RÉSUMÉ
BACKGROUND: Status epilepticus is a common and potentially life-threatening neurological emergency with a high risk for cognitive and neurobiological impairment. Our aim was to evaluate the neuroprotective effects of centrally administered irisin and acute exhausting exercise against oxidative brain injury and memory dysfunction due to a pentylenetetrazole (PTZ)-induced single seizure. Male Sprague Dawley rats with intracerebroventricular (icv) cannulas were randomly divided into intraperitoneally (ip) saline-injected control and PTZ-injected (45 mg/kg) seizure groups. Both the control and PTZ groups were then treated with irisin (7.5 µg/kg, 2 µl, icv), saline (2 µl, icv) or were forced to an acute bout of strenuous exercise before the ip injection of saline (control) or PTZ. Seizures were evaluated using the Racine score. To evaluate memory performance, a passive avoidance test was performed before and after PTZ injection. Following euthanasia at the 24th hour of seizure induction, brain tissues were removed for histopathological examination and for evaluating oxidative damage, antioxidant capacity, and neurotransmitter levels. RESULTS: Glutamate/GABA imbalance observed in PTZ rats was corrected by irisin administration (p < 0.001/p < 0.01), while irisin prevented the generation of reactive oxygen species and lipid peroxidation (p < 0.05 - 0.001) and replenished the antioxidant catalase and glutathione levels (p < 0.01-0.01) in the cerebral tissue, and reduced the histologically evident neuronal injury due to a single seizure (p < 0.05 - 0.01). Irisin also delayed the onset of seizures (p < 0.05) and improved memory dysfunction (p < 0.05), but did not affect the severity of seizures. The acute exhaustive swimming exercise completed before PTZ-seizure depressed glutamate level (p < 0.001), maintained the oxidant/antioxidant balance, alleviated neuronal injury (p < 0.05 - 0.01) and upregulated cerebral BDNF expression (p < 0.05). CONCLUSION: In conclusion, acute high-intensity exercise or exogenously administered irisin provides neuroprotection by maintaining the balance of excitatory/inhibitory neurotransmitters and oxidant/antioxidant systems.
Sujet(s)
Fibronectines , Troubles de la mémoire , Pentétrazol , Conditionnement physique d'animal , Rat Sprague-Dawley , Crises épileptiques , Animaux , Mâle , Troubles de la mémoire/étiologie , Conditionnement physique d'animal/physiologie , Conditionnement physique d'animal/méthodes , Fibronectines/métabolisme , Fibronectines/administration et posologie , Rats , Maladies neuro-inflammatoires , Épilepsie , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/administration et posologie , Stress oxydatif/effets des médicaments et des substances chimiques , Stress oxydatif/physiologieRÉSUMÉ
Pentylenetetrazole- (PTZ)-induced kindling is a broadly used experimental model to evaluate the impact of antiseizure drugs and their novel combination on seizure progression. The current study aimed to evaluate the anti-kindling effects of ivermectin (IVM) and rufinamide (RUFI) alone and their combination with vitamin E. The mice were administered 11 injections of PTZ (40 mg/kg) followed by assessment for anxiety-like behavior and cognitive abilities in a series of behavior tests with subsequent brain isolation for biochemical and histopathological evaluation. The outcomes showed a marked protection by IVM + RUFI (P<0.001) from kindling progression, anxiety-like behavior and cognitive deficit. However, additional supplementation with vitamin E worked superior to duo therapy as these mice were noted to be most fearless to visiting open, illuminated and elevated zones of open field, light/dark and elevated-plus maze (P<0.0001). Further, they showed marked remembrance of the familiar milieu in y-maze (P<0.01) and novel objection recognition (P<0.05) tests. Additionally, their recollection of aversive stimuli in passive avoidance and spatial memory in Morris water maze were evident (P<0.0001), in comparison to kindled mice. The IVM + RUFI duo therapy and its co-administration with vitamin E prevented kindling-triggered oxidative stress in brains and neuronal damage in hippocampus. We conclude that the benefits of the co-administration of vitamin E might be the results of antioxidant and anti-inflammatory effects of vitamin E which might be potentiating the antiseizure effects of RUFI and GABA-A modulating potential by ivermectin.
Sujet(s)
Anticonvulsivants , Comportement animal , Ivermectine , Embrasement , Pentétrazol , Crises épileptiques , Triazoles , Vitamine E , Animaux , Embrasement/effets des médicaments et des substances chimiques , Vitamine E/pharmacologie , Vitamine E/administration et posologie , Souris , Ivermectine/pharmacologie , Ivermectine/administration et posologie , Anticonvulsivants/pharmacologie , Anticonvulsivants/administration et posologie , Mâle , Crises épileptiques/traitement médicamenteux , Comportement animal/effets des médicaments et des substances chimiques , Triazoles/pharmacologie , Triazoles/administration et posologie , Association de médicaments , Anxiété/traitement médicamenteux , Apprentissage du labyrinthe/effets des médicaments et des substances chimiques , Encéphale/effets des médicaments et des substances chimiques , Encéphale/anatomopathologie , Encéphale/métabolismeRÉSUMÉ
Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist-naloxone-and a GABA receptor agonist-diazepam (DZP)-facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.
Sujet(s)
Pentétrazol , Crises épileptiques , Animaux , Pentétrazol/toxicité , Souris , Crises épileptiques/métabolisme , Crises épileptiques/traitement médicamenteux , Crises épileptiques/induit chimiquement , Mâle , Naloxone/pharmacologie , Modèles animaux de maladie humaine , Diazépam/pharmacologie , Prédisposition aux maladies , Anticonvulsivants/pharmacologie , Anticonvulsivants/usage thérapeutique , Antagonistes narcotiques/pharmacologieRÉSUMÉ
Abnormal patterns of brain connectivity characterize epilepsy. However, little is known about these patterns during the stages preceding a seizure induced by pentylenetetrazol (PTZ). To investigate brain connectivity in male Wistar rats during the preictal phase of PTZ-induced seizures (60 mg/kg), we recorded local field potentials in the primary motor (M1) cortex, the ventral anterior (VA) nucleus of the thalamus, the hippocampal CA1 area, and the dentate gyrus (DG) during the baseline period and after PTZ administration. While there were no changes in power density between the baseline and preictal periods, we observed an increase in directional functional connectivity in theta from the hippocampal formation to M1 and VA, as well as in middle gamma from DG to CA1 and from CA1 to M1, and also in slow gamma from M1 to CA1. These findings are supported by increased phase coherence between DG-M1 in theta and CA1-M1 in middle gamma, as well as enhanced phase-amplitude coupling of delta-middle gamma in M1 and delta-fast gamma in CA1. Interestingly, we also noted a slight decrease in phase synchrony between CA1 and VA in slow gamma. Together, these results demonstrate increased functional connectivity between brain regions during the PTZ-induced preictal period, with this increase being particularly driven by the hippocampal formation.
Sujet(s)
Encéphale , Pentétrazol , Rat Wistar , Crises épileptiques , Animaux , Pentétrazol/pharmacologie , Mâle , Crises épileptiques/induit chimiquement , Crises épileptiques/physiopathologie , Encéphale/effets des médicaments et des substances chimiques , Encéphale/physiopathologie , Rats , Voies nerveuses/physiopathologie , Voies nerveuses/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Électroencéphalographie/méthodes , Région CA1 de l'hippocampe/effets des médicaments et des substances chimiques , Région CA1 de l'hippocampe/physiopathologie , Convulsivants/toxicité , Convulsivants/pharmacologie , Ondes du cerveau/effets des médicaments et des substances chimiques , Ondes du cerveau/physiologie , Cortex moteur/effets des médicaments et des substances chimiques , Cortex moteur/physiopathologieRÉSUMÉ
Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures alongside other neurological comorbidities. Cognitive impairment is the most frequent comorbidity secondary to progressive neurologic changes in epilepsy. Sigma 1 receptors (σ1 receptors) are involved in the neuroprotection and pathophysiology of both conditions and targeting these receptors may have the potential to modulate both seizures and comorbidities. The current research demonstrated the effect of clemastine (10 mg/kg, P.O.), a non-selective σ1 receptor agonist, on pentylenetetrazol (PTZ) (35 mg/kg, i.p., every 48 h for 14 doses)-kindling rats by acting on σ1 receptors through its anti-inflammatory/antioxidant capacity. Clemastine and phenytoin (30 mg/kg, P.O.) or their combination were given once daily. Clemastine treatment showed a significant effect on neurochemical, behavioural, and histopathological analyses through modulation of σ1 receptors. It protected the kindling animals from seizures and attenuated their cognitive impairment in the Morris water maze test by reversing the PTZ hippocampal neuroinflammation/oxidative stress state through a significant increase in inositol-requiring enzyme 1 (IRE1), x-box binding protein 1 (XBP1), along with a reduction of total reactive oxygen species (TROS) and amyloid beta protein (Aß). The involvement of σ1 receptors in the protective effects of clemastine was confirmed by their abrogation when utilizing NE-100, a selective σ1 receptor antagonist. In light of our findings, modulating σ1 receptors emerges as a compelling therapeutic strategy for epilepsy and its associated cognitive impairments. The significant neuroprotective effects observed with clemastine underscore the potential of σ1 receptor-targeted treatments to address both the primary symptoms and comorbidities of neurological disorders.
Sujet(s)
Dysfonctionnement cognitif , Embrasement , Neuroprotecteurs , Pentétrazol , Récepteur sigma , Crises épileptiques , , Animaux , Récepteur sigma/métabolisme , Récepteur sigma/agonistes , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Crises épileptiques/traitement médicamenteux , Crises épileptiques/métabolisme , Mâle , Rats , Dysfonctionnement cognitif/traitement médicamenteux , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/prévention et contrôle , Embrasement/effets des médicaments et des substances chimiques , Repositionnement des médicaments , Rat Wistar , Stress oxydatif/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Antioxydants/pharmacologie , Antioxydants/usage thérapeutique , Anticonvulsivants/pharmacologie , Anticonvulsivants/usage thérapeutiqueRÉSUMÉ
GABA modulators such as phenobarbital (PB) and sodium channel blockers such as phenytoin (PHT) have long been the mainstay of pharmacotherapy for the epilepsies. In the context of neonatal seizures, both PB and PHT display incomplete clinical efficacy. Moreover, in animal models, neonatal exposure to these medications result in neurodegeneration raising concerns about safety. Cenobamate, a more recently approved medication, displays unique pharmacology as it is both a positive allosteric modulator of GABA-A receptors, and a voltage-gated sodium channel blocker. While cenobamate is approved for adult use, its efficacy and safety profile against neonatal seizures is poorly understood. To address this gap, we assessed the efficacy and safety of cenobamate in immature rodents. Postnatal day (P)7 rat pups were pretreated with cenobamate and challenged with the chemoconvulsant pentylenetetrazole (PTZ) to screen for anti-seizure effects. In a separate experiment, P7 rats were treated with cenobamate, and brains were processed to assess induction of cell death. Cenobamate displays dose-dependent anti-seizure efficacy in neonatal rats. Unlike PHB and PHT, it does not induce neurotoxicity in P7 rats. Thus, cenobamate may be effective at treating neonatal seizures while avoiding unwanted neurotoxic side effects such as cell death.
Sujet(s)
Animaux nouveau-nés , Anticonvulsivants , Carbamates , Mort cellulaire , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Rat Sprague-Dawley , Crises épileptiques , Animaux , Crises épileptiques/induit chimiquement , Crises épileptiques/traitement médicamenteux , Anticonvulsivants/pharmacologie , Rats , Mort cellulaire/effets des médicaments et des substances chimiques , Carbamates/pharmacologie , Carbamates/usage thérapeutique , Chlorophénols/pharmacologie , Pentétrazol/toxicité , Mâle , Femelle , Convulsivants/toxicité , Encéphale/effets des médicaments et des substances chimiques , TétrazolesRÉSUMÉ
The aim of the present study was to develop a novel formulation of berberine (BBR) and demonstrate its anti-seizure effect in pentylenetetrazole (PTZ) induced kindling model in rats. Nanoparticles of BBR were formulated using Poly Lactic-co-Glycolic Acid (PLGA) as a polymer. Emulsification and solvent evaporation technique was used. PTZ induced kindling model in male wistar rat was used to demonstrate the anti-seizure effect of nano-BBR. The particle size obtained for the final formulation was 242.8 ± 67.35â¯nm with a PDI of 0.140 ± 0.01. PLGA encapsulated BBR nanoparticles showed the % encapsulation efficiency of 87.33 ± 2.42â¯% and % drug loading of 48.47 ± 1.34â¯%. In-vitro drug release data showed sustained release of nano-BBR as compared to BBR. Kinetic study data showed increase in AUC of nano-BBR (35,429.46â¯h.ng/ml) as compared to BBR (28,211.07â¯h.ng/ml). Cmax for nano- BBR (2251.90â¯ng/ml) is approximately 1.6 times greater than BBR (1505.50â¯ng/ml). Nano- BBR has shown the significant effect on the seizure score. The PLGA encapsulated berberine nanoparticles were prepared by an innovative simple method and offers excellent potential as an antiepileptic agent.
Sujet(s)
Anticonvulsivants , Berbérine , Modèles animaux de maladie humaine , Épilepsie , Nanoparticules , Pentétrazol , Copolymère d'acide poly(lactique-co-glycolique) , Rat Wistar , Berbérine/pharmacologie , Berbérine/administration et posologie , Animaux , Mâle , Épilepsie/traitement médicamenteux , Anticonvulsivants/composition chimique , Copolymère d'acide poly(lactique-co-glycolique)/composition chimique , Embrasement/effets des médicaments et des substances chimiques , Rats , Taille de particule , Acide lactique , Acide polyglycolique , Crises épileptiques/traitement médicamenteuxRÉSUMÉ
Epilepsy, a chronic neurological disorder characterized by recurrent unprovoked seizures, presents a substantial challenge in approximately one-third of cases exhibiting resistance to conventional pharmacological treatments. This study investigated the effect of 4-allyl-2,6-dimethoxyphenol, a phenolic compound derived from various natural sources, in different models of induced seizures and its impact on animal electroencephalographic (EEG) recordings. Adult male Swiss albino mice were pre-treated (i.p.) with a dose curve of 4-allyl-2,6-dimethoxyphenol (50, 100, or 200â¯mg/kg), its vehicle (Tween), or standard antiepileptic drug (Diazepam; or Phenytoin). Subsequently, the mice were subjected to different seizure-inducing models - pentylenetetrazole (PTZ), 3-mercaptopropionic acid (3-MPA), pilocarpine (PILO), or maximal electroshock seizure (MES). EEG analysis was performed on other animals surgically implanted with electrodes to evaluate brain activity. Significant results revealed that animals treated with 4-allyl-2,6-dimethoxyphenol exhibited increased latency to the first myoclonic jerk in the PTZ and PILO models; prolonged latency to the first tonic-clonic seizure in the PTZ, 3-MPA, and PILO models; reduced total duration of tonic-clonic seizures in the PTZ and PILO models; decreased intensity of convulsive seizures in the PTZ and 3-MPA models; and diminished mortality in the 3-MPA, PILO, and MES models. EEG analysis indicated an increase in the percentage of total power attributed to beta waves following 4-allyl-2,6-dimethoxyphenol administration. Notably, the substance protected from behavioral and electrographic seizures in the PTZ model, preventing increases in the average amplitude of recording signals while also inducing an increase in the participation of theta and gamma waves. These findings suggest promising outcomes for the tested phenolic compound across diverse pre-clinical seizure models, highlighting the need for further comprehensive studies to elucidate its underlying mechanisms and validate its clinical relevance in epilepsy management.
Sujet(s)
Anticonvulsivants , Modèles animaux de maladie humaine , Électroencéphalographie , Électrochoc , Pentétrazol , Crises épileptiques , Animaux , Mâle , Crises épileptiques/traitement médicamenteux , Crises épileptiques/induit chimiquement , Crises épileptiques/physiopathologie , Souris , Anticonvulsivants/pharmacologie , Pentétrazol/toxicité , Électroencéphalographie/effets des médicaments et des substances chimiques , Anisoles/pharmacologie , Relation dose-effet des médicaments , Pilocarpine/toxicité , Encéphale/effets des médicaments et des substances chimiques , Encéphale/physiopathologie , Acide 3-sulfanyl-propionique/pharmacologie , Convulsivants/toxicitéRÉSUMÉ
BACKGROUND: Epilepsy is a paroxysmal abnormal hypersynchronous electrical discharge characterized by recurrent seizures. It affects more than 50 million people worldwide. Stress is the leading cause of neurodegeneration and can produce seizures that may lead to or aggravate epilepsy. Inflammation plays a vital role in epilepsy by modulating oxidative stress, and levels of neuroinflammatory cytokines including NF-κB, TNF-α, and IL-1ß. METHODS: Stress-induced changes in behavior were evaluated in mice by employing behavioral assessment tests such as an elevated plus maze, light-dark box, open field test, tail suspension test, Y-maze, novel object recognition test, and Morris water maze in pentylenetetrazole (PTZ) kindled mice. Behavioral changes in all these paradigms including seizure score, latency, and frequency showed an increase in symptoms in PTZ (35 mg/kg) induced seizures in stressed mice (RS-PTZ) as compared to PTZ, Stress, and normal animals. RESULTS: The Enzyme-linked immunosorbent assay (ELISA) results confirmed increased in serum cortisol levels. Histological examinations showed neurodegenerative changes in the hippocampus and cortex regions. The spectrophotometric evaluation showed an increase in oxidative stress by decreasing antioxidant production i.e. reduced glutathione, glutathione -s- transferase, and catalase (CAT), and increasing oxidant levels such as maloaldehyde and nitric oxide. Immunohistochemistry results showed increased expression of NF-κB, TNF-α, and IL-1ß in the cortex and hippocampus of mice brains. CONCLUSIONS: Results from the study conclude that stress increases the likelihood of eliciting an epileptic attack by increasing the level of reactive oxygen species and neuroinflammation.
Sujet(s)
Maladies neuro-inflammatoires , Stress oxydatif , Pentétrazol , Crises épileptiques , Animaux , Souris , Crises épileptiques/métabolisme , Crises épileptiques/induit chimiquement , Crises épileptiques/anatomopathologie , Mâle , Maladies neuro-inflammatoires/métabolisme , Maladies neuro-inflammatoires/étiologie , Maladies neuro-inflammatoires/anatomopathologie , Stress psychologique/complications , Stress psychologique/métabolisme , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Maladie chronique , Comportement animalRÉSUMÉ
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.
Sujet(s)
Anticonvulsivants , Modèles animaux de maladie humaine , Épilepsie , Pentétrazol , Danio zébré , Animaux , Anticonvulsivants/pharmacologie , Anticonvulsivants/usage thérapeutique , Pentétrazol/effets indésirables , Épilepsie/traitement médicamenteux , Épilepsie/induit chimiquement , Crises épileptiques/traitement médicamenteux , Crises épileptiques/induit chimiquement , Électroencéphalographie , Acide valproïque/pharmacologie , Larve/effets des médicaments et des substances chimiques , Encéphale/effets des médicaments et des substances chimiques , Encéphale/anatomopathologie , Inositol/analogues et dérivésRÉSUMÉ
The Ocimum species present active compounds with the potential to develop drugs for treating chronic disease conditions, such as anxiety and seizures. The present study aims to investigate the anticonvulsant and anxiolytic-like effect of the essential oil from O. basilicum Linn (OEFOb) leaves and its major constituent estragole (ES) in vivo on adult zebrafish (aZF) and in silico. The aZF were treated with OEFOb or ES or vehicle and submitted to the tests of toxicity, open-field, anxiety, and convulsion and validated the interactions of the estragole on the involvement of GABAergic and serotonergic receptors by molecular docking assay. The results showed that the oral administration of OEFOb and ES did not have a toxic effect on the aZF and showed anxiolytic-like effects with the involvement of GABAA, 5-HT1, 5-HT2A/2C and 5-HT3A/3B as well on anxiety induced by alcohol withdrawal. The OEFOb and ES showed anticonvulsant potential attenuating the seizures induced by pentylenetetrazole (PTZ) by modulation of the GABAA system. Both anxiolytic and anticonvulsant effects were corroborated by the potential of the interaction of ES by in silico assay. These study samples demonstrate the pharmacological evidence and potential for using these compounds to develop new anxiolytic and anticonvulsant drugs.
Sujet(s)
Dérivés de l'allylbenzène , Anisoles , Anxiolytiques , Anticonvulsivants , Ocimum basilicum , Huile essentielle , Feuilles de plante , Crises épileptiques , Danio zébré , Animaux , Anxiolytiques/pharmacologie , Anxiolytiques/composition chimique , Anxiolytiques/isolement et purification , Anticonvulsivants/pharmacologie , Anticonvulsivants/composition chimique , Anticonvulsivants/isolement et purification , Huile essentielle/pharmacologie , Huile essentielle/isolement et purification , Huile essentielle/composition chimique , Feuilles de plante/composition chimique , Ocimum basilicum/composition chimique , Anisoles/pharmacologie , Anisoles/isolement et purification , Dérivés de l'allylbenzène/pharmacologie , Crises épileptiques/traitement médicamenteux , Crises épileptiques/induit chimiquement , Simulation de docking moléculaire , Anxiété/traitement médicamenteux , Mâle , Pentétrazol/toxicitéRÉSUMÉ
ETHNOPHARMACOLOGICAL RELEVANCE: Saffron, a traditional Chinese medicine, is derived from Crocus sativus L. stigmas and has been reported to possess neuroprotective properties and potentially contribute to the inhibition of apoptosis and inflammation. Safranal, a potent monothyral aldehyde, is a main component of saffron that has been reported to have antiepileptic activity. However, the specific mechanism by which safranal suppresses epileptic seizures via its antiapoptotic and anti-inflammatory properties is unclear. AIM: To evaluate the effect of safranal on seizure severity, inflammation, and postictal neuronal apoptosis in a mouse model of pentetrazole (PTZ)-induced seizures and explore the underlying mechanism involved. MATERIALS AND METHODS: The seizure stage and latency of stage 2 and 4 were quantified to assess the efficacy of safranal in mitigating PTZ-induced epileptic seizures in mice. Electroencephalography (EEG) was employed to monitor epileptiform afterdischarges in each experimental group. The cognitive abilities and motor functions of the mice were evaluated using the novel object recognition test and the open field test, respectively. Neurons were quantified using hematoxylin and eosin staining. Additionally, bioinformatics tools were utilized to predict the interactions between safranal and specific target proteins. Glycogen synthase kinase-3ß (GSK-3ß), mitochondrial apoptosis-related proteins, and inflammatory factor levels were analyzed through western blotting. Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) concentrations in brain tissue were assessed by ELISA. RESULTS: Safranal decreased the average seizure stage and increased the lantency of stage 2 and 4 seizures in PTZ-induced epileptic mice. Additionally, safranal exhibited neuroprotective effects on hippocampal CA1 and CA3 neurons and reduced hyperactivity caused by postictal hyperexcitability. Bioinformatics analysis revealed that safranal can bind to five specific proteins, including GSK-3ß. By promoting Ser9 phosphorylation and inhibiting GSK-3ß activity, safranal effectively suppressed the NF-κB signaling pathway. Moreover, the findings indicate that safranal treatment can decrease TNF-α and IL-1ß levels in the cerebral tissues of epileptic mice and downregulate mitochondrial apoptosis-related proteins, including Bcl-2, Bax, Bak, Caspase 9, and Caspase 3. CONCLUSION: Safranal can suppress the NF-κB signaling pathway and mitochondrial-dependent apoptosis through GSK-3ß inactivation, suggesting that it is a promising therapeutic agent for epilepsy treatment.
Sujet(s)
Apoptose , Cyclohexènes , Glycogen synthase kinase 3 beta , Mitochondries , Facteur de transcription NF-kappa B , Pentétrazol , Crises épileptiques , Transduction du signal , Terpènes , Animaux , Cyclohexènes/pharmacologie , Cyclohexènes/usage thérapeutique , Apoptose/effets des médicaments et des substances chimiques , Terpènes/pharmacologie , Terpènes/usage thérapeutique , Mâle , Glycogen synthase kinase 3 beta/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Facteur de transcription NF-kappa B/métabolisme , Souris , Crises épileptiques/induit chimiquement , Crises épileptiques/traitement médicamenteux , Crises épileptiques/métabolisme , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/métabolisme , Anticonvulsivants/pharmacologie , Épilepsie/traitement médicamenteux , Épilepsie/induit chimiquement , Modèles animaux de maladie humaineRÉSUMÉ
Finding new and effective natural products for designing antiepileptic drugs is highly important in the scientific community. The scorpion venom heat-resistant peptide (SVHRP) was purified from Buthus martensii Karsch scorpion venom, and subsequent analysis of the amino acid sequence facilitated the synthesis of a peptide known as scorpion venom heat-resistant synthesis peptide (SVHRSP) using a technique for peptide synthesis. Previous studies have demonstrated that the SVHRSP can inhibit neuroinflammation and provide neuroprotection. This study aimed to investigate the antiepileptic effect of SVHRSP on both acute and chronic kindling seizure models by inducing seizures in male rats through intraperitoneal administration of pentylenetetrazole (PTZ). Additionally, an N-methyl-D-aspartate (NMDA)-induced neuronal injury model was used to observe the anti-excitotoxic effect of SVHRSP in vitro. Our findings showed that treatment with SVHRSP effectively alleviated seizure severity, prolonged latency, and attenuated neuronal loss and glial cell activation. It also demonstrated the prevention of alterations in the expression levels of NMDA receptor subunits and phosphorylated p38 MAPK protein, as well as an improvement in spatial reference memory impairment during Morris water maze (MWM) testing in PTZ-kindled rats. In vitro experiments further revealed that SVHRSP was capable of attenuating neuronal action potential firing, inhibiting NMDA receptor currents and intracellular calcium overload, and reducing neuronal injury. These results suggest that the antiepileptic and neuroprotective effects of SVHRSP may be mediated through the regulation of NMDA receptor function and expression. This study provides new insight into therapeutic strategies for epilepsy.
Sujet(s)
Anticonvulsivants , Neuroprotecteurs , Peptides , Rat Sprague-Dawley , Récepteurs du N-méthyl-D-aspartate , Venins de scorpion , Crises épileptiques , Animaux , Mâle , Récepteurs du N-méthyl-D-aspartate/métabolisme , Venins de scorpion/pharmacologie , Venins de scorpion/composition chimique , Rats , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Crises épileptiques/traitement médicamenteux , Crises épileptiques/prévention et contrôle , Peptides/pharmacologie , Peptides/usage thérapeutique , Peptides/composition chimique , Anticonvulsivants/pharmacologie , Anticonvulsivants/usage thérapeutique , Anticonvulsivants/composition chimique , Pentétrazol , p38 Mitogen-Activated Protein Kinases/métabolisme , Température élevée , Épilepsie/traitement médicamenteux , Épilepsie/induit chimiquement , Neurones/effets des médicaments et des substances chimiques , Neurones/métabolisme , Neurones/anatomopathologie , Modèles animaux de maladie humaineRÉSUMÉ
Zebrafish larvae exposed to chemoconvulsants show behavioral seizures and electrographic abnormalities similar to the other mammalian models, making it a potential tool in epilepsy research. During the embryonic stage, zebrafish remains transparent which enables real-time developmental detection and in-situ gene/protein expression. However, pigmentation during the larval stage restricts transparency. Phenylthiourea (1-phenyl-2-thiourea; PTU) is a commonly used pigmentation blocker that maintains larval transparency. It is widely used along with chemoconvulsants to study in situ expressions in epileptic larvae, however, its effect on seizures largely remains unknown. Therefore, in the present study, the effect of PTU-mediated depigmentation was studied on pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. After spawning, the fish embryos were subjected to standard depigmentation protocol using 0.13 mM PTU. At 7-days post fertilization seizures were induced using 8 mM PTZ. PTU exposure significantly reduced PTZ-mediated hyperactive responses indicated by decreased distance travelled and swimming velocity of the larvae. Furthermore, PTU-exposed depigmented larvae also showed an increase in the latency to the onset of PTZ-mediated clonic-like seizures. The results concluded that PTU depigmentation protocol reduces the seizurogenic response of PTZ, hence its usage for imaging zebrafish larvae must be carefully monitored to avoid erroneous results.
Sujet(s)
Larve , Pentétrazol , Phényl-thiourée , Crises épileptiques , Danio zébré , Animaux , Danio zébré/embryologie , Larve/effets des médicaments et des substances chimiques , Phényl-thiourée/pharmacologie , Crises épileptiques/induit chimiquement , Pigmentation/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , ConvulsivantsRÉSUMÉ
Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of these pathways. Trigonelline (TRG) has been shown to possess various pharmacological effects like neuroprotection. Therefore, this study was performed to determine TRG's anticonvulsant effects, focusing on its potential effects on N-methyl-D-aspartate (NMDA) receptors, a type of glutamate receptor, and oxidative stress state in the prefrontal cortex (PFC) in PTZ-induced seizure in mice. Seventy-two male mice were randomly divided into nine groups. The groups included mice that received normal saline, TRG at doses of 10, 50, and 100 mg/kg, diazepam, NMDA (an agonist), ketamine (an antagonist), the effective dose of TRG with NMDA, as well as sub-effective dose of TRG with ketamine, respectively. All agents were administrated intraperitoneally 60 min before induction of seizures by PTZ. Latency to seizure, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels in serum and PFC were measured. Furthermore, the gene expression of NR2A and NR2B, subunits of NMDA receptors, was measured in the PFC. TRG administration increased the latency to seizure onset and enhanced TAC while reducing MDA levels in both the PFC and serum. TRG also decreased the gene expression of NR2B in the PFC. Unexpectedly, the findings revealed that the concurrent administration of ketamine amplified, whereas NMDA mitigated, the impact of TRG on latency to seizure. Furthermore, NMDA diminished the positive effects of TRG on antioxidant capacity and oxidative stress, while ketamine amplified these beneficial effects, indicating a complex interaction between TRG and NMDA receptor modulation. In the gene expression of NMDA receptors, results showed that ketamine significantly decreased the gene expression of NR2B when co-administrated with a sub-effective dose of TRG. It was found that, at least partially, the anticonvulsant effect of TRG in PTZ-induced seizures in male mice was mediated by the attenuation of glutamatergic neurotransmission as well as the reduction of oxidative stress.
Sujet(s)
Alcaloïdes , Anticonvulsivants , Stress oxydatif , Récepteurs du N-méthyl-D-aspartate , Crises épileptiques , Animaux , Récepteurs du N-méthyl-D-aspartate/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Anticonvulsivants/pharmacologie , Souris , Mâle , Alcaloïdes/pharmacologie , Crises épileptiques/traitement médicamenteux , Crises épileptiques/métabolisme , Crises épileptiques/induit chimiquement , Cortex préfrontal/métabolisme , Cortex préfrontal/effets des médicaments et des substances chimiques , Malonaldéhyde/métabolisme , Kétamine/pharmacologie , Pentétrazol/toxicité , Antioxydants/pharmacologieRÉSUMÉ
New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. All the synthesized compounds were characterized by thin layer chromatography and spectral analysis. The antiepileptic potential of the synthesized compounds has been tested by following standard animal screening models, including maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The neurotoxic and antidepression effects of the synthesized compounds were checked by utilizing rotarod apparatus, and motor impairment test (by actophotometer) respectively. The study concluded that compounds 9c, 9d, 9f, 9i, 9n, and 9o possessed good antiepileptic potential compared to standard drugs like carbamazepine and phenytoin. The results of the rotarod performance test also established them without any neurotoxicity. The motor impairment test revealed that the synthesized compounds are also good antidepressants. In-silico studies have been performed for calculation of pharmacophore pattern, prediction of pharmacokinetic properties which determine the eligibility of synthesized compounds as orally administered molecules and interactions with the target proteins. The result of in-silico studies reinforced results obtained by inâ vivo study of the synthesized compounds and their possible mechanism of antiepileptic action i. e. via inhibiting voltage-gated sodium channels (VGSCs) and gamma-aminobutyric acid-A receptor.
Sujet(s)
Anticonvulsivants , Benzothiazoles , Pyrazoles , Anticonvulsivants/composition chimique , Anticonvulsivants/synthèse chimique , Anticonvulsivants/pharmacologie , Animaux , Benzothiazoles/composition chimique , Benzothiazoles/antagonistes et inhibiteurs , Benzothiazoles/pharmacologie , Benzothiazoles/synthèse chimique , Souris , Pyrazoles/composition chimique , Pyrazoles/pharmacologie , Pyrazoles/synthèse chimique , Pentétrazol , Électrochoc , Relation structure-activité , Crises épileptiques/traitement médicamenteux , Crises épileptiques/induit chimiquement , Mâle , Structure moléculaire , Simulation de docking moléculaire , Modèles animaux de maladie humaineRÉSUMÉ
Natural compounds are increasingly being studied for their potential neuroprotective effects against inflammatory neurological diseases. Epilepsy is a common neurological disease associated with inflammatory processes, and around 30% of people with epilepsy do not respond to traditional treatments. Some flavonoids, when taken along with antiseizure medications can help reduce the likelihood of drug-resistant epilepsy. Baicalin, a plant-based compound, has been shown to possess pharmacological properties such as anti-inflammatory, neuroprotective, anticonvulsant, and antioxidant activities. In this study, we tested the effect of baicalin on an established model of pharmacologically induced seizure in zebrafish using measures of both locomotor behavior and calcium imaging of neuronal activity. The results of our study showed that, at the tested concentration, and contrary to other studies in rodents, baicalin did not have an anti-seizure effect in zebrafish larvae. However, given its known properties, other concentrations and approaches should be explored to determine if it could potentially have other beneficial effects, either alone or when administered in combination with classic antiseizure medications.
Sujet(s)
Calcium , Flavonoïdes , Larve , Neurones , Pentétrazol , Crises épileptiques , Danio zébré , Animaux , Flavonoïdes/pharmacologie , Crises épileptiques/traitement médicamenteux , Crises épileptiques/induit chimiquement , Larve/effets des médicaments et des substances chimiques , Calcium/métabolisme , Neurones/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Anticonvulsivants/pharmacologie , Relation dose-effet des médicaments , Convulsivants/toxicité , Locomotion/effets des médicaments et des substances chimiques , Activité motrice/effets des médicaments et des substances chimiquesRÉSUMÉ
OBJECTIVE: The objective of this study is to determine whether inhibition of mitophagy affects seizures through Clathrin-mediated endocytosis (CME). METHODS: Pentylenetetrazol (PTZ) was intraperitoneally injected daily to establish a chronic PTZ-kindled seizure. The Western blot (WB) was used to compare the differences in Parkin protein expression between the epilepsy group and the control group. Immunofluorescence was used to detect the expression of MitoTracker and LysoTracker. Transferrin-Alexa488 (Tf-A488) was injected into the hippocampus of mice. We evaluated the effect of 3-methyladenine (3-MA) on epilepsy behavior through observation in PTZ-kindled models. RESULTS: The methylated derivative of adenine, known as 3-MA, has been extensively utilized in the field of autophagy research. The transferrin protein is internalized from the extracellular environment into the intracellular space via the CME pathway. Tf-A488 uses a fluorescent marker to track CME. Western blot showed that the expression of Parkin was significantly increased in the PTZ-kindled model (p < 0.05), while 3-MA could reduce the expression (p < 0.05). The fluorescence uptake of MitoTracker and LysoTracker was increased in the primary cultured neurons induced by magnesium-free extracellular fluid (p < 0.05); the fluorescence uptake of Tf-A488 was significantly decreased in the 3-MA group compared with the control group (p < 0.05). Following hippocampal injection of Tf-A488, both the epilepsy group and the 3-MA group exhibited decreased fluorescence uptake, with a more pronounced effect observed in the 3-MA group. Inhibition of mitophagy by 3-MA from day 3 to day 9 progressively exacerbated seizure severity and shortened latency. SIGNIFICANCE: It is speculated that the aggravation of seizures by 3-MA may be related to the failure to remove damaged mitochondria in time and effectively after inhibiting mitochondrial autophagy, affecting the vesicle endocytosis function of CME and increasing the susceptibility to epilepsy. SUMMARY: Abnormal mitophagy was observed in a chronic pentylenetetrazol-induced seizure model and a Mg2+-free-induced spontaneous recurrent epileptiform discharge model. A fluorescent transferrin marker was utilized to track clathrin-mediated endocytosis. Using an autophagy inhibitor (3-methyladenine) on primary cultured neurons, we discovered that inhibition of autophagy led to a reduction in fluorescent transferrin uptake, while impairing clathrin-mediated endocytosis function mediated by mitophagy. Finally, we examined the effects of 3-methyladenine in an animal model of seizures showing that it exacerbated seizure severity. Ultimately, this study provides insights into potential mechanisms through which mitophagy regulates clathrin-mediated endocytosis in epilepsy.
Sujet(s)
Autophagie , Clathrine , Endocytose , Épilepsie , Mitochondries , Mitophagie , Animaux , Souris , Épilepsie/induit chimiquement , Épilepsie/métabolisme , Endocytose/physiologie , Endocytose/effets des médicaments et des substances chimiques , Autophagie/effets des médicaments et des substances chimiques , Autophagie/physiologie , Mitochondries/métabolisme , Mitochondries/effets des médicaments et des substances chimiques , Mitophagie/effets des médicaments et des substances chimiques , Mitophagie/physiologie , Clathrine/métabolisme , Mâle , Pentétrazol , Adénine/analogues et dérivés , Adénine/pharmacologie , Hippocampe/métabolisme , Hippocampe/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Ubiquitin-protein ligases/métabolismeRÉSUMÉ
The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c-fos and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out (CACNA2D2 KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-fos and ΔFosB expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1â h after handling-associated convulsions, KO mice had fewer c-fos-positive cells but dramatically increased ΔFosB expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c-fos expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.
Sujet(s)
Canaux calciques , Hippocampe , Souris knockout , Protéines proto-oncogènes c-fos , Crises épileptiques , Animaux , Souris , Canaux calciques/métabolisme , Canaux calciques/génétique , Convulsivants/toxicité , Modèles animaux de maladie humaine , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Souris de lignée C57BL , Neurones/métabolisme , Neurones/anatomopathologie , Pentétrazol , Protéines proto-oncogènes c-fos/métabolisme , Crises épileptiques/métabolisme , Crises épileptiques/génétique , Crises épileptiques/anatomopathologieRÉSUMÉ
Two series, "a" and "b", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1-3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a-9a and 1b-9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "b" series, particularly for compound 8b.