RESUMEN
Background: Edaravone is an anti-stroke medication that may have nitric oxide (NO) modulating properties. This study evaluated the role of NO in the acute and sub-chronic anticonvulsant effects of edaravone in murine models of seizures induced by intraperitoneal (IP) or intravenous (IV) injections of pentylenetetrazole (PTZ) or electroshock (maximal electroshock seizure [MES]). Methods: 132 male albino mice were randomly divided into 22 groups (n=6) and given IP injections of vehicle or edaravone either acutely or for eight days (sub-chronically). The seizure was induced by electroshock or PTZ (IP or IV). The following edaravone doses were used: 7.5, 10, 12.5 (acute); 5, 7.5, 10 (sub-chronic) in IP PTZ model; 5, 7.5, 10 in IV PTZ model; and 5, 10 mg/Kg in the MES. To evaluate NO involvement, 216 mice were randomly divided into 36 groups (n=6) and pretreated with vehicle, edaravone, a non-specific nitric oxide synthase (NOS) inhibitor: N(ω)-nitro-L-arginine methyl ester (L-NAME) (5 mg/Kg), a specific nNOS inhibitor: 7-nitroindazole (7-NI) (60 mg/Kg), or a combination of edaravone plus L-NAME or 7-NI, either acutely or for eight days before seizure induction. Doses of edaravone were as follows: in IP PTZ model: 12.5 (acute) and 10 (sub-chronic); in IV PTZ model: 10; and in the MES: 5 mg/Kg. Data were analyzed using the one-way analysis of variance (ANOVA) followed by Tukey's test (SPSS 18). P≤0.05 was considered statistically significant. Results: In the IP PTZ model, edaravone increased time latencies to seizures (P<0.001), prevented tonic seizures, and death. Edaravone increased the seizure threshold (P<0.001) in the IV PTZ model and shortened the duration of tonic hind-limb extension (THE) in the MES model (P<0.001). In comparison to mice treated with edaravone alone, adding L-NAME or 7-NI reduced seizure time latencies (P<0.001), reduced seizure threshold (P<0.001), and increased THE duration (P<0.001). Conclusion: Edaravone (acute or sub-chronic) could prevent seizures by modulating NO signaling pathways.
Asunto(s)
Anticonvulsivantes , Pentilenotetrazol , Masculino , Ratones , Animales , Pentilenotetrazol/efectos adversos , Anticonvulsivantes/efectos adversos , Edaravona/efectos adversos , Óxido Nítrico/efectos adversos , Óxido Nítrico/metabolismo , NG-Nitroarginina Metil Éster/efectos adversos , Electrochoque/efectos adversos , Convulsiones/etiología , Convulsiones/inducido químicamente , Inhibidores Enzimáticos/efectos adversosRESUMEN
In contrast to the other components of the medium-chain triglycerides ketogenic diet (MCT KD), i.e., caprylic acid (CA8), a comprehensive evaluation of caproic (CA6) and lauric acids' (CA12) properties in standard chemical and electrical seizure tests in mice has not yet been performed. We investigated their effects in maximal electroshock seizure threshold (MEST), 6 Hz seizure threshold and intravenous (i.v.) pentylenetetrazole (PTZ) seizure tests. Since ketone body production can be regulated by the activation of 5'AMP-activated protein kinase (AMPK), we hypothesized that metformin (an AMPK activator) enhance ketogenesis and would act synergistically with the fatty acids to inhibit convulsions. We assessed the effects of acute and chronic co-treatment with metformin and CA6/CA8 on seizures. CA6 and CA12 (p.o.) increased seizure threshold in the 6 Hz seizure test. CA6 at the highest tested dose (30 mmol/kg) developed toxicity in several mice, impaired motor performance and induced ketoacidosis. Acute and chronic co-treatment with metformin and CA6/CA8 did not affect seizure thresholds. Moreover, we observed the pro-convulsive effect of the acute co-administration of CA8 (5 mmol/kg) and metformin (100 mg/kg). Since this co-treatment was pro-convulsive, the safety profile and risk/benefit ratio of MCT KD and metformin concomitant therapy in epileptic patients should be further evaluated.
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Epilepsia , Metformina , Ratones , Animales , Anticonvulsivantes/efectos adversos , Metformina/farmacología , Metformina/uso terapéutico , Proteínas Quinasas Activadas por AMP , Convulsiones/inducido químicamente , Epilepsia/tratamiento farmacológico , Pentilenotetrazol/efectos adversos , Electrochoque/efectos adversos , Relación Dosis-Respuesta a Droga , Modelos Animales de EnfermedadRESUMEN
N-(2-hydroxyethyl) nicotinamide nitrate (nicorandil), a nitrate that activates adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, is generally used in the treatment of angina and offers long-term cardioprotective effects. It has been reported that several KATP channel openers can effectively alleviate the symptoms of seizure. The purpose of this study was to investigate the improvement in seizures induced by nicorandil. In this study, seizure tests were used to evaluate the effect of different doses of nicorandil by analysing seizure incidence, including minimal clonic seizure and generalised tonic-clonic seizure. We used a maximal electroshock seizure (MES) model, a metrazol maximal seizure (MMS) model and a chronic pentylenetetrazol (PTZ)-induced seizure model to evaluate the effect of nicorandil in improving seizures. Each mouse in the MES model was given an electric shock, while those in the nicorandil group received 0.5, 1, 2, 3 and 6 mg/kg of nicorandil by intraperitoneal injection, respectively. In the MMS model, the mice in the PTZ group and the nicorandil group were injected subcutaneously with PTZ (90 mg/kg), and the mice in the nicorandil group were injected intraperitoneally with 1, 3 and 5 mg/kg nicorandil, respectively. In the chronic PTZ-induced seizure model, the mice in the PTZ group and the nicorandil group were injected intraperitoneally with PTZ (40 mg/kg), and the mice in the nicorandil group were each given 1 and 3 mg/kg of PTZ at a volume of 200 nL. Brain slices containing the hippocampus were prepared, and cell-attached recording was used to record the spontaneous firing of pyramidal neurons in the hippocampal CA1 region. Nicorandil (i.p.) significantly increased both the maximum electroconvulsive protection rate in the MES model and the seizure latency in the MMS model. Nicorandil infused directly onto the hippocampal CA1 region via an implanted cannula relieved symptoms in chronic PTZ-induced seizures. The excitability of pyramidal neurons in the hippocampal CA1 region of the mice was significantly increased after both the acute and chronic administration of PTZ. To a certain extent, nicorandil reversed the increase in both firing frequency and proportion of burst spikes caused by PTZ (P < 0.05). Our results suggest that nicorandil functions by downregulating the excitability of pyramidal neurons in the hippocampal CA1 region of mice and is a potential candidate for the treatment of seizures.
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Anticonvulsivantes , Pentilenotetrazol , Animales , Anticonvulsivantes/efectos adversos , Nicorandil/efectos adversos , Electrochoque/efectos adversos , Nitratos/efectos adversos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Hipocampo , Células Piramidales , Adenosina Trifosfato , Modelos Animales de EnfermedadRESUMEN
Varenicline (VAR) is a partial agonist of brain α4ß2 nicotinic acetylcholine receptors recommended as a first line pharmacotherapy for smoking cessation. The aim of this study was to examine whether VAR affects the protective activity of four classic antiseizure medications, i.e., carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) on maximal electroshock (MES)-induced seizures, which may serve as an experimental model of human-generalized tonic-clonic seizures in mice. VAR administered intraperitoneally (i.p.) at a subthreshold dose of 0.5 mg/kg decreased the protective activity of CBZ against MES-induced convulsions, increasing its median effective dose (ED50) from 10.92 ± 1.0 to 18.15 ± 1.73 mg/kg (p < 0.01). The effect of VAR was dose-dependent because a lower dose of VAR (0.25 mg/kg) failed to antagonize the protective activity of CBZ. VAR administered at the subthreshold dose of 0.5 mg/kg had no impact on the protective activity of PB, PHT, and VPA in the mouse MES model. The inhibitory effect of VAR on the protective activity of CBZ against tonic-clonic convulsions most likely resulted from the pharmacodynamic mechanism(s) and was not associated with the changes in total brain concentrations of CBZ. VAR-evoked alterations in the anticonvulsive activity of CBZ may be of serious concern for epileptic tobacco smokers.
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Anticonvulsivantes , Convulsiones , Humanos , Ratones , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Vareniclina/farmacología , Vareniclina/uso terapéutico , Electrochoque/efectos adversos , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Encéfalo , Carbamazepina/farmacología , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Ácido Valproico/farmacología , Fenitoína , Relación Dosis-Respuesta a Droga , Modelos Animales de EnfermedadRESUMEN
Electroconvulsive shock (ECT) is the most effective treatment for depression but can impair learning and memory. ECT is increasingly being shown to activate astrocytes and induce neuroinflammation, resulting in cognitive decline. Activated astrocytes can differentiate into two subtypes, A1-type astrocytes and A2-type astrocytes. Regarding cognitive function, neurotoxic A1 astrocytes and neuroprotective A2 astrocytes may exhibit opposite effects. Specifically, prokineticin 2 (PK2) functions as an essential mediator of inflammation and induces a selective A2-protective phenotype in astrocytes. This study aimed to clarify how PK2 promotes improved learning memory following electroconvulsive shock (ECS). As part of the study, rats were modeled using chronic unpredictable mild stress. Behavioral experiments were conducted to assess their cognitive abilities and depression-like behaviors. Western blot was used to determine the expression of PK2. Immunohistochemical and electron microscopy analyses of the hippocampal CA1 region were conducted to study the activation of astrocyte subtypes and synaptic ultrastructure, respectively. In this study, rats' spatial learning and memory impairment began to improve as activated A1-subtype astrocytes gradually decreased, and PK2 and A2 phenotype activation peaked on the third day after ECS. PKRA7 (PK2 antagonist) inhibits A2-type astrocyte activation partially and suppresses spatial learning and memory improvement. Collectively, our findings support that PK2 may induce a selective modulation of astrocytic polarization to a protective phenotype to promote learning and memory improvement after ECS.
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Astrocitos , Depresión , Animales , Ratas , Astrocitos/metabolismo , Depresión/metabolismo , Electrochoque/efectos adversos , Electrochoque/métodos , Aprendizaje , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismoRESUMEN
The G-protein coupled receptor 39 (GPR39) is gaining increasing attention as a target for future drugs, yet there are gaps in the understanding of its pharmacology. Zinc is an endogenous agonist or an allosteric modulator, while TC-G 1008 is a synthetic, small molecule agonist. Zinc is also a positive allosteric modulator for the activity of TC-G 1008 at GPR39. Activation of GPR39 by TC-G 1008 facilitated the development of epileptogenesis in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy. Congruently, TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure threshold (MEST) test. Here, we investigated the effects of TC-G 1008 under the condition of zinc deficiency. Mice were fed a zinc-adequate diet (ZnA, 50 mg Zn/kg) or a zinc-deficient diet (ZnD, 3 mg Zn/kg) for 4 weeks. Following 4 weeks of dietary zinc restriction, TC-G 1008 was administered as a single dose and the MEST test was performed. Additional groups of mice began the PTZ-kindling model during which TC-G 1008 was administered repeatedly and the diet was continued. TC-G 1008 administered acutely decreased the seizure threshold in the MEST test in mice fed the ZnD diet but not in mice fed the ZnA diet. TC-G 1008 administered chronically increased the maximal seizure severity and the percentage of fully kindled mice in those fed the ZnA diet, but not in mice fed the ZnD diet. Our data showed that the amount of zinc in a diet is a factor contributing to the effects of TC-G 1008 in vivo.
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Epilepsia , Pentilenotetrazol , Ratones , Animales , Electrochoque/efectos adversos , Epilepsia/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Receptores Acoplados a Proteínas G/agonistas , ZincRESUMEN
In the present study, cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), and combinations of CBD and THC, were evaluated in the mouse maximal electroshock (MES) seizure test - an animal model of generalized-onset seizures. Male CF-1 mice were injected intraperitoneally (i.p.) with either CBD, THC or a combination of CBD and THC. The MES test was conducted 2 h after the injection of CBD and 1 h after the injection of THC. A wide range of doses was tested to allow the construction of dose-response curves. Toxicity was assessed using a behavioral rating scale. It was found that: 1) the ED50 for THC alone was 52 mg/kg and its therapeutic index (TI) was 1.7; 2) the ED50 for CBD alone was 190 mg/kg and its TI was 2.4; and 3) the ED50 for a 15:1 combination of CBD+THC was 130 mg/kg + 8.6 mg/kg (CBD + THC). Thus, CBD and THC were both effective in the MES model, and CBD was somewhat more effective in the presence of low (non-therapeutic) doses of THC. The improvement in CBD's effect, however, was less dramatic than that seen in past experiments with the amygdala-kindling model (Fallah et al., 2021). Both CBD alone and CBD+THC in combination might be useful in the treatment of generalized-onset seizures. The advantage of adding THC to CBD, however, might be less than in the treatment of focal-onset seizures.
Asunto(s)
Cannabidiol , Excitación Neurológica , Masculino , Ratones , Animales , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Dronabinol/farmacología , Dronabinol/uso terapéutico , Electrochoque/efectos adversos , Convulsiones/tratamiento farmacológicoRESUMEN
OBJECTIVES: Caffeine is the most widely used psychoactive substance in the world. Animal studies indicate that acute caffeine exposure at high doses may induce seizures and diminish the anticonvulsant activity of antiepileptic drugs (AEDs) at much lower doses. The aim of the current study was to assess the effect of caffeine on the anticonvulsant action of levetiracetam (LEV) and vigabatrin (VGB). METHODS: The anticonvulsant activity of LEV and VGB was examined in the maximal electroshock seizure threshold test in mice (MEST test). All drugs were administered intraperitoneally by single injections, and caffeine was applied at doses capable of interfering with AEDs. Effects of caffeine exposure on AEDs were also investigated in tests of memory and motor performance. RESULTS: Caffeine reduced the protective effect of LEV against electroconvulsions. Total brain concentration of LEV was unaffected by caffeine as well as inversely; LEV had no significant impact on the brain caffeine concentration, suggesting a pharmacodynamic nature of the interaction between LEV and caffeine in the MEST test. VGB at applied doses did not affect the convulsive threshold. Administration of VGB, but not LEV, alone or in combination with caffeine, impaired memory retention. In the chimney test, the combined treatment with AEDs and caffeine did not cause motor coordination impairment. CONCLUSIONS: It is suggested that caffeine may negatively affect the anticonvulsant action of LEV in patients with epilepsy.
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Anticonvulsivantes , Cafeína , Animales , Ratones , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Levetiracetam/farmacología , Levetiracetam/uso terapéutico , Cafeína/farmacología , Electrochoque/efectos adversos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones FarmacológicasRESUMEN
Ranolazine, an antianginal and antiarrhythmic drug blocking slow inactivating persistent sodium currents, is described as a compound with anticonvulsant potential. Since arrhythmia often accompanies seizures, patients suffering from epilepsy are frequently co-treated with antiepileptic and antiarrhythmic drugs. The aim of this study was to evaluate the effect of ranolazine on maximal-electroshock (MES)-induced seizures in mice as well as interactions between ranolazine and classical antiepileptic drugs in this model of epilepsy. Types of pharmacodynamic interactions were established by isobolographic analysis of obtained data. The main findings of the study were that ranolazine behaves like an antiseizure drug in the MES test. Moreover, ranolazine interacted antagonistically with carbamazepine, phenytoin, and phenobarbital in the proportions of 1:3 and 1:1. These interactions occurred pharmacodynamic, since ranolazine did not change the brain levels of antiepileptic drugs measured in the fluorescence polarization immunoassay. Ranolazine and its combinations with carbamazepine, phenytoin, and phenobarbital did not impair motor coordination evaluated in the chimney test. Unfortunately, an attempt to conduct a passive avoidance task (evaluating long-term memory) resulted in ranolazine-induced delayed lethality. In conclusion, ranolazine exhibits clear-cut anticonvulsant properties in the MES test but interacts antagonistically with some antiepileptic drugs. The obtained results need confirmation in clinical studies. The mechanisms of ranolazine-induced toxicity require specific explanation.
Asunto(s)
Anticonvulsivantes , Epilepsia , Animales , Ratones , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Ranolazina/farmacología , Ranolazina/uso terapéutico , Fenitoína/farmacología , Interacciones Farmacológicas , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Epilepsia/tratamiento farmacológico , Carbamazepina/farmacología , Fenobarbital/farmacología , Encéfalo , Electrochoque/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Reacción de PrevenciónRESUMEN
Trimetazidine (TMZ), an anti-ischemic drug for improving cellular metabolism, is mostly administered to patients with poorly controlled ischemic heart disease (IHD). Since IHD is considered the most frequent causative factor of cardiac arrhythmias, and these often coexist with seizure disorders, we decided to investigate the effect of TMZ in the electroconvulsive threshold test (ECT) and its influence on the action of four first-generation antiepileptic drugs in the maximal electroshock test (MES) in mice. The TMZ (up to 120 mg/kg) did not affect the ECT, but applied at doses of 20-120 mg/kg it decreased the antielectroshock action of phenobarbital. The TMZ (50-120 mg/kg) reduced the effect of phenytoin, and, when administered at a dose of 120 mg/kg, it diminished the action of carbamazepine. All of these revealed interactions seem to be pharmacodynamic, since the TMZ did not affect the brain levels of antiepileptic drugs. Furthermore, the combination of TMZ with valproate (but not with other antiepileptic drugs) significantly impaired motor coordination, evaluated using the chimney test. Long-term memory, assessed with a passive-avoidance task, was not affected by either the TMZ or its combinations with antiepileptic drugs. The obtained results suggest that TMZ may not be beneficial as an add-on therapy in patients with IHD and epilepsy.
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Epilepsia , Trimetazidina , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Reacción de Prevención , Encéfalo/metabolismo , Carbamazepina/farmacología , Carbamazepina/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Sinergismo Farmacológico , Electrochoque/efectos adversos , Epilepsia/metabolismo , Ratones , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Fenitoína , Trimetazidina/farmacología , Trimetazidina/uso terapéutico , Ácido Valproico/uso terapéuticoRESUMEN
Combinatorial drug therapy has attracted substantial attention as an emerging strategy for the treatment of diseases with complex pathological mechanisms. We previously developed a potentially universal computational screening approach for combination drugs and used this approach to successfully identify some beneficial combinations for the treatment of heart failure. Herein, this screening approach was used to identify novel combination drugs for the treatment of epilepsy in an approved drug library. The combination of guaifenesin-andrographolide was first discovered as a promising therapy with synergistic anticonvulsant activities in maximal electroshock (MES)- and subcutaneous pentylenetetrazol (sc-PTZ)-induced epilepsy models in vivo. The studies of network analysis, fluorescence imaging, and N-methyl-d-aspartate (NMDA)-induced cytotoxicity further revealed that guaifenesin-andrographolide might synergistically affect NMDA receptors and then alleviate the pathogenesis of epilepsy. Therefore, we report that the combination of guaifenesin-andrographolide exerts effects against epilepsy through a novel synergistic mechanism and is thus a potential treatment for epilepsy, providing a promising mechanism for the design of novel combinatorial drug treatments against epilepsy.
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Epilepsia , Guaifenesina , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Diterpenos , Electrochoque/efectos adversos , Epilepsia/complicaciones , Epilepsia/tratamiento farmacológico , Guaifenesina/efectos adversos , Humanos , Pentilenotetrazol , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S) is a gasotransmitter that promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures or during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS following acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the early phases of the corneally kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels and expressions of related genes in whole brain homogenates from corneally kindled mice were not altered. However, plasma H2S levels were significantly lower during kindling, but not after established kindling. Moreover, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, OPA1, MFN2, Drp1, and Mff during kindling, which did not correlate with changes in gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.
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Electrochoque/efectos adversos , Epilepsia/metabolismo , Sulfuro de Hidrógeno/sangre , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Animales , Cromatografía Liquida , Modelos Animales de Enfermedad , Epilepsia/etiología , Regulación de la Expresión Génica , Excitación Neurológica , Masculino , Metilación , Ratones , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development.
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Anticonvulsivantes/uso terapéutico , Carbamatos/uso terapéutico , Potenciales Evocados Motores , Lamotrigina/uso terapéutico , Fenilendiaminas/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Electrochoque/efectos adversos , Masculino , Ratas , Ratas Sprague-Dawley , Convulsiones/etiología , Estimulación Magnética TranscranealRESUMEN
Increasing evidence suggests that hippocampal neurotrophy may be related to the development of major depressive disorders. Neurogenesis, which can be regulated by neurotrophic factors, is also involved in antidepressant efficacy. This paper reviewed literature on neurotrophic signaling and cell proliferation after electroconvulsive shock (ECS) treatment. All articles were from PubMed, Web of Science, and Scopus databases between 2000 and 2020. The keywords used in the literature search are: "ECS," "ECT," "electroconvulsive seizure," "electroconvulsive shock," "electroconvulsive therapy," "neurotrophic factor," "nerve growth factor," "neurotrophins," "neurogenesis," and "cell proliferation." Eighty-two articles were included in the final analysis. It was shown that compared with acute ECS, repeated ECS increased neurotrophin expression in more brain regions at higher levels and was maintained for a longer time. Similarly, ECS increased cell proliferation in a dose- and time-dependent manner. The increase in cell proliferation was positively correlated with the amount of ECS administered and the newly born cells survived for a long time. The effects of ECS in inducing increases in neurotrophin levels and neurogenesis may contribute to brain function changes and antidepressant effects. Future research may focus on optimal sessions of ECT treatment to obtain the best therapeutic effect.
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Trastorno Depresivo Mayor , Terapia Electroconvulsiva , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Electrochoque/efectos adversos , Hipocampo , Humanos , Factores de Crecimiento Nervioso , NeurogénesisRESUMEN
Epilepsy, one of the most common and most disabling neurological disorders, is characterized by spontaneous recurrent seizures, often associated with structural brain alterations and cognitive and psychiatric comorbidities. In about 30% of patients, the seizures are resistant to current treatments; so more effective treatments are urgently needed. Among the â¼30 clinically approved antiseizure drugs, retigabine (ezogabine) is the only drug that acts as a positive allosteric modulator (or opener) of voltage-gated Kv7 potassium channels, which is particularly interesting for some genetic forms of epilepsy. Here we describe a novel dual-mode-of-action compound, GRT-X (N-[(3-fluorophenyl)-methyl]-1-(2-methoxyethyl)-4-methyl-2-oxo-(7-trifluoromethyl)-1H-quinoline-3-carboxylic acid amide) that activates both Kv7 potassium channels and the mitochondrial translocator protein 18 kDa (TSPO), leading to increased synthesis of brain neurosteroids. TSPO activators are known to exert anti-inflammatory, neuroprotective, anxiolytic, and antidepressive effects, which, together with an antiseizure effect (mediated by Kv7 channels), would be highly relevant for the treatment of epilepsy. This prompted us to compare the antiseizure efficacy of retigabine and GRT-X in six mouse and rat models of epileptic seizures, including the 6-Hz model of difficult-to-treat focal seizures. Furthermore, the tolerability of the two compounds was compared in mice and rats. Potency comparisons were based on both doses and peak plasma concentrations. Overall, GRT-X was more effective than retigabine in three of the six seizure models used here, the most important difference being the high efficacy in the 6-Hz (32 mA) seizure model in mice. Based on drug plasma levels, GRT-X was at least 30 times more potent than retigabine in the latter model. These data indicate that GRT-X is a highly interesting novel anti-seizure drug with a unique (first-in-class) dual-mode mechanism of action.
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Anticonvulsivantes/uso terapéutico , Carbamatos/uso terapéutico , Fenilendiaminas/uso terapéutico , Canales de Potasio con Entrada de Voltaje/metabolismo , Receptores de GABA/metabolismo , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Animales , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Células CHO , Carbamatos/farmacología , Cricetulus , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Masculino , Ratones , Ratones Endogámicos DBA , Ratones Transgénicos , Fenilendiaminas/farmacología , Canales de Potasio con Entrada de Voltaje/agonistas , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Convulsiones/etiología , Resultado del TratamientoRESUMEN
We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model (scPTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED50 MES = 49.6 mg/kg, ED50 6 Hz (32 mA) = 31.3 mg/kg, ED50scPTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.
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Acetamidas/administración & dosificación , Analgésicos/administración & dosificación , Anticonvulsivantes/administración & dosificación , Epilepsia Refractaria/tratamiento farmacológico , Dolor/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Acetamidas/farmacología , Administración Intravenosa , Analgésicos/química , Analgésicos/farmacología , Animales , Anticonvulsivantes/farmacología , Canales de Calcio/metabolismo , Capsaicina/efectos adversos , Modelos Animales de Enfermedad , Epilepsia Refractaria/etiología , Epilepsia Refractaria/metabolismo , Electrochoque/efectos adversos , Formaldehído/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Oxaliplatino/efectos adversos , Dolor/inducido químicamente , Dolor/metabolismo , Pentilenotetrazol/efectos adversos , Convulsiones/etiología , Convulsiones/metabolismo , Canales de Sodio/metabolismo , Canales Catiónicos TRPV/metabolismoRESUMEN
Exposure to stress plays a detrimental role in the pathogenesis of hypertension via neuroinflammation pathways. Microglial neuroinflammation in the rostral ventrolateral medulla (RVLM) exacerbates stress-induced hypertension (SIH) by increasing sympathetic hyperactivity. Mitochondria of microglia are the regulators of innate immune response. Sigma-1R (σ-1R) localizes to the mitochondria-associated membranes (MAMs) and regulates endoplasmic reticulum (ER) and mitochondria communication, in part through its chaperone activity. The present study aims to investigate the protective role of σ-1R on microglial-mediated neuroinflammation. Stress-induced hypertension (SIH) was induced in rats using electric foot shocks and intermittent noise. Arterial blood pressure (ABP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured to evaluate the sympathetic nervous system (SNS) activities. SKF10047 (100 µM), an agonist of σ-1R, was administrated to rats, then σ-1R localization and MAM alterations were detected by immuno-electron microscopy. Mitochondrial calcium homeostasis was examined in primary microglia and/or BV-2 microglia cells. The effect of SKF10047 treatment on the mitochondrial respiratory function of cultured microglia was measured using a Seahorse Extracellular Flux Analyzer. Confocal microscopic images were performed to indicate mitochondrial dynamics. Stress reduces σ-1R's localization at the MAMs, leading to decreased ER-mitochondria contact and IP3R-GRP75-VDAC calcium transport complexes expression in the RVLM of rats. SKF10047 promotes the length and coverage of MAMs in the prorenin-treated microglia. Prorenin treatment increases mitoROS levels, and inhibits Ca2+ signalling between the two organelles, therefore negatively affects ATP production in BV2 cells, and these effects are reversed by SKF10047 treatment. We found mitochondrial hyperfusion and microglial M1 polarization in prorenin-treated microglia. SKF10047 suppresses microglial M1 polarization and RVLM neuroinflammation, subsequently ameliorates sympathetic hyperactivity in stress-induced hypertensive rats. Sigma-1 receptor activation suppresses microglia M1 polarization and neuroinflammation via regulating endoplasmic reticulum-mitochondria contact and mitochondrial functions in stress-induced hypertension rats.
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Retículo Endoplásmico/metabolismo , Hipertensión/metabolismo , Microglía/metabolismo , Mitocondrias/metabolismo , Receptores sigma/agonistas , Animales , Presión Sanguínea/fisiología , Calcio/metabolismo , Polaridad Celular/efectos de los fármacos , Electrochoque/efectos adversos , Retículo Endoplásmico/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipertensión/etiología , Hipertensión/fisiopatología , Mitocondrias/efectos de los fármacos , Fenazocina/análogos & derivados , Fenazocina/farmacología , Ratas , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatología , Receptor Sigma-1RESUMEN
Mental and neurological diseases including depression, Parkinson's disease, dementia, epilepsy, anxiety disorders and bipolar disorders account for a considerable amount of the world's disease burden. Unfortunately, drugs used in the treatment of neurological diseases are expensive, symptomatic and they produce undesirable side effects. People from different cultures prefer to use medicinal plants for the treatment of various ailments ranging from plain to perplex disorders because they are most affordable, cost effective and easily accessible source of treatment in the primary healthcare system throughout the world. Withania coagulans, an erect grayish under-shrub belongs to family Solanaceae. It is common in Pakistan, East India, Iran and Afghanistan. The objective of this study was to analyze the anti-seizure activity of crude methanolic extract of Withania coagulans fruits (MeWc). For screening of this activity, maximal electroshock seizures model (MES) and chemically-induced seizures models were used. In maximal electroshock seizures test MeWc showed significant dose dependent percent protection against hind-limb tonic extension; significant and dose-dependent increase in latency to myoclonic jerks and tonic clonic convulsions and decrease in seizures duration were observed in PTZ-induced seizures. In strychnine-induced convulsions MeWc significantly increased latency to hind-limb tonic extension and percent protection from death in a dose-dependent manner. Thus, it was inferred from the experiments that extract of Withania coagulans showed anticonvulsant activity.
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Anticonvulsivantes , Withania , Animales , Anticonvulsivantes/efectos adversos , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Humanos , Metanol/efectos adversos , Ratones , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
Inhibition of the activity of extracellular signal-regulated kinases (ERK1/2) induced by the activation of the dopamine D2 receptor signalling cascade may be a promising pharmacological target. The aim of this work was to study the involvement of ERK1/2 and dopamine D2 receptor in the mechanism of the anticonvulsant action of valproic acid (VA) and a new benzoylpyridine oxime derivative (GIZH-298), which showed antiepileptic activity in different models of epilepsy. We showed that subchronic exposure to maximal electroshock seizures (MES) for 5 days reduced the density of dopamine D2 receptors in the striatum of mice. GIZH-298 counteracted the decrease in the number of dopamine D2 receptors associated with MES and increased the number of ligand binding sites of dopamine D2 receptors in mice without MES. The affinity of dopamine D2 receptors to the ligand was not changed by GIZH-298. MES caused an increase in ERK1/2 and synapsin I phosphorylation in the striatum while GIZH-298, similar to VA, reduced the levels of both phospho-ERK1/2 and phosphosynapsin I after MES, which correlated with the decrease in the intensity of seizure in mice. In addition, GIZH-298 suppressed ERK1/2 phosphorylation in SH-SY5Y human neuroblastoma cells at therapeutic concentrations, while VA inhibited ERK1/2 phosphorylation in vivo but not in vitro. The data obtained expand the understanding of the mechanisms of action of VA and GIZH-298, which involve regulating the activity of ERK1/2 kinases, probably by modulating dopamine D2 receptors in limbic structures, as well as (in the case of GIZH-298) directly inhibiting of the ERK1/2 cascade.
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Anticonvulsivantes/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Convulsiones/tratamiento farmacológico , Ácido Valproico/farmacología , Animales , Anticonvulsivantes/administración & dosificación , Línea Celular Tumoral , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Electrochoque/efectos adversos , Humanos , Masculino , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neuroblastoma/metabolismo , Fosforilación/efectos de los fármacos , Convulsiones/etiología , Convulsiones/metabolismo , Sinapsinas/metabolismo , Ácido Valproico/administración & dosificación , Ácido Valproico/análogos & derivadosRESUMEN
INTRODUCTION: DL-3-hydroxy-3-phenylpentanamide (HEPP) and DL-3-hydroxy-3-(4'chlorophenyl)-pentanamide (Cl-HEPP) are phenyl-alcohol-amides that are metabotropic GABAB receptor (MGBR) antagonists and protective against absence seizures. This study aims to further characterize the anticonvulsant profile of these drugs. METHODS: HEPP and Cl-HEPP were evaluated in various standardized acute seizure and toxic tests in female Swiss-OF1 mice. RESULTS: Toxicities of HEPP and Cl-HEPP were limited; doses up to 30 mg/kg did not result in hypothermia, reduced spontaneous locomotor activity, or failure of the rotarod test, with doses >15 mg/kg potentiating pentobarbital-induced sleep. In maximal electroshock-induced seizures, 20 mg/kg Cl-HEPP protected 100 % of mice; lower doses shortened post-ictal recovery. Seizure protection occurred against subcutaneous pentylenetetrazole and picrotoxin, being limited against N-methyl-d-aspartate. In bicuculline test, clonic or fatal tonic seizures were decreased, onset delayed, and recovery improved; ED50 values (dose protecting 50 % of the animals) were 37.5 and 25 mg/kg for HEPP and Cl-HEPP, respectively. In magnesium deficiency-dependent audiogenic seizures (MDDAS), ED50 values were 3 and 8 mg/kg for Cl-HEPP and HEPP, respectively. The components of MDDAS (latency, wild running, seizure, and recovery phases) in unprotected animals were only minimally affected by near ED50 doses of Cl-HEPP and HEPP. DISCUSSION: HEPP and, to a greater extent, Cl-HEPP provide anti-seizure protections in several acute seizure tests in mice at nontoxic doses. These results are consistent with the action of these drugs on diverse molecular targets directly resulting from their MGBR antagonistic properties. However, other mechanisms might occur possibly for the protection given in the MES test. Finally, a similarity in the modulation of MDDAS components between the two phenyl alcohol amides and ethosuximide could also be based on the MGBR antagonistic properties of the former, given the recently re-evaluated therapeutic relevant targets of the latter.