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1.
Braz J Biol ; 83: e246194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34468514

RESUMO

Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P<0.01) increased and LPO reduced significantly (P<0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.


Assuntos
Anticonvulsivantes , Transtorno Depressivo Maior , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Encéfalo , Transtorno Depressivo Maior/tratamento farmacológico , Succinato de Desvenlafaxina/farmacologia , Camundongos , Estresse Oxidativo
2.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575901

RESUMO

The term epileptogenesis defines the usually durable process of converting normal brain into an epileptic one. The resistance of a significant proportion of patients with epilepsy to the available pharmacotherapy prompted the concept of a causative treatment option consisting in stopping or modifying the progress of epileptogenesis. Most antiepileptic drugs possess only a weak or no antiepileptogenic potential at all, but a few of them appear promising in this regard; these include, for example, eslicarbazepine (a sodium and T-type channel blocker), lamotrigine (a sodium channel blocker and glutamate antagonist) or levetiracetam (a ligand of synaptic vehicle protein SV2A). Among the approved non-antiepileptic drugs, antiepileptogenic potential seems to reside in losartan (a blocker of angiotensin II type 1 receptors), biperiden (an antiparkinsonian drug), nonsteroidal anti-inflammatory drugs, antioxidative drugs and minocycline (a second-generation tetracycline with anti-inflammatory and antioxidant properties). Among other possible antiepileptogenic compounds, antisense nucleotides have been considered, among these an antagomir targeting microRNA-134. The drugs and agents mentioned above have been evaluated in post-status epilepticus models of epileptogenesis, so their preventive efficacy must be verified. Limited clinical data indicate that biperiden in patients with brain injuries is well-tolerated and seems to reduce the incidence of post-traumatic epilepsy. Exceptionally, in this regard, our own original data presented here point to c-Fos as an early seizure duration, but not seizure intensity-related, marker of early epileptogenesis. Further research of reliable markers of early epileptogenesis is definitely needed to improve the process of designing adequate antiepileptogenic therapies.


Assuntos
Anticonvulsivantes/farmacologia , Biomarcadores , Suscetibilidade a Doenças , Descoberta de Drogas , Epilepsia/etiologia , Epilepsia/metabolismo , Animais , Anticonvulsivantes/química , Antioxidantes/administração & dosagem , Terapia Combinada , Suplementos Nutricionais , Descoberta de Drogas/métodos , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Humanos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/metabolismo
3.
Seizure ; 92: 195-199, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34551366

RESUMO

OBJECTIVE: Results of observational investigations have demonstrated that the risk of a traffic accident is independent of use of AEDs. However, no reports of driving tests conducted with patients administered AEDs have been presented. This study examined this scenario in a simulated driving setting. METHODS: Driving performance of 43 patients with epilepsy (PWE) and prescribed an AED, who were licensed to drive and drove regularly (subject group), was assessed, with the results compared to 40 age- and gender-matched healthy volunteers (control group). Daily driving skills associated with a traffic accident were examined using two different tests provided by a driving simulator software package, road-tracking and car-following. Standard deviation of lateral position (SDLP) and distance coefficient of variation (DCV) were determined as primary and exploratory outcomes, respectively. RESULTS: There was no statistically significant difference for primary outcome shown by SDLP between the subject and control groups (p = 0.906), nor for exploratory outcome shown by DCV (p = 0.063). Multiple regression analysis revealed that age (ß=0.967, p = 0.001), female gender (ß=0.469, p<0.001), and duration of driving experience (ß=-0.583, p = 0.038) were correlated with SDLP. SIGNIFICANCE: The present results demonstrated that the driving performance of PWE taking AEDs was not different from that of healthy volunteers.


Assuntos
Condução de Veículo , Epilepsia , Acidentes de Trânsito , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Feminino , Humanos , Desempenho Psicomotor
4.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361071

RESUMO

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the "bath salts". Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.


Assuntos
Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Benzodioxóis/toxicidade , Canabidiol/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Pirrolidinas/toxicidade , Inibidores da Captação Adrenérgica/toxicidade , Animais , Anticonvulsivantes/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/patologia , Condicionamento Clássico/efeitos dos fármacos , Masculino , Camundongos
5.
Gene ; 805: 145907, 2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-34411648

RESUMO

The gene polymorphisms of ABCB1, EPHX1, and SCN1A were found to influence carbamazepine (CBZ) metabolism and resistance in epilepsy patients, but the relevance remains controversial. To reveal the relationships among the gene polymorphisms of ABCB1, EPHX1, SCN1A and the metabolism and resistance of CBZ, the databases of PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals, China Biology medicine disc and Wan Fang were retrieved for suitable studies up to April 2021. 18 studies containing 3293 epilepsy patients were included. The result revealed the gene polymorphism of ABCB1 c.3435C > T is significantly associated with altered concentration-dose ratios of CBZ (CDRCBZ) (CC vs. CT, OR = 0.25 (95% CI: 0.08-0.42), P = 0.004), and EPHX c.416A > G gene polymorphism may also significantly adjusted the concentration-dose ratios of carbamazepine-10, 11-trans dihydrodiol (CDRCBZD) (AA vs. GG, OR = 0.48 (95% CI: 0.01-0.96), P = 0.045; AG vs. GG, OR = 0.68 (95% CI: 0.16-1.20), P = 0.010, respectively) and the ratio of CBZD:carbamazepine-10,11-epoxide (CBZE) (CDRCBZD:CDRCBZE) (AG vs GG, OR = 0.83 (95% CI: 0.31-1.36), P = 0.002). Furthermore, ABCB1 c.3435C > T polymorphism was also observed to be significantly influenced CBZ resistance (CC vs TT, OR = 1.78 (95% CI: 1.17-2.72), P = 0.008; CT vs TT, OR = 1.60 (95% CI: 1.12-2.30), P = 0.01; CC + CT vs TT, OR = 1.61 (95% CI: 1.15-2.26), P = 0.006, respectively). Therefore, CBZ metabolism and resistance in patients with epilepsy may be adjusted by the gene polymorphisms of ABCB1 c.3435C > T and EPHX1 c.416A > G which provides the further scientific basis for clinical individualized therapy of epilepsy. However, larger sample size studies are still needed to provide further conclusive evidence.


Assuntos
Carbamazepina/metabolismo , Epóxido Hidrolases/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Anticonvulsivantes/farmacologia , Carbamazepina/sangue , Carbamazepina/farmacologia , China , Bases de Dados Genéticas , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Epóxido Hidrolases/metabolismo , Feminino , Genótipo , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Polimorfismo de Nucleotídeo Único/genética
6.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445144

RESUMO

Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.


Assuntos
Encefalopatias/metabolismo , Síndromes Epilépticas/metabolismo , Receptores sigma/metabolismo , Animais , Anticonvulsivantes/farmacologia , Encefalopatias/tratamento farmacológico , Síndromes Epilépticas/tratamento farmacológico , Fenfluramina/farmacologia , Humanos , Convulsões/tratamento farmacológico , Convulsões/metabolismo
7.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360553

RESUMO

Neurotrophins and their receptors are relevant factors in controlling neuroblastoma growth and progression. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) has been shown to downregulate TrkB and upregulate the p75NTR/sortilin receptor complex. In the present study, we investigated the VPA effect on the expression of the neurotrophin-3 (NT-3) receptor TrkC, a favorable prognostic marker of neuroblastoma. We found that VPA induced the expression of both full-length and truncated (TrkC-T1) isoforms of TrkC in human neuroblastoma cell lines without (SH-SY5Y) and with (Kelly, BE(2)-C and IMR 32) MYCN amplification. VPA enhanced cell surface expression of the receptor and increased Akt and ERK1/2 activation by NT-3. The HDAC inhibitors entinostat, romidepsin and vorinostat also increased TrkC in SH-SY5Y, Kelly and BE(2)-C but not IMR 32 cells. TrkC upregulation by VPA involved induction of RUNX3, stimulation of ERK1/2 and JNK, and ERK1/2-mediated Egr1 expression. In SH-SY5Y cell monolayers and spheroids the exposure to NT-3 enhanced the apoptotic cascade triggered by VPA. Gene silencing of both TrkC-T1 and p75NTR prevented the NT-3 proapoptotic effect. Moreover, NT-3 enhanced p75NTR/TrkC-T1 co-immunoprecipitation. The results indicate that VPA upregulates TrkC by activating epigenetic mechanisms and signaling pathways, and sensitizes neuroblastoma cells to NT-3-induced apoptosis.


Assuntos
Anticonvulsivantes/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia de Alvo Molecular , Neuroblastoma/tratamento farmacológico , Receptor trkC/metabolismo , Ácido Valproico/farmacologia , Apoptose , Proliferação de Células , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Receptor trkC/genética , Células Tumorais Cultivadas
8.
Biomolecules ; 11(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34439801

RESUMO

The potential, multifaceted therapeutic profile of cannabidiol (CBD), a major constituent derived from the Cannabis sativa plant, covers a wide range of neurological and psychiatric disorders, ranging from anxiety to pediatric epilepsy and drug addiction. However, the molecular targets responsible for these effects have been only partially identified. In this view, the involvement of the orexin system, the key regulator in arousal and the sleep/wake cycle, and in motivation and reward processes, including drug addiction, prompted us to explore, using computational and experimental approaches, the possibility that CBD could act as a ligand of orexin receptors, orexin 1 receptor of type 1 (OX1R) and type 2 (OX2R). Ligand-binding assays showed that CBD is a selective ligand of OX1R in the low micromolar range (Ki 1.58 ± 0.2 µM) while in vitro functional assays, carried out by intracellular calcium imaging and mobilization assays, showed that CBD acts as an antagonist at this receptor. Finally, the putative binding mode of CBD has been inferred by molecular docking and molecular dynamics simulations and its selectivity toward the OX1R subtype rationalized at the molecular level. This study provides the first evidence that CBD acts as an OX1R antagonist, supporting its potential use in addictive disorders and/or body weight regulation.


Assuntos
Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Canabidiol/farmacologia , Receptores de Orexina/química , Orexinas/química , Animais , Ansiolíticos/química , Ansiolíticos/metabolismo , Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Sítios de Ligação , Células CHO , Cálcio/metabolismo , Canabidiol/química , Canabidiol/metabolismo , Cricetulus , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Imagem Molecular , Antagonistas dos Receptores de Orexina , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Ensaio Radioligante , Transgenes
9.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445626

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta, leading to classical PD motor symptoms. Current therapies are purely symptomatic and do not modify disease progression. Cannabidiol (CBD), one of the main phytocannabinoids identified in Cannabis Sativa, which exhibits a large spectrum of therapeutic properties, including anti-inflammatory and antioxidant effects, suggesting its potential as disease-modifying agent for PD. The aim of this study was to evaluate the effects of chronic treatment with CBD (10 mg/kg, i.p.) on PD-associated neurodegenerative and neuroinflammatory processes, and motor deficits in the 6-hydroxydopamine model. Moreover, we investigated the potential mechanisms by which CBD exerted its effects in this model. CBD-treated animals showed a reduction of nigrostriatal degeneration accompanied by a damping of the neuroinflammatory response and an improvement of motor performance. In particular, CBD exhibits a preferential action on astrocytes and activates the astrocytic transient receptor potential vanilloid 1 (TRPV1), thus, enhancing the endogenous neuroprotective response of ciliary neurotrophic factor (CNTF). These results overall support the potential therapeutic utility of CBD in PD, as both neuroprotective and symptomatic agent.


Assuntos
Comportamento Animal/efeitos dos fármacos , Canabidiol/farmacologia , Fator Neurotrófico Ciliar/metabolismo , Modelos Animais de Doenças , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Canais de Cátion TRPV/metabolismo , Animais , Anticonvulsivantes/farmacologia , Fator Neurotrófico Ciliar/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Masculino , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/genética
10.
Epilepsy Behav ; 122: 108223, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34388666

RESUMO

Glucose metabolism is altered in epilepsy, and this may contribute to seizure generation. Recent research has shown that metabolic therapies including the ketogenic diet and medium chain triglycerides can improve energy metabolism in the brain. Fructose 1,6-bisphosphate (F16BP) is an intermediate of glycolysis and when administered exogenously is anticonvulsant in several rodent seizure models and may alter glucose metabolism. Here, we showed that F16BP elevated the seizure threshold in the acute 6-Hz mouse seizure model and investigated if F16BP could restore impairments in glucose metabolism occurring in the chronic stage of the pilocarpine mouse model of epilepsy. Two weeks after the pilocarpine injections, mice that experienced status epilepticus (SE, "epileptic") and did not experience SE (no SE, "nonepileptic") were injected with vehicle (0.9% saline) or F16BP (1 g/kg in 0.9% saline) daily for 5 consecutive days. At 3 weeks, mice were injected with [U-13C6]-glucose and the % enrichment of 13C in key metabolites in addition to the total levels of each metabolite was measured in the hippocampal formation and liver. Fructose 1,6-bisphosphate increased total GABA in the hippocampal formation, regardless of whether mice had experienced SE. In the hippocampal formation, F16BP prevented reductions in the % 13C enrichment of citrate, succinate, malate, glutamate, GABA and aspartate that occurred in the chronic stage of the pilocarpine model. Interestingly, % 13C enrichment in glucose-derived metabolites was reduced in the liver in the chronic stage of the pilocarpine model. Fructose 1,6-bisphosphate was also beneficial in the liver, preventing reductions in % 13C enrichment of lactate and alanine that were associated with SE. This study confirmed that F16BP is anticonvulsant and can improve elements of glucose metabolism that are dysregulated in the chronic stage of the pilocarpine model, which may be due to reduction of spontaneous seizures. Our results highlight that F16BP may be therapeutically beneficial for epilepsies refractory to treatment.


Assuntos
Epilepsia , Estado Epiléptico , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Frutose/uso terapêutico , Frutosedifosfatos , Glucose/metabolismo , Hipocampo , Fígado , Camundongos , Estresse Oxidativo , Pilocarpina/toxicidade , Estado Epiléptico/tratamento farmacológico
11.
PLoS One ; 16(8): e0255591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34352013

RESUMO

BACKGROUND: Canine urothelial carcinoma is the most common form of canine bladder cancer. Treatment with chemotherapy has variable response rates leading to most dogs succumbing to their disease within a year. Cannabidiol is an emerging treatment within the field of oncology. In reported in vivo studies, cannabidiol has induced apoptosis, reduced cell migration, and acted as a chemotherapy sensitizer in various human tumor types. The aim of this study was to characterize the effects of cannabidiol on canine urothelial carcinoma cell viability and apoptosis as both a single agent and in combination with chemotherapy in vitro. RESULTS: Cannabidiol reduced cell viability and induced apoptosis in canine urothelial cells as determined by crystal violet viability assay and annexin V/propidium iodide flow cytometry. Furthermore, combinations of cannabidiol with mitoxantrone and vinblastine chemotherapy yielded significantly reduced cell viability and increased apoptosis compared to single agent treatment alone. The drug interactions were deemed synergistic based on combination index calculations. Conversely, the combination of cannabidiol and carboplatin did not result in decreased cell viability and increased apoptosis compared to single agent treatment. Combination index calculations suggested an antagonistic interaction between these drugs. Finally, the combination of the non-steroidal anti-inflammatory drug piroxicam with cannabidiol did not significantly affect cell viability, although, some cell lines demonstrated decreased cell viability when mitoxantrone was combined with piroxicam. CONCLUSIONS: Cannabidiol showed promising results as a single agent or in combination with mitoxantrone and vinblastine for treatment of canine urothelial carcinoma cells. Further studies are justified to investigate whether these results are translatable in vivo.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Canabidiol/farmacologia , Doenças do Cão/tratamento farmacológico , Piroxicam/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticonvulsivantes/farmacologia , Apoptose , Carboplatina/administração & dosagem , Sobrevivência Celular , Doenças do Cão/patologia , Cães , Quimioterapia Combinada , Mitoxantrona/administração & dosagem , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/patologia
12.
Psychopharmacology (Berl) ; 238(11): 3167-3181, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34333674

RESUMO

RATIONALE: Pterostilbene is the 3,5-dimethoxy derivative of resveratrol with numerous beneficial effects including neuroprotective properties. Experimental studies revealed its anticonvulsant action in the acute seizure tests. OBJECTIVES: The purpose of the present study was to evaluate the effect of pterostilbene in the pentetrazol (PTZ)-induced kindling model of epilepsy in mice as well as to assess some possible mechanisms of its anticonvulsant action in this model. METHODS: Mice were repeatedly treated with pterostilbene (50-200 mg/kg) and its effect on the development of seizure activity in the PTZ kindling was estimated. Influence of pterostilbene on the locomotor activity and anxiety- and depression-like behavior in the PTZ-kindled mice was also assessed. To understand the possible mechanisms of anticonvulsant activity of pterostilbene, γ-aminobutyric acid (GABA) and glutamate concentrations in the prefrontal cortex and hippocampus of the PTZ-kindled mice were measured using LC-MS/MS method. Moreover, mRNA expression of BDNF, TNF-α, IL-1ß, IL-6, GABRA1A, and GRIN2B was determined by RT-qPCR technique. RESULTS: We found that pterostilbene at a dose of 200 mg/kg considerably reduced seizure activity but did not influence the locomotor activity and depression- and anxiety-like behavior in the PTZ-kindled mice. In the prefrontal cortex and hippocampus, pterostilbene reversed the kindling-induced decrease of GABA concentration. Neither in the prefrontal cortex nor hippocampus pterostilbene affected mRNA expression of IL-1ß, IL-6, GABRA1A, and GRIN2B augmented by PTZ kindling. Pterostilbene at a dose of 100 mg/kg significantly decreased BDNF and TNF-α mRNA expression in the hippocampus of the PTZ-kindled mice. CONCLUSIONS: Although further studies are necessary to understand the mechanism of anticonvulsant properties of pterostilbene, our findings suggest that it might be considered a candidate for a new antiseizure drug.


Assuntos
Anticonvulsivantes , Excitação Neurológica , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Cromatografia Líquida , Depressão/tratamento farmacológico , Camundongos , Pentilenotetrazol/farmacologia , Estilbenos , Espectrometria de Massas em Tandem
14.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205930

RESUMO

BACKGROUND: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. OBJECTIVE: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. METHODS: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. RESULTS: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of "open field" and "elevated plus maze" (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of "forced swimming" (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at -7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor. CONCLUSIONS: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.


Assuntos
Azepinas/administração & dosagem , Azepinas/síntese química , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Convulsões/tratamento farmacológico , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Azepinas/química , Azepinas/farmacologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Pentilenotetrazol/efeitos adversos , Pirimidinas/química , Pirimidinas/farmacologia , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Ratos , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
15.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299361

RESUMO

Zingiber officinale is one of the most frequently used medicinal herbs in Asia. Using rodent seizure models, it was previously shown that Zingiber officinale hydroethanolic extract exerts antiseizure activity, but the active constituents responsible for this effect have not been determined. In this paper, we demonstrated that Zingiber officinale methanolic extract exerts anticonvulsant activity in the pentylenetetrazole (PTZ)-induced hyperlocomotion assay in larval zebrafish. Next, we isolated 6-gingerol (6-GIN)-a major constituent of Zingiber officinale rhizoma. We observed that 6-GIN exerted potent dose-dependent anticonvulsant activity in the PTZ-induced hyperlocomotion seizure assay in zebrafish, which was confirmed electroencephalographically. To obtain further insight into the molecular mechanisms of 6-GIN antiseizure activity, we assessed the concentration of two neurotransmitters in zebrafish, i.e., inhibitory γ-aminobutyric acid (GABA) and excitatory glutamic acid (GLU), and their ratio after exposure to acute PTZ dose. Here, 6-GIN decreased GLU level and reduced the GLU/GABA ratio in PTZ-treated fish compared with only PTZ-bathed fish. This activity was associated with the decrease in grin2b, but not gabra1a, grin1a, gria1a, gria2a, and gria3b expression in PTZ-treated fish. Molecular docking to the human NR2B-containing N-methyl-D-aspartate (NMDA) receptor suggests that 6-GIN might act as an inhibitor and interact with the amino terminal domain, the glutamate-binding site, as well as within the ion channel of the NR2B-containing NMDA receptor. In summary, our study reveals, for the first time, the anticonvulsant activity of 6-GIN. We suggest that this effect might at least be partially mediated by restoring the balance between GABA and GLU in the epileptic brain; however, more studies are needed to prove our hypothesis.


Assuntos
Anticonvulsivantes/farmacologia , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Gengibre/química , Pentilenotetrazol/farmacologia , Extratos Vegetais/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/metabolismo , Peixe-Zebra , Ácido gama-Aminobutírico/metabolismo
16.
Phytomedicine ; 90: 153646, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34280827

RESUMO

BACKGROUND: Gamma-aminobutyric acid A (GABAA) receptors have been implicated in anxiety and epileptic disorders. HYPOTHESIS/PURPOSE: This study aimed to investigate the effects of stigmasterol, a plant sterol (phytosterol) isolated from Artemisia indica Linn on neurological disorders. METHODS: Stigmasterol was evaluated on various recombinant GABAA receptor subtypes expressed in Xenopus laevis oocytes and its anxiolytic and anticonvulsant potential was assessed using the elevated plus maze (EPM), light-dark box (LDB) test, and pentylenetetrazole- (PTZ-) induced seizure paradigms. Furthermore, computational modeling of α2ß2γ2L, α4ß3δ, and α4ß3 subtypes was performed to gain insights into the GABAergic mechanism of stigmasterol. For the first time, a model of GABAδ subtype was generated. Stigmasterol was targeted to all the binding sites (neurotransmitters, positive and negative modulator binding sites) of GABAA α2ß2γ2L, α4ß3, and α4ß3δ complexes by in silico docking. RESULTS: Stigmasterol enhanced GABA-induced currents at ternary α2ß2γ2L, α4ß3δ, and binary α4ß3 GABAAR subtypes. The potentiation of GABA-induced currents at extrasynaptic α4ß3δ was significantly higher compared to the binary α4ß3 subtype, indicating that the δ subunit is important for efficacy. Stigmasterol was found to be a potent positive modulator of the extrasynaptic α4ß3δ subtype, which was also confirmed by computational analysis. The computational analysis reveals that stigmasterol preferentially binds at the transmembrane region shared by positive modulators or a binding site constituted by the M2-M3 region of α4 and M1-M2 of ß3 at α4ß3δ complex. In in vivo studies, Stigmasterol (0.5-3.0 mg/kg, i.p.) exerted significant anxiolytic and anticonvulsant effects in an identical manner of allopregnanolone, indicating the involvement of a GABAergic mechanism. CONCLUSION: To our knowledge, this is the first study reporting the positive modulation of GABAA receptors, anxiolytic and anticonvulsant potential of stigmasterol. Thus, stigmasterol is considered to be a candidate steroidal drug for the treatment of neurological disorders due to its positive modulation of GABA receptors.


Assuntos
Ansiolíticos , Anticonvulsivantes/farmacologia , Moduladores GABAérgicos/farmacologia , Estigmasterol , Animais , Ansiolíticos/farmacologia , Oócitos , Receptores de GABA-A , Convulsões/tratamento farmacológico , Estigmasterol/farmacologia , Xenopus laevis
17.
Expert Opin Drug Metab Toxicol ; 17(9): 1075-1090, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34310255

RESUMO

INTRODUCTION: The present evidence indicates that approximately 70% of patients with epilepsy can be successfully treated with antiepileptic drugs (AEDs). A significant proportion of patients are not under sufficient control, and pharmacoresistant epilepsy is clearly associated with poor quality of life and increased morbidity and mortality. There is a great need for newer therapeutic options able to reduce the percentage of drug-resistant patients. AREAS COVERED: A number of hypotheses trying to explain the development of pharmacoresistance have been put forward. These include: target hypothesis (altered AED targets), transporter (overexpression of brain efflux transporters), pharmacokinetic (overexpression of peripheral efflux transporters in the intestine or kidneys), intrinsic severity (initial high seizure frequency), neural network (aberrant networks), and gene variant hypothesis (genetic polymorphisms). EXPERT OPINION: A continuous search for newer AEDs or among non-AEDs (blockers of efflux transporters, interleukin antagonists, cyclooxygenase inhibitors, mTOR inhibitors, angiotensin II receptor antagonists) may provide efficacious drugs for the management of drug-resistant epilepsy. Also, combinations of AEDs exerting synergy in preclinical and clinical studies (for instance, lamotrigine + valproate, levetiracetam + valproate, topiramate + carbamazepine) might be of importance in this respect. Preclinically antagonistic combinations must be avoided (lamotrigine + carbamazepine, lamotrigine + oxcarbazepine).


Assuntos
Anticonvulsivantes/farmacologia , Resistência a Medicamentos/fisiologia , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Epilepsia/fisiopatologia , Humanos , Qualidade de Vida
18.
Toxicol Appl Pharmacol ; 427: 115655, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329640

RESUMO

Several studies with larvae and adult zebrafish have shown that old and new antiseizure drugs (ASDs) produce discrepant results in seizure tests, locomotor activity or anxiety models. In this study, the pentylenetetrazole seizure test (PTZ) was performed to assess the effectiveness of four new ASDs: lamotrigine (LTG), topiramate (TPM), felbamate (FBM), and levetiracetam (LEV) in the subsequent stages of seizures in adult fish. All ASDs were administered intraperitoneally (i.p.). The time of maximal anticonvulsant effect and the dose-response relationship of the drugs were assessed. The effects of studied ASDs on the locomotor activity and the anxiety-like behavior in the color preference test were also investigated. Furthermore, drug concentrations in zebrafish homogenates were determined. LTG, TPM, and LEV significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII), while FBM was effective only at SI. Locomotor activity decreased after TPM treatment. TPM and FBM exhibited a strong anxiolytic-like effect in the color preference test. LEV at the highest dose tested had a weak anxiolytic-like effect. The HPLC analysis showed average concentrations of the studied ASDs in the fish body during their maximum anticonvulsant activity. The present study shows that FBM cannot inhibit all subsequent PTZ seizure stages in the adult fish. Except for LTG, the studied drugs affected the anxiety-like behavior of treated animals. Furthermore, only TPM significantly changed locomotion parameters. Our findings support the need to accurately characterize the efficacy of new ASDs at different stages of the PTZ-induced seizures in adult zebrafish.


Assuntos
Ansiolíticos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fatores Etários , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Ansiedade/psicologia , Relação Dose-Resposta a Droga , Felbamato/farmacologia , Felbamato/uso terapêutico , Feminino , Lamotrigina/farmacologia , Lamotrigina/uso terapêutico , Levetiracetam/farmacologia , Levetiracetam/uso terapêutico , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Pentilenotetrazol/toxicidade , Convulsões/psicologia , Topiramato/farmacologia , Topiramato/uso terapêutico , Peixe-Zebra
19.
Biomed Res Int ; 2021: 5526780, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34222471

RESUMO

Background: Cannabinoid system affects memory and has anticonvulsant effects in epileptic models. In the current study, the role of cannabinoid 1 (CB1) receptors was investigated in amelioration of the effects of low-frequency stimulation (LFS) on learning and memory impairments in kindled rats. Methods: Electrical stimulation of the hippocampal CA1 area was employed to kindle the animals. LFS was applied to the CA1 area in four trials following the last kindling stimulation. One group of animals received intraperitoneal injection of AM251 (0.1 µg/rat), a CB1 receptor antagonist, before the LFS application. Similarly, CB1 agonist WIN55-212-2 (WIN) was administrated to another group prior to LFS. The Morris water maze (MWM) and the novel object recognition (NOR) tests were executed 48 h after the last kindling stimulation to assess learning and memory. Results: Applying LFS in the kindled+LFS group restored learning and memory impairments in the kindled rats. There was a significant difference between the kindled and the kindled+LFS groups in learning and memory. The application of AM251 reduced the LFS effects significantly. Adversely, WIN acted similarly to LFS and alleviated learning and memory deficits in the kindled+WIN group. In addition, WIN did not counteract the LFS enhancing effects in the KLFS+WIN group. Conclusions: Improving effects of LFS on learning and memory impairments are mediated through the activation of the endocannabinoid (ECB) system.


Assuntos
Endocanabinoides/metabolismo , Hipocampo/efeitos dos fármacos , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/fisiologia , Convulsões/terapia , Animais , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Estimulação Elétrica , Masculino , Aprendizagem em Labirinto , Memória , Transtornos da Memória , Ratos , Ratos Wistar
20.
Molecules ; 26(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074008

RESUMO

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber's rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.


Assuntos
Anticonvulsivantes/farmacologia , Eletrochoque , Animais , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Camundongos , Força Muscular/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pilocarpina/toxicidade , Desempenho Psicomotor/efeitos dos fármacos
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