Anticonvulsant Effects Research Articles

Poloxamer®s anchored with TAT enhance blood–brain barrier penetration of carbamazepine for the treatment of epilepsy: an in vivo study

Carbamazepine is a pharmacological medication commonly prescribed to treat epilepsy. Dose adjustments, poor bioavailability, and prolonged side effects present significant challenges associated with its use. Poloxamer micelles have demonstrated exceptional properties as nanocarriers for drug delivery. This research aimed to develop Poloxamer nanomicelles containing carbamazepine and assess their potential to cross the blood–brain barrier.Poloxamer 407 and P-85 micelles, anchored with TAT as a ligand and containing carbamazepine, were prepared. The morphology, entrapment efficiency, drug release, stability, and toxicity of nanomicelles were examined, along with animal studies conducted to evaluate their anticonvulsant effects. The distribution of carbamazepine-Poloxamer in the brain and plasma was assessed.The results indicated the successful formation of spherical nanomicelles with an average size of less than 100 nm, and carbamazepine was effectively incorporated into the micelles. Formulations composed of mixtures of Poloxamer exhibited a high encapsulation efficiency of approximately 92.1% and remained stable for three months. A sustained release of carbamazepine was observed for up to 72 h. The anticonvulsant effect of carbamazepine-loaded nanomicelles in mice was found to be significantly greater than that of those treated with carbamazepine solution, with the effect increasing by approximately tenfold. Compared to free carbamazepine, the carbamazepine-loaded nanomicelles exhibited a 5.5-fold increase in the brain targeting index, with no toxicity observed in mice treated with these nanomicelles. These findings suggest that Poloxamer micelles represent a promising nanoscale, controlled-release delivery system that is free from toxicity and can enhance the penetration of carbamazepine into the brain while improving its anticonvulsant activity.Graphical

Rauvolfia vomitoria phenol extract relieves pentylenetetrazol-induced seizures in Swiss mice and protects some temporal lobe structures

BackgroundRauvolfia vomitoria (R. vomitoria) is a plant of economic importance due to its diverse ethnomedicinal properties, including the anticonvulsant effect. In this study, we studied the antiseizure and neuroprotective potentials of R. vomitoria extracts against pentylenetetrazol (PTZ)-induced kindling.MethodsTwenty-five adult Swiss mice (25–30 g) were assigned to five groups (n = 5): control group, PTZ treatment group, and PTZ treatment after receiving oral R. vomitoria crude extract (100 mg/kg), R. vomitoria phenol extract (50 mg/kg) or sodium valproate (15 mg/kg) every 48 h for 28 days. Seizure scores, cognitive behavioral tests including novel object test, Y-maze test, and the elevated plus maze test, as well as brain neurochemicals and histomorphology studies, were performed.ResultsCompared with the control group, the PTZ group showed comparable body weight and durations in closed and open arms (P > 0.05), but preference for familiar objects, significant (P < 0.05) spontaneous alternation, increased monoamine oxidase activity and nitric oxide level, and Nissl chromatolysis in the temporal lobe structures including the cortex, hippocampus, and amygdala. R. vomitoria phenol extract pretreatment significantly (P < 0.05) reduced seizures, prevented adverse cognitive behaviors, decreased the nitric oxide level, and reduced the temporal lobe Nissl chromatolysis compared with the R. vomitoria crude extract pretreatment group and the sodium valproate pretreatment groups.ConclusionsThus, R. vomitoria phenol extract showed promising results against seizures and potential for general brain protection, suggesting that the anticonvulsant property of R. vomitoria may be attributed to its phenol constituent. More studies are needed to delineate the mechanisms of its action.

Tandem mass tag-based proteomics reveals the antiepileptic mechanism of steroidal saponins from Anemarrhena asphodeloides in Kainic acid induced epileptic rat model.

Epilepsy (EP) is one of the most common neurological diseases in the world. Anemarrhena asphodeloides Bunge. (AA), as a typical heat-cleaning medicine, has been proven to possess the antiepileptic effect in clinical and experimental studies. Anemarrhena asphodeloides steroidal saponins (AAS) are main components. However, the therapeutic effects and underlying mechanisms of AAS against EP are not been fully elucidated. In this study, 63 steroidal saponins were discovered in AAS by UPLC-Q-TOF/MS analysis. Pharmacological and behavioral analysis demonstrated that AAS could significantly lower the Racine classification and reduce the frequency of generalized spike rhythm the rate of tetanic seizures in kainic acid-induced epileptic rats. Hematoxylin and eosin and Nissl staining-indicated AAS could significantly improve hippocampal injury and neuron loss in epileptic rats. TMT proteomic analysis discovered 26 different expressed proteins (DEPs), which were identified as the rescue proteins. After bioinformatic analysis, Heat Shock Protein 90 Alpha Family Class B Member 1 (Hsp90ab1) and Tyrosine 3-Monooxygenase (Ywhab) were screened as key DEPs and verified by western blotting. AAS could significantly inhibited the up-regulation of Hsp90ab1 and Ywhab in EP rats; these two proteins might be the key targets of AAS in treating EP.

Anticonvulsant, Anticholinesterase and Cytoprotective Effects of the Aqueous Extract of Lippia sidoides Cham

(1) Background: Lippia sidoides Cham is a Brazilian aromatic plant rich in phenolic compounds. In traditional medicine, its leaves are used to treat diseases of the Central Nervous System such as stress and anxiety. This study evaluates the capacity of the aqueous extract of L. sidoides as an anticonvulsant, anticholinesterase and antihemolytic agent. (2) Methods: The extract was obtained from the leaves using water as a solvent, then dried in a spray dryer. The anticonvulsant effect was evaluated in zebrafish models using the pentylenetetrazol (PTZ) method. The anticholinesterase effect was determined using the acetylcholinesterase enzyme and physostigmine as a positive control. The antihemolytic action was evaluated by exposing erythrocytes to different concentrations of NaCl in the presence and absence of the extract. (3) Results: The anticonvulsant effect was observed at a concentration of 400 mg/kg, delaying convulsive crises. In the anticholinesterase assay, a dose-dependent action and variation in the effect over time were observed, demonstrating a reversible effect of the extract. For the osmotic fragility test, the extract showed satisfactory results, providing cellular protection across all variations of NaCl concentration. (4) Conclusions: These results demonstrate the promising potential of L. sidoides extract for the development of drugs that act in the treatment of diseases that affect the Central Nervous System.

Structure–function relationship of dynorphin B variants using naturally occurring amino acid substitutions

Dynorphins (Dyn) represent the subset of endogenous opioid peptides with the highest binding affinity to kappa opioid receptors (KOPrs). Activation of the G-protein-coupled pathway of KOPrs has strong anticonvulsant effects. Dyn also bind to mu (MOPrs) and delta opioid receptors (DOPrs) with lower affinity and can activate the β-arrestin pathway. To fully exploit the therapeutic potential of dynorphins and reduce potential unwanted effects, increased selectivity for KOPrs combined with reduced activation of the mTOR complex would be favorable. Therefore, we investigated a series of dynorphin B (DynB) variants, substituted in one or two positions with naturally occurring amino acids for differential opioid receptor activation, applying competitive radio binding assays, GTPγS assays, PRESTO-Tango, and Western blotting on single-opioid receptor-expressing cells. Seven DynB derivatives displayed at least 10-fold increased selectivity for KOPrs over either MOPrs or DOPrs. The highest selectivity for KOPrs over MOPrs was obtained with DynB_G3M/Q8H, and the highest selectivity for KOPrs over DOPrs was obtained with DynB_L5S. Increased selectivity for KOPr over MOPr and DOPr was based on a loss of affinity or potency at MOPr and DOPr rather than a higher affinity or potency at KOPr. This suggests that the investigated amino acid exchanges in positions 3, 5, and 8 are of higher importance for binding and activation of MOPr or DOPr than of KOPr. In tests for signal transduction using the GTPγS assay, none of the DynB derivatives displayed increased potency. The three tested variants with substitutions of glycine to methionine in position 3 displayed reduced efficacy and are, therefore, considered partial agonists. The two most promising activating candidates were further investigated for functional selectivity between the G-protein and the β-arrestin pathway, as well as for activation of mTOR. No difference was detected in the respective read-outs, compared to wild-type DynB. Our data indicate that the assessment of affinity to KOPr alone is not sufficient to predict either potency or efficacy of peptidergic agonists on KOPr. Further assessment of downstream pathways is required to allow more reliable predictions of in vivo effects.

Sida cordifolia Linn- An widely used herbs in the village of Falta, west Bengal, India: Pharmacological evaluation of antiepileptic activity of root extract of Sida cordifolia Linn.

As per the observation of the social work activitist it was found that the raw extract of the root of Sida cordifolia Linn. Are been used by some old people in the village of Falta Block of South 24 PGS district of West Bengal, India to treat epileptic attack on some villagers. The identified plant were collected and handed over the research scientists for the further study. The dried coarse powder of the root of Sida cordifolia Linn. Were soxheleted successively with petroleum ether (PESC), methanol (MESE), with boiled water (AESC) and the epileptic study was performed on the Albino mice using 100 and 300 mg/kg body weight of PESC, MESE and using clonazepam as standard using Maximum Electroshock induced seizure model and result depicted that PESC exhibited a significant antiepileptic effect at both low and high doses where as MESC exhibited the significant antiepileptic effect only at high dose. Hence, the petroleum ether extract may be chosen to be more effective than that of the methanol extract.

Sinapinic acid as a potential therapeutic agent for epilepsy through targeting NMDA receptors and nitrite level

Epilepsy, a widespread neural ailment considered by prolonged neuronal depolarization and repetitive discharge, has been linked to extreme stimulus of N-methyl-D-aspartate receptors (NMDARs). Despite the availability of approved anti-seizure medications (ASMs) in many developed nations, approximately 30% of epilepsy patients continue to experience drug-resistant seizures. Thus, a growing interest in discovering natural compounds as potential sources for new medications is growing. Sinapinic acid, a natural derivative of cinnamic acid found in food sources, is known for its neuroprotective properties. This study investigated how sinapinic acid interacts with NMDA receptors and its potential role in providing anticonvulsant effects. Male mice were randomly allocated into nine groups: a control group receiving normal saline (1 ml/kg), groups treated with sinapinic acid at doses of 1, 3, and 10 mg/kg, a group treated with diazepam at 10 mg/kg, a group treated with an NMDA agonist at 75 mg/kg, a group treated with an NMDA antagonist at 0.5 mg/kg, a group receiving the ineffective dose of sinapinic acid (1 mg/kg) along with the NMDA antagonist, and a group receiving the effective dose of sinapinic acid (10 mg/kg) along with the NMDA agonist. Sinapinic acid and other treatments were administered intraperitoneally 30 min prior to inducing seizures with PTZ injection. Seizure onset time was recorded following PTZ injection. Blood and brain samples were collected after anesthesia to determine serum and brain nitrite levels. Real-time PCR assessed NMDAR gene expression in the prefrontal cortex (PFC). Data were analyzed using Prism software. The time seizures began was notably extended in groups treated with sinapinic acid at doses of 3 and 10 mg/kg compared to those treated with saline (P < 0.05). Additionally, in the receiving group of an ineffective dose of sinapinic acid alongside ketamine, the beginning of seizure time was significantly prolonged compared to the group that received the ineffective dose of sinapinic acid alone (P < 0.05). Serum and prefrontal cortex (PFC) nitrite levels were significantly lower in mice treated with sinapinic acid at doses of 1, 3, and 10 mg/kg compared to the saline-treated group (P < 0.05). The gene expression of the NMDAR NR2B subunit in the PFC was decreased in groups treated with sinapinic acid at 1 and 10 mg/kg compared to the saline-treated group. Furthermore, co-administration of sinapinic acid (10 mg/kg) with NMDA resulted in significantly lower NR2A gene expression than the group treated with 10 mg/kg of sinapinic acid alone. Conversely, co-administration of ketamine with sinapinic acid (1 mg/kg) significantly increased NR2B subunit gene expression compared to the group treated with sinapinic acid at 1 mg/kg alone. Sinapinic acid showed anticonvulsant effects through reduced serum and PFC nitrite and modulation of glutamatergic signaling.

Gentiopicroside Attenuates Lithium/Pilocarpine-Induced Epilepsy Seizures by Down-Regulating NR2B/CaMKII/CREB and TLR4/NF-κB Signaling Pathways in the Hippocampus of Mice

Background: Epilepsy is a prevalent and disabling neurological condition characterized by recurrent seizures. Approximately 50% of adults with active epilepsy have at least one comorbidity and they are at a greater risk of premature death than the general population. Gentiopicroside (Gent) is a primary component of Gentiana macrophylla Pall. that has been shown to have diverse pharmacological properties. However, its role in epileptic seizures in adult mice and its underlying mechanism of action remain obscure. We aimed to explore the anti-epileptic effect and mechanism of Gent on lithium/pilocarpine (Pilo)-induced epilepsy seizures in mice. Methods: In this study, we established a lithium/Pilo-induced epilepsy model, and Gent was first given to mice 30 min before Pilo administration. Then, we detected behavioral and histopathological changes through electrocorticographic (ECoG) measurements, Nissl staining, Fluoro-Jade B (FJB) staining, and immunohistochemical staining. We then used molecular biology techniques, such as Western blotting, quantitative polymerase chain reaction (qPCR) analysis, and the enzyme-linked immunosorbent assay (ELISA) to investigate the mechanisms of Gent in lithium/Pilo-induced epileptic seizures in mice and lipopolysaccharide (LPS)-induced inflammatory astrocytes. Results: We confirmed that Gent could prevent abnormal ECoG activity, behavioral changes, and neurodegeneration. Subsequently, we found Gent could downregulate the factors that could promote apoptosis (i.e., the NR2B/CaMKII/CREB signaling cascade) and neuroinflammatory-related factors (i.e., the TLR4/NF-κB signaling cascade). Conclusions: Gent could be a potential therapeutic agent for epilepsy, offering possibilities for both prevention and treatment. Our research establishes a preliminary experimental framework for ongoing studies into Gent’s efficacy as a treatment for epilepsy.

Pharmacological interventions for co-occurring psychopathology in people with borderline personality disorder: secondary analysis of the Cochrane systematic review with meta-analyses.

Medications are commonly used to treat co-occurring psychopathology in persons with borderline personality disorder (BPD). To systematically review and integrate the evidence of medications for treatment of co-occurring psychopathology in people with BPD, and explore the role of comorbidities. Building on the current Cochrane review of medications in BPD, an update literature search was done in March 2024. We followed the methods of this Cochrane review, but scrutinised all identified placebo-controlled trials post hoc for reporting of non BPD-specific ('co-occurring') psychopathology, and explored treatment effects in subgroups of samples with and without defined co-occurring disorders. GRADE ratings were done to assess the evidence certainty. Twenty-two trials were available for quantitative analyses. For antipsychotics, we found very-low-certainty evidence (VLCE) of an effect on depressive symptoms (standardised mean difference (SMD) -0.22, P = 0.04), and low-certainty evidence (LCE) of an effect on psychotic-dissociative symptoms (SMD -0.28, P = 0.007). There was evidence of effects of anticonvulsants on depressive (SMD -0.44, P = 0.02; LCE) and anxious symptoms (SMD -1.11, P < 0.00001; VLCE). For antidepressants, no significant findings were observed (VLCE). Exploratory subgroup analyses indicated a greater effect of antipsychotics in samples including participants with co-occurring substance use disorders on psychotic-dissociative symptoms (P = 0.001). Our findings, based on VLCE and LCE only, do not support the use of pharmacological interventions in people with BPD to target co-occurring psychopathology. Overall, the current evidence does not support differential treatment effects in persons with versus without defined comorbidities. Medications should be used cautiously to target co-occurring psychopathology.

PTZ KINDLING MODEL: EVALUATION OF EEG FACTOR AND BIOCHEMISTRY PARAMETERS UNDER THE INFLUENCE OF RAMELTEON

Many selective synthetic melatonin receptor agonists have anticonvulsant/anti-epileptogenic properties. These agonists bind to melatonin receptor 1 (MT1) and receptor 2 (MT2), causing their activation. Therefore, we evaluated the anticonvulsant effect of Ramelteon (RMLT) as a melatonin agonist in the PTZ (Pentylenetetrazol)-kindling model. In the study, 36 male Wistar Albino rats were assessed in 6 groups (Sham, PTZ, dimethylsulphoxide (DMSO), Valproic acid (VPA) (150 mg/kg) + PTZ, RMLT (30 mg/kg)+PTZ, VPA+RMLT+PTZ). Cortical electroencephalography (EEG) data were recorded for all groups. Seizures were scored according to the Racine scale. Seizure scores and onset times of the first myoclonic movements were compared in EEG traces. Total antioxidant status (TAS), total oxidant status (TOS), catalase, myeloperoxidase (MPO), and Thiol levels were measured in serum samples. Also, Calcineurin (CaN), Neuropeptide-Y (NPY), Neuron Specific Enolase (NSE), and S100B levels were measured in brain tissue samples. There was a significant difference between the PTZ and PTZ+Valproic acid+RMLT groups for the onset of the first myoclonic movements and the rate of spikes in the EEG traces in Racine's convulsion stages (P 0.05). RMLT has anticonvulsant properties. Additionally, the receptor preference of RMLT can be investigated.

Phytocannabinoids restore seizure-induced alterations in emotional behaviour in male rats.

Epilepsy often presents with severe emotional comorbidities including anxiety and abnormal fear responses which impose a significant burden on, and reduce, quality of life in people living with the disease. Our lab has recently shown that kindled seizures lead to changes in emotional processing resulting from the downregulation of anandamide signalling within the amygdala. Phytocannabinoids derived from the Cannabis sativa plant have attracted a lot of interest as a new class of drugs with potential anticonvulsant effects. Among the wide number of compounds occurring in Cannabis sativa, Δ9- tetrahydrocannabinol (THC), the one responsible for its main psychoactive effects, and the nonpsychoactive cannabidiol (CBD) have been extensively examined under pre-clinical and clinical contexts to control seizures, however, neither have been assessed in the context of the management of emotional comorbidities associated with seizure activity. We used two behavioural procedures to assess anxiety- and fear-like responding in adult male Long-Evans rats: elevated plus maze and auditory fear conditioning. In agreement with previous reports, we found seizure-induced increases in anxiety- and fear-like responding. These effects were reversed by either CBD (vaporized) or THC (oral). We also found that antagonism of serotonin 1 A receptors prior to CBD exposure prevented its protective effects. Phytocannabinoids offer a novel and reliable opportunity to treat seizure induced comorbid emotional alterations.

Low-frequency stimulation of corpus callosum suppresses epileptiform activity in the cortex through γ-aminobutyric acid type B receptor and slow afterhyperpolarization-mediated reduction in tissue excitability.

Deep brain stimulation, particularly low-frequency stimulation (LFS) targeting fiber tracts, has emerged as a potential therapy for drug-resistant epilepsy (DRE) and for generalized epilepsy, both of which pose significant treatment challenges. LFS diffusely suppresses seizures in the cortex when applied to fiber tracts like the corpus callosum (CC). Nevertheless, the specific processes responsible for suppressing epileptic activity in the cortex induced by LFS remain unclear. This study investigates the mechanisms underlying the antiepileptic effect in the cortex of LFS of the CC in coronal rodent brain slices. An invitro 4-aminopyridine (4-AP) seizure model of cortical seizures was generated. LFS stimulation parameters were optimized to provide the largest antiepileptic effect in the cortex when applied to the CC. Changes to tissue excitability and percent time spent seizing were measured due to LFS in artificial cerebrospinal fluid, 4-AP, and in the presence of various specific and nonspecific γ-aminobutyric acid type B (GABAB) and slow afterhyperpolarization (sAHP) antagonists. LFS significantly suppressed seizure activity in the cortex, with an optimal frequency of 5 Hz (76.5%). Tissue excitability during LFS reduces across a wide range of interstimulus intervals, with a maximum reduction at 200 ms. Notably, the tissue excitability remains depressed at 1000 ms. LFS, in the presence of GABAB antagonists, had diminished seizure reduction (<15%) and failed to reduce tissue excitability in the 50-400-ms range. Tissue excitability measured with paired pulses in the 600-1000-ms range was depressed in the presence of GABAB antagonists, suggesting a different antiepileptic mechanism was active. Upon administering sAHP antagonists, seizure reduction was once again diminished (<15%). Upon administration of both sAHP and GABAB antagonists, LFS failed to provide any meaningful seizure reduction (<5%). LFS of the CC provides an antiepileptic effect in the cortex with well-understood mechanisms and could be an alternative to surgical intervention for patients suffering from DRE.

Empagliflozin modulates seizure activity and oxidative stress in rats with epilepsy

Drug-resistant epilepsy, a commonly devastating condition, affects more than 50 million people globally. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of neurological disorders, and a potential association between epilepsy and subsequent T2DM has emerged. Inhibiting sodium-glucose linked transporters (SGLTs), which are differentially expressed in the brain, has been shown to reduce epileptic episode activity. This study aimed to evaluate the anticonvulsive effect of empagliflozin in rats with seizures induced by maximal electric shock (MES) and pentylenetetrazol (PTZ). Generalized tonic‒clonic seizures were induced in the rats using an electroconvulsive meter, and pentylenetetrazol was injected to induce absence seizures. The duration of all the stages of seizure and Racine stage scoring (RSS) were performed. Malondialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) levels in the brain tissues were determined. Histopathological analysis of the brain tissues was carried out. A significant (p &amp;lt;0.01) decrease in the duration of tonic hind limb extension (THLE), a significant decrease in the levels of pro-oxidants such as MDA and NO, and an increase in the levels of antioxidants such as GSH were observed in the low dose 10 mg/kg and high dose 20 mg/kg empagliflozin groups compared to the disease control group. Histopathological analysis revealed a greater number of healthy neurons with few dark-stained cells in the treatment groups, suggesting the neuroprotective effect of empagliflozin. The present study showed that empagliflozin modulates epileptic activity. Empagliflozin has a potential role in the management of epilepsy in diabetic patients.

The bidirectional role of music effect in epilepsy: Friend or foe?

Epilepsy is a prevalent neurological disease that impacts around 70 million individuals globally. Anti-seizure medications (ASMs) are the first choice for clinicians to control unprovoked epileptic seizures. Although more than 30 ASMs are available in the market, patients with epilepsy (PWEs) still show poor responses to adequate drug treatment. Meanwhile, long-term medications not only bring heavy financial burdens but also lead to undesirable side effects. Music, a ubiquitous art form throughout human history, has been confirmed as therapeutically effective in various neurological conditions, including epilepsy. This alternative therapy offers convenience and a relatively safe approach to alleviating epileptic symptoms. Paradoxically, besides anti-convulsant effect, some particular music would cause seizures inversely, indicating the pro-convulsant effect of it. Considering that investigating the impact of music on epilepsy emerges as a compelling subject. In this review, we tried to present the following sections of content on this topic. Initially, we overviewed the impact of music on the brain and the significant progress of music therapy in central neurological disorders. Afterward, we classified the anti-convulsant and pro-convulsant effects of music in epilepsy, relying on both clinical and laboratory evidences. Finally, possible mechanisms and neural basis of the music effect were concluded, and the translational potentials and some future outlooks about the music effect in epilepsy were proposed. PLAIN LANGUAGE SUMMARY: Epilepsy is an extremely severe neurological disorder. Although anti-seizure medications are preferred choice to control seizures, the efficacy is not satisfied due to the tolerance. Anecdotal music effect had been deemed functional diversity but not clarified on epilepsy, pro-convulsive, or anti-convulsive. Here, we reviewed this interesting but puzzling topic, as well as illustrating the potential mechanisms and its translational potential.

Regulating the NMDA/NR2B signaling pathway mediates anticonvulsant, antineuroinflammation, and anti-oxidative stress effects of 1,3,benzothiazole derivative 1M in pentylenetetrazole-induced kindling in mice.

Periodic epileptic episodes are the hallmark of epilepsy, a prevalent neurological disorder. Research suggests a significant correlation between neuroinflammation and oxidative stress in a variety of neurological diseases, such as epilepsy. A substantial amount of evidence supports the role of N-methyl-D-aspartate receptors (NMDARs) in the progression of epilepsy. Although several lines of research have disclosed numerous biochemical effects of early seizures, its connection with disturbed NMDAR/NR2B subunit expression remains unclear. 2-Mercaptobenzothiazole (MBT) is a vital scaffold with several biological activities, and its various substitutes show promising anti-inflammatory potential. The current study aimed to investigate the newly synthesized 1,3-(benzothiazole-2-sulfanyl)-1-(morpholine-4-yl)ethan-1-one (1M), a substituted MBT, for its neuroprotective potential in a mice model of pentylenetetrazole-induced epilepsy (PTZ), by modulating NMDA/NR2B pathway. The compound was tested for docking and simulation analysis, demonstrating a solid and stable bond with the NR2B subunit of NMDA. To ascertain the effects of 1M, as well as to further illustrate its mechanism of neuroprotection via NMDA/NR2B in PTZ-induced kindling model, mice of either sex were given two doses of test compound, 1M (10mg/kg and 20mg/kg). The behavioral assessments were evaluated using open-field, Y-maze, and elevated-plus maze tests, which indicated improved behavioral alterations caused by PTZ after 1M treatment. The antioxidant profiling was done by estimating glutathione-S-transferase (GST), catalase (CAT), reduced glutathione (GSH), and LPO (lipid peroxidation) in hippocampal tissues, where the test compound 1M significantly restored the depleted antioxidants, showcasing its antioxidant potential. Moreover, the cellular morphological damages induced by PTZ were detected by H&E staining, which was rescued after 1M administration. Furthermore, the activation of the inflammatory pathway was confirmed by quantitative analysis of inflammatory mediators tumor necrotic factor (TNF-α), nuclear factor kappa B (NF-κB), and cylooxegenase2 (COX-2) by enzyme-linked immunosorbent assay (ELISA), where 1M administration significantly ameliorated their expression. Furthermore, to demonstrate the involvement of the NR2B pathway, NR2B-antagonist ifenprodil was employed, and results were further confirmed through RT-PCR analysis. Our results, when considered collectively, indicate that 1M may act by inhibiting the NR2B subunit of the NMDA receptor, subsequently mitigating downstream oxidative stress and inflammatory mediators through various pathways.

Anxiolytic and Anticonvulsant Effects of Fisetin Isolated from Bauhinia pentandra on Adult Zebrafish (Danio rerio).

Anxiety and epilepsy are common worldwide and represent a primary global health concern. Fisetin, a flavonoid isolated from Bauhinia pentandra, has a wide range of biological activities may be a promising alternative to combat diseases related to the central nervous system (CNS). The present study aimed to investigate the anxiolytic and anticonvulsant effects of fisetin on adult zebrafish. Furthermore, molecular docking simulations were performed to improve the results. Fisetin did not present toxicity and caused anxiolytic behavior and delayed seizures in animals. This effect may occur through serotonin neurotransmission at 5-HT3A and/or 5-HT3B receptors. Molecular docking simulations showed that fisetin interacts with the orthosteric site of the 5-HT3A receptor with strong H-bond interactions with the Trp156 residue, with a strong contribution from the catechol ring, a behavior similar to that of the antagonist co-crystallized inhibitor granisetron (CWB). Fisetin may be a promising alternative to combat diseases related to the central nervous system.

Gamma-Decanolactone Increases Stress Resistance and Improves Toxicity Parameters on the Caenorhabditis elegans Alternative Model.

Gamma-decanolactone (GD) is a monoterpene compound with anticonvulsant, antiparkinsonian, and neuroprotective effects in preclinical trials. This study aimed to evaluate the toxicity and antioxidant profile of GD in silico and in the Caenorhabditis elegans (C. elegans) experimental model. The C. elegans was used to determine the median lethal concentration (LC50) of GD, as well as its effect on survival, development, reproduction, pharyngeal pumping, and stress resistance assays. The in silico study did not indicate hepatotoxic, cardiotoxic, or mutagenic potential to GD. It reduced the worms' survival, both at the L1 and L4 stages, in a concentration-dependent manner with an LC50 value of 212.16 ± 5.56 μmol/mL. GD did not alter the development, reproduction, and pharyngeal pumping under normal experimental conditions in the three concentrations tested (25, 50, and 100 μmol/mL). In the thermal stress assay, GD did not change the survival pattern of the worms. Hydrogen peroxide (H2O2) reduced the survival of C. elegans and decreased the number of pharyngeal pumping, with these effects being reversed by GD. Also, GD presents an antioxidant activity by modulation the expression of the stress response genes such as sod-3, ctl-1,2,3, and gst-4. In conclusion, GD showed low toxicity in the C. elegans model and antioxidant profile both in the in silico study and invivo assays.

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.

Anxiolytic and Anticonvulsant Potential of Biosynthetic Limonene Derivatives in Adult Zebrafish.

This study investigated the anxiolytic and anticonvulsant effects and safety profile of limonene enantiomers and their oxidized derivatives.The toxicity test was performed by monitoring the animals for 96 hours, with no deaths or significant toxicity observed up to the highest dose, which allowed the determination of the LD50. Doses of 4, 20 and 40 mg/kg were tested, with no toxicity observed up to 96h (LD50 > 40 mg/kg). Anxiolytic activity was measured in a preference test for light and dark areas, and the effect of the compounds was evaluated in the presence of serotonergic antagonists. The (S)-(-)-LIM and (R)-(+)-LIM enantiomers showed anxiolytic effects, with (S)-(-)-LIM being effective at all doses. In the anticonvulsant test, the oxidized derivatives, such as perilyl acid (PAC), significantly delayed PTZ-induced seizures, an effect blocked by flumazenil (FMZ). The oxidized derivatives, especially perilyl acid (PAC), showed anxiolytic effects at all doses and significantly delayed the three PTZ-induced seizure events. This effect was blocked by FMZ, suggesting a relationship between PAC and the GABAergic pathway. PAC, being the most oxidized derivative, was the most effective for both anxiety and delaying seizure progression, suggesting that oxidation of limonene compounds may increase their therapeutic efficacy.

Synthesis, characterization, anxiolytic and anticonvulsant activity, DFT, molecular docking, DMPK studies of chalcone derived from maleic anhydride

Anxiety typically doesn't cause convulsions, but intense stress can reduce the threshold for convulsive bouts in predisposed individuals. Chalcones are known to act directly on the central nervous system (CNS) and the presence of electron donor and acceptor groups attached to the aromatic rings in various positions can alter the properties of the molecule. Thus, this work investigated the anxiolytic and anticonvulsant potential of the new chalcone derivative (E)-6-(4-((E)-3-(3-nitrophenyl)acryloyl)phenyl)-5-oxohex-2-enoic acid (CAMEL). 1H and 13C NMR and ATR-FTIR analyses helped to determine the molecular structure of this chalcone. The energy gap analysis and the higher hardness values than the softness values confirm the stability of CAMEL, with CGDRs indicating that it is more electrophilic in nature. In relation to its potential anxiolytic effect, the tested dose of 40 mg kg-1 of the derivative showed behavior like Diazepam, with activity via GABAA. In addition, the derivative also exhibited a possible anticonvulsant effect at the dose of 20 mg kg-1, being like Diazepam, showing involvement in stages 2 and 3 of GABAA receptors in this process. Given the anxiolytic and anticonvulsant activity shown in vivo and in silico tests, CAMEL is a promising candidate for the treatment of diseases that affect the CNS.