavior. Based on results shown in this work, AM6527 can be developed as a first in class CB1R neutral antagonist to treat AUD in both males and females.

Differential Pharmacokinetic Interplay of Atorvastatin on Lacosamide and Levetiracetam on Experimental Convulsions in Mice.

The beneficial effects of statins, other than their hypocholesterolemia role, have been well documented, however, their use as an adjuvant drug with other antiseizure drugs, in the treatment of epilepsy is poorly understood. This study aimed to investigate the symbiotic effect of ATOR along with either lacosamide (LACO) or levetiracetam (LEVE) on experimentally induced epilepsy (Maximal electro-shock-MES or pentylenetetrazol- PTZ) in mice models. Conventional elevated-maze (EPM) and rotarod methods were performed to observe the behavioral effects. In both the animal models, we found that co-administration of ATOR along with LACO showed a significant reduction in hind-limb extension (HLE) and clonic convulsion (CC) responses, respectively, but not in the ATOR+LEVE treated group. Intriguingly, comparable Straub tail response and myoclonic convulsion as the diazepam (DIA) group were observed only in the ATOR+LACO treated group. Moreover, a significant muscle-grip strength was observed in both groups. Also, pharmacokinetic analysis has indicated that the mean plasma concentration of ATOR peaked at 2ndhr in the presence of LACO but marginally peaked in the presence of LEVE. An Insilico study has revealed that ATOR has a higher binding affinity toward neuronal sodium channels. This study has demonstrated that the plasma concentration of ATOR was potentiated in the presence of LACO, but not in the presence of LEVE and it has provided significant protection against both the electro and chemo-convulsive models in mice. This could be due to the symbiotic pharmacokinetic interplay of ATOR with LACO, and possibly, this interplay may interfere with sodium channel conductance.

Evaluation of the anticonvulsant activity of ethanol leaf extract of Panicum maximum in pentylenetetrazole and strychnine induced seizure in mice.

Epilepsy is a chronic neurological condition affecting around 50 million people worldwide. This study evaluated the anticonvulsant effect of Panicium maxmium in pentylenetetrazole (PTZ) and strychnine (STN) induced convulsions in mice. For each model, 25 mice were divided into five groups; group 1 received 10 ml/kg distilled water, groups 2-4 received 100 mg/kg, 200 mg/kg and 400 mg/kg of extract p.o respectively. Group 5 received 3 mg/kg of diazepam p.o. Convulsion was induced intraperitoneally using PTZ and STN, thirty minutes after the extract was administered. The onset of myoclonic, tonic-clonic seizure, time of death within 60 minutes of PTZ and STN administration were monitored. Data were statistically analyzed using one-way ANOVA followed by Dunnet’s comparison tests. In STN-induced seizure model, 100 mg/kg of P. maximum exhibited a significant (p < 0.001) anticonvulsant activity by delaying myoclonic seizure onset in mice when compared to the control. Significant (p < 0.001) activity was also observed in the onset of tonic clonic seizure at same dose when compared to control. In PTZ-induced seizure model, 200 mg/kg exhibited more significant (p < 0.001) activity followed by 100 mg/kg (p < 0.05) by delaying myoclonic seizure onset in mice when compared to the control. Significant (p < 0.001) activity were observed in tonic clonic phase at same doses respectively. The different doses administered couldn’t protect the mice from death. Diazepam, standard drug used, protected all the animals without any signs of convulsions. The results provide evidence that the extract possesses anticonvulsant activity.

SYNTHESIS AND ANTICONVULSANT ACTIVITY OF 4-THIAZOLIDINONE ANALOGUES OF 2-AMINO-5-CHLOROPYRIDINE

The synthesis of 4-thiazolidinones of 2-amino-5-chloropyridine was performed by novel method of stirring involving the cyclocondensation of the appropriate Schiffs bases (2a–c) with thioglycolic acid, followed by the addition of zinc chloride in the presence of molecular sieves. Characterization of the synthesized compounds, determination of purity and identity of the compounds using following spectroscopic and chromatographic techniques- Solubility,Thin Layer Chromatographic studies, Ultra-Violet studies,Rotational and vibrational studies (FT-IR), 1H-NMR studies. The compounds were investigated for their Anticonvulsant activity by isoniazid induced convulsions in mice model.Compound3-(5-chloropyridin-2-yl)-2-(4-fluorophenyl) thiazolidin-4-one(3c)was found to be the most activeand compound 3-(5-chloropyridin-2-yl)-2-(2-hydroxyphenyl) thiazolidin-4-one (3a) was found to be less active among the tested compound according to pharmacological evaluation exhibited anticonvulsant activity.

Ameliorative effects of Albizia adianthifolia aqueous extract against pentylenetetrazole-induced epilepsy and associated memory loss in mice: Role of GABAergic, antioxidant defense and anti-inflammatory systems

Albizia adianthifolia (Schumach.) (Fabaceae) is a medicinal herb used for the treatment of epilepsy and memory impairment. This study aims to investigate the anticonvulsant effects of Albizia adianthifolia aqueous extract against pentylenetetrazole (PTZ)-induced spontaneous convulsions in mice; and determine whether the extract could mitigate memory impairment, oxidative/nitrergic stress, GABA depletion and neuroinflammation. Ultra-high performance liquid chromatography/mass spectrometry analysis was done to identify active compounds from the extract. Mice were injected with PTZ once every 48 h until kindling was developed. Animals received distilled water for the normal group and negative control groups, doses of extract (40, 80, or 160 mg/kg) for the test groups and sodium valproate (300 mg/kg) for the positive control group. Memory was measured using Y maze, novel object recognition (NOR) and open field paradigms, while the oxidative/nitrosative stresses (MDA, GSH, CAT, SOD and NO), GABAergic transmission (GABA, GABA-T and GAD) and neuro-inflammation (TNF-α, IFN-γ, IL- 1β, and IL-6) were determined. Brain photomicrograph was also studied. Apigenin, murrayanine and safranal were identified in the extract. The extract (80–160 mg/kg) significantly protected mice against seizures and mortality induced by PTZ. The extract significantly increased the spontaneous alternation and the discrimination index in the Y maze and NOR tests, respectively. PTZ kindling induced oxidative/nitrosative stress, GABA depletion, neuroinflammation and neuronal cells death was strongly reversed by the extract. The results suggest that the anticonvulsant activity of Albizia adianthifolia extract is accompanied by its anti-amnesic property, and may be supported by the amelioration of oxidative stress, GABAergic transmission and neuroinflammation.

Evaluation of Flurbiprofen's anticonvulsant properties in pilocarpine-induced convulsions in mice

Background: Flurbiprofen is a nonsteroidal anti-inflammatory drug, it has non-selective COX inhibition properties, some NSAIDS has an anticonvulsant effect and benefit as an analgesic in seizure patient.
 Objective: we aimed to evaluate the possible anticonvulsant effect of flurbiprofen in mice.
 Methods: We used 25 mature male mice for our study, the mice were divided into five groups, then to prevent peripheral cholinergic activation, mice in all groups were injected intraperitoneally with atropine sulphate (1 mg/kg) subcutaneously one hour after dosing. Seizures were induced ten minutes later with a 300 mg/kg i.p. injection of pilocarpine. After the pilocarpine injection, the animals were monitored for 1 hour. seizures severity was tested by the Racine scale.
 Results: flurbiprofen at 0, 10, 20 and 40 mg/kg orally causes a significant decrease in the onset of convulsion and a considerable decrease in the duration of convulsion in comparison with the control group. Flurbiprofen at 20 and 40 mg/kg orally inhibited seizure scores in pilocarpine-treated mice in a dose-dependent manner. High-dose of flurbiprofen (40 mg/kg) significantly reduced seizure scores, similar to diazepam.
 Conclusion: flurbiprofen has potential anticonvulsant properties in mice models, further study must be conducted to assess the primary mechanism of action.

Evaluation of the anticonvulsant properties of flurbiprofen in pilocarpine-induced convulsions in mice

Background and objective: Flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), possesses non-selective COX inhibition properties. Some NSAIDs exhibit anticonvulsant effects and provide analgesic benefits for seizure patients. This study aimed to assess the potential anticonvulsant action of flurbiprofen in mice. Methods: Twenty-five mature male mice were divided into five groups for the study. To prevent peripheral cholinergic activation, mice in each group were injected intraperitoneally with atropine sulfate (1 mg/kg) subcutaneously one hour after dosing. Seizures were induced ten minutes later using an intraperitoneal injection of 300 mg/kg of pilocarpine. Following pilocarpine injection, the animals were monitored for 1 hour. Seizure severity was assessed using the Racine scale. Results: Oral administration of flurbiprofen at doses of 0, 10, 20, and 40 mg/kg resulted in a significant decrease in convulsion onset and a substantial reduction in convulsion duration compared to the control group. Flurbiprofen at 20 and 40 mg/kg inhibited seizure scores in pilocarpine-injected mice in a dose-dependent manner. A high dose of flurbiprofen (40 mg/kg) significantly reduced the duration of convulsions, delayed convulsion onset, and decreased seizure scores in mice (p <0.05). Conclusions: Flurbiprofen exhibits significant dose-dependent anticonvulsant activity. Further studies are necessary to determine the primary mechanism of action.

Xanthohumol Alleviates Epileptic Seizures in Pentylenetetrazol-Induced Convulsions in Mice by Regulating Inflammation and Oxidative Stress

Background: Epilepsy is a prevalent neurobehavioral disorder, which affects more the 50 million individuals worldwide. It is characterized by neuron hyperexcitability mediated by repetitive convulsions. The current investigation was planned to study the therapeutic properties of the xanthohumol against pentylenetetrazol (PTZ)-induced convulsions in mice by regulating inflammation and oxidative stress. Methods: The 70 mg/kg of PTZ was administered (i.p.) to the mice for stimulating the epileptic seizures and 20 mg/kg of xanthohumol was pre-treated by oral route before the 30 min of PTZ administration. The mice were observed closely for 30 min after the PTZ treatment to detect the onset and duration of clonic/tonic convulsions and mortality. The status of glutamate, GABA, dopamine, Na+K+ATPase, and Ca+ATPase were quantified using respective kits. The level of MDA, NO, GSH, and SOD were detected using standard methods. The levels of inflammatory biomarkers such as COX-2, TNF-α, NF-κB, TLR-4, and IL-1β in the brain tissues were inspected using kits. The histopathological analysis was done on the brain tissues. Results: The xanthohumol significantly (p < 0.05) reduced the onset and duration of convulsions, mortality, and behavioral changes in the epileptic mice. The levels of COX-2, TNF-α, NF-κB, TLR-4, and IL-1β were significantly (p < 0.05) decreased in the epileptic mice by 20 mg/kg xanthohumol treatment. The levels of MDA and NO was reduced and GSH and SOD were increased by the 20 mg/kg xanthohumol treatment. The 20 mg/kg xanthohumol significantly (p < 0.05) decreased the glutamate and improved the dopamine, GABA, Na+K+ATPase, and Ca+ATPase in the epileptic mice. The findings of histopathological studies revealed that 20 mg/kg xanthohumol decreased the inflammatory signs and pyknosis in the brain tissues. Conclusion: Pre-treatment with the 20 mg/kg xanthohumol ameliorates the PTZ-triggered seizures in a mice model through its antioxidant and anti-inflammatory potentials. Hence, xanthohumol can be a promising antiepileptic candidate in the future to treat epilepsy.

INTRANASAL FORMULATION AND CHARACTERIZATION OF CHITOSAN MICROSPHERE FOR IMPROVING IN VITRO MUCOADHESION, RESIDENCE TIME AND ABSORPTION RATE OF PREGABALIN

Objective: Chitosan-based pregabalin microsphere (CBPM) formulation was prepared to improve in vitro mucoadhesion and absorption of pregabalin via intranasal administration. Methods: The CBPM formulations were prepared using the inotropic gelation method and optimized using the Box-behnken design. The optimized CBPM formulation was physico-chemically characterized using scanning electron microscopy, thermal analysis, Fourier transform infrared spectrometry and powder x-ray diffraction. Additionally, the CBPM formulation was characterized for functional parameters such as in vitro mucoadhesion, in vitro drug release, ex vivo permeability across the sheep nasal mucosa and in vivo anticonvulsant activity in pentylenetetrazol (PTZ)-induced seizures model in mice. Results: The design-optimized CBPM exhibited a 91.45 % inclusion efficiency of pregabalin in the microspheres. The Physico-chemical analysis of the individual components and the optimized formulation confirmed the formation of CBPM. The in vitro mucoadhesion study revealed ~80% mucoadhesive of the CBPM to the sheep nasal mucosa. The in vitro dissolution profiles of CBPM was significantly higher (~97%) than that of pure pregabalin (~70%). The CBPM displayed a higher rate and extent of permeability (~90%) than pure pregabalin (~76%) across the sheep nasal mucosa. The in vivo anticonvulsant activity showed that intranasal administration of CBPM resulted in significant (P<0.01) protection against PTZ-induced convulsions in mice. Conclusion: The chitosan-based microsphere intranasal formulation could be employed as promising delivery for rapid pregabalin absorption.

Participation of Brain Receptors in the Mechanism of Anticonvulsant Action of a New 4-Benzoylpyridine Oxime Derivative GIZH-298

The aim of the work was to study the involvement of glutamate, dopamine and serotonin receptors in the mechanism of the anticonvulsant action of the 4-benzoylpyridine oxime derivative (GIZh-298). After a single exposure to the cornea with maximum electric shock (MES) and subsequent tonic-clonic seizures, an increase in the density (Bmax) of NMDA receptors in the hippocampus by 27% and a decrease in the number of mGluII receptors (mGluR2/3) by 25% in the prefrontal cortex of the brain of rats are noted. At the same time, the number of 5-HT2A receptors in the prefrontal cortex did not change. GIZh-298 (60 mg/kg) with a single application inhibits convulsive reactions, but does not affect the quantitative changes induced by MES in glutamate receptors and does not affect them under normal conditions, without MES. In tests on mice, subchronic (5 days) corneal exposure to MES reduced the density (Bmax) of D2 receptors in the striatum by 17% and did not change this parameter in the prefrontal cortex. GIZh-298 (60 mg/kg/5 days) eliminates clonic-tonic convulsions in mice and prevents a decrease in the number of D2 receptors from striatal membranes, and also increases their number by 13% in mice without MES in the same structure. The data obtained indicate significant changes in the functional activity of NMDA, mGluII and D2 receptors in the brains of animals that suffered seizures. The anticonvulsant effects of GIZH-298 are accompanied by the restoration of the number of D2 receptors in the striatum..

Antiepileptic Effect of Neuroaid® on Strychnine-Induced Convulsions in Mice.

NeuroAid II, a folk Chinese Medicine, is currently used in Asia for the treatment of stroke. An experimental study demonstrated that NeuroAid enables neuronal cells to be more resistant to glutamate toxicity. This research was constructed to evaluate the efficacy of NeuroAid in the prevention of epilepsy (EP). Forty healthy adult male mice were used and divided into four groups (10 mice/group): normal control group; positive control group; NeuroAid-treated group (10 mg/kg); topiramate-treated group (10 mg/kg). The treatment continued for 7 days, and on the last day, EP was induced using strychnine at a dose of 2 mg/kg via intraperitoneal (ip) administration. Seizure severity, latency to the seizure onset, the number of seizures, and the duration of each seizure episode were observed for one hour. The death and protection rates over the next twenty-four hours were recorded. Brain specimens from surviving animals were extracted and examined pathologically for quantification of glutamate receptor (GluR) gene expression in the isolated hippocampus employing real-time PCR analysis. Treatment with NeuroAid resulted in a significant reduction in seizure severity, prolonged the onset of seizures, decreased the number and duration of episodes, reduced brain insult, and decreased mortality rate. Reductions in the gene expression of GluRs in the hippocampus with minor histopathological changes were observed in the NeruoAid- and topiramate-treated groups. It is concluded that NeuroAid has a potential antiepileptic effect (EP) with the ability to prevent convulsion through its effect on the glutamate receptor.

Lemon Balm (Melissa officinalis) Essential Oil Moderately Affects Strychnine-Induced and Pentylenetetrazol-Induced Convulsions —In Silico and In Vivo Studies

Epileptic seizures are a consequence of uncontrolled neuronal discharge and demand urgent and prolonged treatment. Due to a lack of potent and low-risk drugs that could prevent seizures, efforts are underway to discover new drugs, and plant metabolites are often considered valuable candidates in this search. Lemon balm ( Melissa officinalis L., Lamiaceae) is a world-renowned medicinal plant affecting central nervous system function. In this study, we aimed to examine whether the results from in silico modeling of the interactions of major lemon balm essential oil constituents with GABAA and glycine receptors correspond to in vivo results of the convulsions in mice induced by the application of either pentylenetetrazol (GABAA antagonistic) or strychnine (glycine receptor antagonist). While molecular docking experiments of essential oil constituents to the two receptors demonstrated the possibility of ligand–receptor interactions, no binding poses were scored highly, and as the in vivo effect of the essential oil on convulsions seems to be only moderate, the results of the in silico study seem not to contradict results obtained by in vivo models. Thus, we can say that molecular docking might be a useful tool in initial screening for active constituents of natural product mixtures and the potential prediction of their activity in models in vivo.

DOE based Formulation development and Evaluation of Niosomal dispersion of Pregabalin

Objective: The purpose of this study was to prepare pregabalin loaded niosomal dispersion for controlled release of drug and achieve therapeutic effect for longer duration than the available drug delivery. Methods: The niosome carriers were formulated using non-ionic surfactants and cholesterol ratio of 1:1. The effects of non-ionic surfactant and cholesterol on the average particle size and percent entrapment efficiency were studied. Optimization of the formulation was performed by factorial design using Design expert software 11.0. Results: Based on the solutions provided by the design expert software, the formulation resulted in the particle size of 490 nm and 92.4% EE as compared to the predicted values of 491.02nm for particle size and 90% EE. The optimized niosome carriers appeared as multilamellar vesicles, as evident by a scanning electron microscopy study. Anticonvulsant activity of the niosomal dispersion was determined by Pentylenetetrazol (PTZ) induced convulsions in mice. Pregabalin-loaded niosomal dispersion displayed a sustained and moderate anticonvulsant effect upto 24 h. Conclusion: Therefore, the present study revealed the possibility of using non-ionic surfactant niosomes as carrier systems for prolonged release of pregabalin.

Synthesis of Mesoionic 1-aryl-4-(phenyl/p-chlorophenyl)imidazo[2,1-b]thiazol-4-ones and Study of their Monoamine Oxidase, Succinate Dehydrogenase Inhibitory, Anti-convulsant, and Antibacterial Activity

1-Aryl-2-mercapto-4-(phenyl/p-chlorophenyl)imidazoles (Ia-j) were condensed with monochloroacetic acid to give 1-aryl-4-(phenyl/p-chlorophenyl)imidazo-2-mercaptoacetic acid (IIa-j). These acids were subsequently cyclized with an acetic anhydride-pyridine mixture to give a new fused ring mesoionic 1-aryl-4-(phenyl/p-chlorophenyl)imidazo[2,1-b]thiazol-1-3-ones (IIIa-j). These compounds possess AID50 values ranging from 500 to 1000 mg kg-1, inhibit monoamineoxidase (32-68%), and succinate dehydrogenase (28-55%) in vitro at a concentration of 2×10-4 M, and provide 20-60% protection against pentylenetetrazole induced convulsions in mice.

Glyphaea brevis (Spreng) Monachino (Tiliaceae) leaf fractions protect against pentylenetetrazole (PTZ)-induced convulsion in mice


 
 
 
 Purpose: To investigate the anticonvulsant effect of Glyphaea brevis leaf fractions using a pentylenetetrazole (PTZ)-induced seizure model in mice.
 Methods: Glyphaea brevis leaf methanol extract was partitioned using n-hexane and hydro-methanol (8:2). Seizure was assessed in terms of onset of myoclonic and tonic-clonic seizure, duration of seizure and frequency of seizure. The concentrations of glutathione of catalase, glutathione peroxidase, superoxide dismutase and malondialdehyde in the brain of the mice were also determined.
 Results: The administration of the different fractions of Glyphaea brevis leaf prior to induction of seizure with PTZ prolonged the latency of convulsion in mice as well as a significant (p < 0.05) decline in the intensity of convulsion was observed. In relation to the untreated mice, there was a rise in the levels of glutathione peroxidase, superoxide dismutase, and catalase in the brain, but a decrease in malondialdehyde levels.
 Conclusion: The study results show that the fractions of Glyphaea brevis leaf have anticonvulsive properties, proving that the plant’s use in folklore medicine for treating convulsion.
 
 
 

Electrophysiological Evidence for Anti-epileptic Property of Taurine.

Taurine, 2-aminoethanesulfonic acid, is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Several lines of evidence suggest that taurine may function as a potent inhibitory neuromodulator that regulate neuronal activity in many cerebral areas. Parenteral injection of kainic acid (KA), a glutamate receptor agonist, causes severe and stereotyped behavioral convulsions in mice and is used as a rodent model for human temporal lobe epilepsy. In the adult brain, inhibitory GABAergic interneurons modulate the activity of principal excitatory cells via their GABAA receptors and thus adjust excitatory output of neuronal circuits. The goal of this study was to examine the potential anti-convulsive effects of the neuro-active amino acid taurine, in the mouse model of limbic seizures. We used the glutamic acid decarboxylase (GAD) inhibitor isoniazid (100mg.kg-1, s.c.) which induces seizures by interfering with GABA synthesis through inhibition of GAD activity followed by kainic acid (5mg.kg-1, s.c.) a glutamate receptor agonist which is commonly used to induce limbic seizures.Using intracerebral recordings of field potentials found that taurine (43mg.kg-1, s.c.) had a significant anti-epileptic effect when injected prior to isoniazid and KA. Furthermore, injection of taurine to a mouse undergoing limbic seizure completely stopped burst population spikes and restored neuronal firing to its baseline. Therefore, taurine is potentially capable of treating seizure-associated brain damage.

The Role and Mechanism of AMIGO3 in the Formation of Aberrant Neural Circuits After Status Convulsion in Immature Mice.

Leucine rich repeat and immunoglobulin-like domain-containing protein 1 (Lingo-1) has gained considerable interest as a potential therapy for demyelinating diseases since it inhibits axonal regeneration and myelin production. However, the results of clinical trials targeted at Lingo-1 have been unsatisfactory. Amphoterin-induced gene and open reading frame-3 (AMIGO3), which is an analog of Lingo-1, might be an alternative therapeutic target for brain damage. In the present study, we investigated the effects of AMIGO3 on neural circuits in immature mice after status convulsion (SC) induced by kainic acid. The expression of both AMIGO3 and Lingo-1 was significantly increased after SC, with levels maintained to 20 days after SC. Following SC, transmission electron microscopy revealed the impaired microstructure of myelin sheaths and Western blot analysis showed a decrease in myelin basic protein expression, and this damage was alleviated by downregulation of AMIGO3 expression. The ROCK/RhoA signaling pathway was inhibited at 20 days after SC by downregulating AMIGO3 expression. These results indicate that AMIGO3 plays important roles in seizure-induced damage of myelin sheaths as well as axon growth and synaptic plasticity via the ROCK/RhoA signaling pathway.