RESUMO
Encapsulating antiepileptic drugs (AEDs), including ethosuximide (Etho), into nanoparticles shows promise in treating epilepsy. Nanomedicine may be the most significant contributor to addressing this issue. It presents several advantages compared to traditional drug delivery methods and is currently a prominent area of focus in cancer research. Incorporating Etho into bismuth ferrite (BFO) nanoparticles within diverse controlled drug delivery systems is explored to enhance drug efficacy. This approach is primarily desired to aid in targeted drug delivery to the brain's deepest regions while limiting transplacental permeability, reducing fetal exposure, and mitigating associated adverse effects. In this investigation, we explored Etho, an antiepileptic drug commonly employed for treating absence seizures, as the active ingredient in BFO nanoparticles at varying concentrations (10 and 15 mg). Characterization of the drug-containing BFO nanoparticles involved scanning electron microscopy (SEM) and elemental analysis. The thermal properties of the drug-containing BFO nanoparticles were evaluated via differential scanning calorimetry (DSC) analysis. Cytotoxicity evaluations using the MTT assay were conducted on all nanoparticles, and human neuroblastoma cell line cultures (SH-SY5Y) were treated with each particle over multiple time intervals. Cell viability remained at 135% after 7 days when exposed to 15 mg of Etho in BFO nanoparticles. Additionally, in vitro drug release kinetics for Etho revealed sustained release lasting up to 5 hours with a drug concentration of 15 mg.
Assuntos
Anticonvulsivantes , Bismuto , Epilepsia , Etossuximida , Compostos Férricos , Bismuto/química , Humanos , Compostos Férricos/química , Etossuximida/administração & dosagem , Etossuximida/química , Etossuximida/farmacologia , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/farmacocinética , Epilepsia/tratamento farmacológico , Linhagem Celular Tumoral , Nanopartículas/química , Sistemas de Liberação de Medicamentos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Portadores de Fármacos/químicaRESUMO
In our current study, we developed a focused series of original ((benzyloxy)benzyl)propanamide derivatives that demonstrated potent activity across in vivo mouse seizure models, specifically, maximal electroshock (MES) and 6 Hz (32 mA) seizures. Among these derivatives, compound 5 emerged as a lead molecule, exhibiting robust protection following intraperitoneal (i.p.) injection, as follows: ED50 = 48.0 mg/kg in the MES test, ED50 = 45.2 mg/kg in the 6 Hz (32 mA) test, and ED50 = 201.3 mg/kg in the 6 Hz (44 mA) model. Additionally, compound 5 displayed low potential for inducing motor impairment in the rotarod test (TD50 > 300 mg/kg), indicating a potentially favorable therapeutic window. In vitro toxicity assays further supported its promising safety profile. We also attempted to identify a plausible mechanism of action of compound 5 by applying both binding and functional in vitro studies. Overall, the data obtained for this lead molecule justifies the more comprehensive preclinical development of compound 5 as a candidate for a potentially broad-spectrum and safe anticonvulsant.
Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Eletrochoque , Convulsões , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Camundongos , Convulsões/tratamento farmacológico , Masculino , Eletrochoque/efeitos adversos , Humanos , Relação Estrutura-AtividadeRESUMO
Nano-based drug delivery systems are regarded as a promising tool for efficient epilepsy treatment and seizure medication with the least general side effects and socioeconomic challenges. In the current study, we have designed a smart nanoscale drug delivery platform and applied it in the kindling model of epilepsy that is triggered rapidly by epileptic discharges and releases anticonvulsant drugs in situ, such as carbamazepine (CBZ). The CBZ-loaded electroactive ferrocene nanoliposomes had an average diameter of 100.6 nm, a surface charge of -7.08 mV, and high drug encapsulation efficiency (85.4 %). A significant increase in liposome size was observed in response to direct current (50-500 µA) application. This liposome-based drug delivery system can release CBZ at a fast rate in response to both direct current and pulsatile electrical stimulation in vitro. The CBZ-liposome can release the anticonvulsant drug upon epileptiform activity in the kindled rat model and can decline electrographic and behavioral seizure activity in response to electrical stimulation of the hippocampus with an initially subconvulsive current. With satisfactory biosafety results, this "smart" nanocarrier has promising potential as an effective and safe drug delivery system to improve the therapeutic index of antiepileptic drugs.
Assuntos
Anticonvulsivantes , Carbamazepina , Sistemas de Liberação de Medicamentos , Epilepsia , Lipossomos , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Carbamazepina/administração & dosagem , Carbamazepina/química , Carbamazepina/farmacocinética , Epilepsia/tratamento farmacológico , Masculino , Liberação Controlada de Fármacos , Ratos Sprague-Dawley , Ratos , Hipocampo/efeitos dos fármacos , Nanopartículas/administração & dosagem , Nanopartículas/química , Metalocenos/química , Metalocenos/administração & dosagem , Compostos Ferrosos/administração & dosagem , Compostos Ferrosos/química , Estimulação Elétrica , Excitação Neurológica/efeitos dos fármacos , Tamanho da Partícula , Convulsões/tratamento farmacológicoRESUMO
We developed a focused series of original phenyl-glycinamide derivatives which showed potent activity across in vivo mouse seizure models, namely, maximal electroshock (MES) and 6 Hz (using both 32 and 44 mA current intensities) seizure models. Following intraperitoneal (i.p.) administration, compound (R)-32, which was identified as a lead molecule, demonstrated potent protection against all seizure models with ED50 values of 73.9 mg/kg (MES test), 18.8 mg/kg (6 Hz, 32 mA test), and 26.5 mg/kg (6 Hz, 44 mA test). Furthermore, (R)-32 demonstrated efficacy in both the PTZ-induced kindling paradigm and the ivPTZ seizure threshold test. The expression of neurotrophic factors, such as mature brain-derived neurotrophic factor (mBDNF) and nerve growth factor (NGF), in the hippocampus and/or cortex of mice, and the levels of glutamate and GABA were normalized after PTZ-induced kindling by (R)-32. Importantly, besides antiseizure activity, (R)-32 demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (i.p.). No influence on muscular strength and body temperature in mice was observed. Pharmacokinetic studies and in vitro ADME-Tox data (i.e., high metabolic stability in human liver microsomes, a weak influence on CYPs, no hepatotoxicity, satisfactory passive transport, etc.) proved favorable drug-like properties of (R)-32. Thermal stability of (R)-32 shown in thermogravimetry and differential scanning calorimetry gives the opportunity to develop innovative oral solid dosage forms loaded with this compound. The in vitro binding and functional assays indicated its multimodal mechanism of action. (R)-32, beyond TRPV1 antagonism, inhibited calcium and sodium currents at a concentration of 10 µM. Therefore, the data obtained in the current studies justify a more detailed preclinical development of (R)-32 for epilepsy and pain indications.
Assuntos
Analgésicos , Anticonvulsivantes , Convulsões , Animais , Analgésicos/farmacologia , Camundongos , Convulsões/tratamento farmacológico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Masculino , Glicina/farmacologia , Glicina/análogos & derivados , Glicina/química , Modelos Animais de Doenças , Eletrochoque , Humanos , Excitação Neurológica/efeitos dos fármacos , Pentilenotetrazol , Dor/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Descoberta de DrogasRESUMO
Epilepsy is a highly prevalent neurological disease and valproic acid (VPA) is used as a first-line chronic treatment. However, this drug has poor oral bioavailability, which requires the administration of high doses, resulting in adverse effects. Alternative routes of VPA administration have therefore been investigated, such as the nose-to-brain route, which allows the drug to be transported directly from the nasal cavity to the brain. Here, the use of nanostructured lipid carriers (NLC) to encapsulate drugs administered in the nasal cavity has proved advantageous. The aim of this work was to optimise a mucoadhesive formulation of VPA-loaded NLC for intranasal administration to improve the treatment of epilepsy. The Design of Experiment (DoE) was used to optimise the formulation, starting with component optimisation using Mixture Design (MD), followed by optimisation of the manufacturing process parameters using Central Composite Design (CCD). The optimised VPA-loaded NLC had a particle size of 76.1 ± 2.8 nm, a polydispersity index of 0.190 ± 0.027, a zeta potential of 28.1 ± 2.0 mV and an encapsulation efficiency of 85.4 ± 0.8%. The in vitro release study showed VPA release from the NLC of 50 % after 6 h and 100 % after 24 h. The in vitro biocompatibility experiments in various cell lines have shown that the optimised VPA-loaded NLC formulation is safe up to 75 µg/mL, in neuronal (SH-SY5Y), nasal (RPMI 2650) and hepatic (HepG2) cells. Finally, the interaction of the optimised VPA-loaded NLC formulation with nasal mucus was investigated and mucoadhesive properties were observed. The results of this study suggest that the use of intranasal VPA-loaded NLC may be a promising alternative to promote VPA targeting to the brain, thereby improving bioavailability and minimising adverse effects.
Assuntos
Administração Intranasal , Anticonvulsivantes , Encéfalo , Portadores de Fármacos , Lipídeos , Nanoestruturas , Mucosa Nasal , Ácido Valproico , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacocinética , Ácido Valproico/química , Portadores de Fármacos/química , Lipídeos/química , Humanos , Mucosa Nasal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/química , Nanoestruturas/química , Nanoestruturas/administração & dosagem , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Liberação Controlada de Fármacos , Tamanho da Partícula , Adesividade , Animais , Sobrevivência Celular/efeitos dos fármacosRESUMO
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.
Assuntos
Anticonvulsivantes , Berberina , Modelos Animais de Doenças , Epilepsia , Nanopartículas , Pentilenotetrazol , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Wistar , Berberina/farmacologia , Berberina/administração & dosagem , Animais , Masculino , Epilepsia/tratamento farmacológico , Anticonvulsivantes/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Excitação Neurológica/efeitos dos fármacos , Ratos , Tamanho da Partícula , Ácido Láctico , Ácido Poliglicólico , Convulsões/tratamento farmacológicoRESUMO
Antiepileptic drugs (AEDs) are used in the treatment of epilepsy, a neurodegenerative disease characterized by recurrent and untriggered seizures that aim to prevent seizures as a symptomatic treatment. However, they still have significant side effects as well as drug resistance. In recent years, especially 1,3,4-thiadiazoles and 1,2,4-triazoles have attracted attention in preclinical and clinical studies as important drug candidates owing to their anticonvulsant properties. Therefore, in this study, which was conducted to discover AED candidate molecules with reduced side effects at low doses, a series of chiral 2,5-disubstituted-1,3,4-thiadiazoles (4a-d) and 4,5-disubstituted-1,2,4-triazole-3 thiones (5a-d) were designed and synthesized starting from l-phenylalanine ethyl ester hydrochloride. The anticonvulsant activities of the new chiral compounds were assessed in several animal seizure models in mice and rats for initial (phase I) screening after their chemical structures including the configuration of the chiral center were elucidated using spectroscopic methods and elemental analysis. First, all chiral compounds were pre-screened using acute seizure tests induced electrically (maximal electroshock test, 6 Hz psychomotor seizure model) and induced chemically (subcutaneous metrazol seizure model) in mice and also their neurotoxicity (TOX) was determined in the rotorad assay. Two of the tested compounds were used for quantitative testing, and (S)-(+)5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b) and (S)-(+)-(5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5c) emerged as the most promising anticonvulsant drug candidates and also showed low neurotoxicity. The antiepileptogenic potential of these compounds was determined using a chronic seizure induced electrically corneal kindled mouse model. Furthermore, all chiral compounds were tested for their neuroprotective effect against excitotoxic kainic acid (KA) and N-methyl-d-aspartate (NMDA) induced in vitro neuroprotection assay using an organotypic hippocampal slice culture. The KA-induced neuroprotection assay results revealed that compounds 5b and 5c, which are the leading compounds for anticonvulsant activity, also had the strongest neuroprotective effects with IC50 values of 103.30 ± 1.14 and 113.40 ± 1.20 µM respectively. Molecular docking studies conducted to investigate the molecular binding mechanism of the tested compounds on the GABAA receptor showed that compound 5b exhibits a strong affinity to the benzodiazepine (BZD) binding site on GABA. It also revealed that the NaV1.3 binding interactions were consistent with the experimental data and the reported binding mode of the ICA121431 inhibitor. This suggests that compound 5b has a high affinity for these specific binding sites, indicating its potential as a ligand for modulating GABAA and NaV1.3 receptor activity. Furthermore, the ADME properties displayed that all the physicochemical and pharmacological parameters of the compounds stayed within the specified limits and revealed a high bioavailability profile.
Assuntos
Anticonvulsivantes , Tiadiazóis , Tionas , Triazóis , Canais de Sódio Disparados por Voltagem , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/síntese química , Animais , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Camundongos , Relação Estrutura-Atividade , Tionas/química , Tionas/farmacologia , Tionas/síntese química , Canais de Sódio Disparados por Voltagem/metabolismo , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Estrutura Molecular , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Relação Dose-Resposta a Droga , Masculino , RatosRESUMO
Cannabidiol has been reported to interact with broad-spectrum biological targets with pleiotropic pharmacology including epilepsy although a cohesive mechanism is yet to be determined. Even though some studies propose that cannabidiol may manipulate glutamatergic signals, there is insufficient evidence to support cannabidiol direct effect on glutamate signaling, which is important in intervening epilepsy. Therefore, the present study aimed to analyze the epilepsy-related targets for cannabidiol, assess the differentially expressed genes with its treatment, and identify the possible glutamatergic signaling target. In this study, the epileptic protein targets of cannabidiol were identified using the Tanimoto coefficient and similarity index-based targets fishing which were later overlapped with the altered expression, epileptic biomarkers, and genetically altered proteins in epilepsy. The common proteins were then screened for possible glutamatergic signaling targets with differentially expressed genes. Later, molecular docking and simulation were performed using AutoDock Vina and GROMACS to evaluate binding affinity, ligand-protein stability, hydrophilic interaction, protein compactness, etc. Cannabidiol identified 30 different epilepsy-related targets of multiple protein classes including G-protein coupled receptors, enzymes, ion channels, etc. Glutamate receptor 2 was identified to be genetically varied in epilepsy which was targeted by cannabidiol and its expression was increased with its treatment. More importantly, cannabidiol showed a direct binding affinity with Glutamate receptor 2 forming a stable hydrophilic interaction and comparatively lower root mean squared deviation and residual fluctuations, increasing protein compactness with broad conformational changes. Based on the cheminformatic target fishing, evaluation of differentially expressed genes, molecular docking, and simulations, it can be hypothesized that cannabidiol may possess glutamate receptor 2-mediated anti-epileptic activities.
Assuntos
Canabidiol , Epilepsia , Ácido Glutâmico , Simulação de Acoplamento Molecular , Transdução de Sinais , Canabidiol/farmacologia , Canabidiol/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Epilepsia/genética , Humanos , Transdução de Sinais/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologiaRESUMO
Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED50 values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.
Assuntos
Anticonvulsivantes , Epilepsia , Canal de Sódio Disparado por Voltagem NAV1.2 , Pirimidinas , Animais , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacocinética , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Relação Estrutura-Atividade , Humanos , Modelos Animais de Doenças , Masculino , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Descoberta de Drogas , Eletrochoque , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: Epilepsy poses a significant global health challenge, particularly in regions with limited financial resources hindering access to treatment. Recent research highlights neuroinflammation, particularly involving cyclooxygenase-2 (COX-2) pathways, as a promising avenue for epilepsy management. METHODS: This study aimed to develop a Cyclooxygenase-2 inhibitor with potential anticonvulsant properties. A promising drug candidate was identified and chemically linked with phospholipids through docking analyses. The activation of this prodrug was assessed using phospholipase A2 (PLA2)-mediated hydrolysis studies. The conjugate's confirmation and cytotoxicity were evaluated using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and Sulphoramide B (SRB) assays. RESULTS: Docking studies revealed that the Celecoxib-Phospholipid conjugate exhibited a superior affinity for PLA2 compared to other drug-phospholipid conjugates. FT-IR spectroscopy confirmed the successful synthesis of the conjugate, while DSC analysis confirmed its purity and formation. PLA2-mediated hydrolysis experiments demonstrated selective activation of the prodrug depending on PLA2 concentration. SRB experiments indicated dose-dependent cytotoxic effects of Celecoxib, phospholipid non-toxicity, and efficient celecoxib-phospholipid conjugation. CONCLUSION: This study successfully developed a Celecoxib-phospholipid conjugate with potential anticonvulsant properties. The prodrug's specific activation and cytotoxicity profile makes it a promising therapeutic candidate. Further investigation into underlying mechanisms and in vivo studies is necessary to assess its translational potential fully.
Assuntos
Anticonvulsivantes , Celecoxib , Simulação de Acoplamento Molecular , Fosfolipases A2 , Fosfolipídeos , Pró-Fármacos , Celecoxib/farmacologia , Fosfolipídeos/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/síntese química , Fosfolipases A2/metabolismo , Humanos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Animais , Varredura Diferencial de Calorimetria , Epilepsia/tratamento farmacológico , Hidrólise , Sobrevivência Celular/efeitos dos fármacosRESUMO
The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.
Assuntos
Analgésicos , Anticonvulsivantes , Ácidos Cafeicos , Cinamatos , Convulsões , Animais , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/síntese química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/síntese química , Camundongos , Masculino , Convulsões/tratamento farmacológico , Cinamatos/farmacologia , Cinamatos/química , Cinamatos/síntese química , Cinamatos/uso terapêutico , Ácidos Cafeicos/farmacologia , Ácidos Cafeicos/química , Ácidos Cafeicos/uso terapêutico , Ácidos Cafeicos/síntese química , Peptídeos/farmacologia , Peptídeos/química , Peptídeos/síntese química , Peptídeos/uso terapêutico , Simulação de Acoplamento Molecular , IsomerismoRESUMO
Due to considerable global prevalence and high recurrence rate, the pursuit of effective new medication for epilepsy treatment remains an urgent and significant challenge. Drug repurposing emerges as a cost-effective and efficient strategy to combat this disorder. This study leverages the transformer-based deep learning methods coupled with molecular binding affinity calculation to develop a novel in-silico drug repurposing pipeline for epilepsy. The number of candidate inhibitors against 24 target proteins encoded by gain-of-function genes implicated in epileptogenesis ranged from zero to several hundreds. Our pipeline has repurposed the medications with most anti-epileptic drugs and nearly half psychiatric medications, highlighting the effectiveness of our pipeline. Furthermore, Lomitapide, a cholesterol-lowering drug, first emerged as particularly noteworthy, exhibiting high binding affinity for 10 targets and verified by molecular dynamics simulation and mechanism analysis. These findings provided a novel perspective on therapeutic strategies for other central nervous system disease.
Assuntos
Anticonvulsivantes , Aprendizado Profundo , Reposicionamento de Medicamentos , Epilepsia , Simulação de Dinâmica Molecular , Reposicionamento de Medicamentos/métodos , Epilepsia/tratamento farmacológico , Epilepsia/genética , Humanos , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/química , Simulação por ComputadorRESUMO
The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial blood flow, and circumvention of first-pass metabolism. In traditional medicinal practices, Bacopa monnieri, also known as Brahmi, is known for its benefits in enhancing cognitive functions and potential effects in epilepsy. This study aimed to develop and optimize a thermosensitive in-situ nasal gel for delivering Bacoside A, the principal active compound extracted from Bacopa monnieri. The formulation incorporated Poloxamer 407 as a thermogelling agent and HPMC K4M as the Mucoadhesive polymer. A 32-factorial design approach was employed for Optimization. Among the formulations. F7 exhibited the most efficient Ex-vivo permeation through the nasal mucosa, achieving 94.69 ± 2.54% permeation, and underwent a sol-gel transition at approximately 30.48 °C. The study's factorial design revealed that gelling temperature and mucoadhesive strength were critical factors influencing performance. The potential of in-situ nasal Gel (Optimized Batch-F7) for the treatment of epilepsy was demonstrated in an in-vivo investigation using a PTZ-induced convulsion model. This formulation decreased both the occurrence and intensity of seizures. The optimized formulation F7 showcases significant promise as an effective nasal delivery system for Bacoside A, offering enhanced bioavailability and potentially increased efficacy in epilepsy treatment.
Assuntos
Administração Intranasal , Epilepsia , Géis , Mucosa Nasal , Triterpenos , Animais , Administração Intranasal/métodos , Epilepsia/tratamento farmacológico , Géis/química , Mucosa Nasal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Masculino , Triterpenos/administração & dosagem , Triterpenos/farmacocinética , Triterpenos/farmacologia , Triterpenos/química , Temperatura , Saponinas/administração & dosagem , Saponinas/química , Saponinas/farmacologia , Saponinas/farmacocinética , Química Farmacêutica/métodos , Disponibilidade Biológica , Ratos , Poloxâmero/química , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Anticonvulsivantes/químicaRESUMO
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.
Assuntos
Anticonvulsivantes , Benzotiazóis , Pirazóis , Anticonvulsivantes/química , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Animais , Benzotiazóis/química , Benzotiazóis/antagonistas & inibidores , Benzotiazóis/farmacologia , Benzotiazóis/síntese química , Camundongos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Pentilenotetrazol , Eletrochoque , Relação Estrutura-Atividade , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Masculino , Estrutura Molecular , Simulação de Acoplamento Molecular , Modelos Animais de DoençasRESUMO
Epilepsy is a neurological disease with no defined cause, characterized by recurrent epileptic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the discovery of new substances from natural products that can combat epileptic seizures. Using in silico techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phenylpropanoid compounds to predict biological activities. The LBVS were developed for the targets alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel Ttype (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1 (GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel (NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and later, the best molecules were evaluated in the molecular docking consensus. The TR430 compound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and significant interactions with both targets. The studied compound showed to be a promising molecule with a possible multi-target activity in both fundamental pharmacological targets for the treatment of epilepsy.
Assuntos
Anticonvulsivantes , Epilepsia , Humanos , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/química , Simulação de Acoplamento MolecularRESUMO
A problem of systemic pharmacotherapy is off-target activity, which causes adverse effects. Outstanding examples include neuroinhibitory medications like antiseizure drugs, which are used against epilepsy and neuropathic pain but cause systemic side effects. There is a need of drugs that inhibit nerve signals locally and on-demand without affecting other regions of the body. Photopharmacology aims to address this problem with light-activated drugs and localized illumination in the target organ. Here, we have developed photoswitchable derivatives of the widely prescribed antiseizure drug carbamazepine. For that purpose, we expanded our method of ortho azologization of tricyclic drugs to meta/para and to N-bridged diazocine. Our results validate the concept of ortho cryptoazologs (uniquely exemplified by Carbazopine-1) and bring to light Carbadiazocine (8), which can be photoswitched between 400-590â nm light (using violet LEDs and halogen lamps) and shows good drug-likeness and predicted safety. Both compounds display photoswitchable activity in vitro and in translucent zebrafish larvae. Carbadiazocine (8) also offers in vivo analgesic efficacy (mechanical and thermal stimuli) in a rat model of neuropathic pain and a simple and compelling treatment demonstration with non-invasive illumination.
Assuntos
Anticonvulsivantes , Carbamazepina , Peixe-Zebra , Carbamazepina/química , Carbamazepina/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Luz , Estrutura Molecular , Processos Fotoquímicos , RatosRESUMO
Cannabis sativa has long been used for neurological and psychological healing. Recently, cannabidiol (CBD) extracted from cannabis sativa has gained prominence in the medical field due to its non-psychotropic therapeutic effects on the central and peripheral nervous systems. CBD, also acting as a potent antioxidant, displays diverse clinical properties such as anticancer, antiinflammatory, antidepressant, antioxidant, antiemetic, anxiolytic, antiepileptic, and antipsychotic effects. In this review, we summarized the structural activity relationship of CBD with different receptors by both experimental and computational techniques and investigated the mechanism of interaction between related receptors and CBD. The discovery of structural activity relationship between CBD and target receptors would provide a direction to optimize the scaffold of CBD and its derivatives, which would give potential medical applications on CBD-based therapies in various illnesses.
Assuntos
Canabidiol , Canabidiol/química , Canabidiol/farmacologia , Canabidiol/metabolismo , Humanos , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Cannabis/química , Relação Estrutura-Atividade , Receptores de Canabinoides/metabolismo , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antidepressivos/química , Antidepressivos/farmacologiaRESUMO
A stable Madhuca indica oil-in-water nanoemulsion (99-210 nm, zeta potential: > - 30 mV) was produced employing Tween 20 (surfactant) and Transcutol P (co-surfactant) (3:1). The nanoemulsion (oil: Smix = 3:7, 5:5, and 7:3) were subsequently incorporated into oxcarbazepine-loaded carboxymethylxanthan gum (DS = 1.23) dispersion. The hydrogel microspheres were formed using the ionic gelation process. Higher oil concentration had a considerable impact on particle size, drug entrapment efficiency, and buoyancy. The maximum 92 % drug entrapment efficiency was achieved with the microspheres having oil: Smix ratio 5:5. FESEM study revealed that the microspheres were spherical in shape and had an orange peel-like surface roughness. FTIR analysis revealed a hydrogen bonding interaction between drug and polymer. Thermal and x-ray examinations revealed the transformation of crystalline oxcarbazepine into an amorphous form. The microspheres had a buoyancy period of 7.5 h with corresponding release of around 83 % drug in 8 h in simulated stomach fluid, governed by supercase-II transport mechanism. In vivo neurobehavioral studies on PTZ-induced rats demonstrated that the microspheres outperformed drug suspension in terms of rotarod retention, number of crossings, and rearing activity in open field. Thus, Madhuca indica oil-in-water nanoemulsion-entrapped carboxymethyl xanthan gum microspheres appeared to be useful for monitoring oxcarbazepine release and managing epileptic seizures.
Assuntos
Mananas , Microesferas , Animais , Ratos , Mananas/química , Hidrogéis/química , Tamanho da Partícula , Epilepsia/tratamento farmacológico , Masculino , Portadores de Fármacos/química , Emulsões , Convulsões/tratamento farmacológico , Liberação Controlada de Fármacos , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Galactose/análogos & derivadosRESUMO
Owing to their incomplete digestion in the human body and inadequate removal by sewage treatment plants, antiepileptic drugs (AEDs) accumulate in water bodies, potentially affecting the exposed humans and aquatic organisms. Therefore, sensitive and reliable detection methods must be urgently developed for monitoring trace AEDs in environmental water samples. Herein, a novel phenylboronic acid-functionalized magnetic cyclodextrin microporous organic network (Fe3O4@CD-MON-PBA) was designed and synthesized via the thiol-yne click post-modification strategy for selective and efficient magnetic solid-phase extraction (MSPE) of trace AEDs from complex sample matrices through the specific B-N coordination, π-π, hydrogen bonding, electrostatic, and host-guest interactions. Fe3O4@CD-MON-PBA exhibited a large surface area (118.5 m2 g-1), rapid magnetic responsiveness (38.6 emu g-1, 15 s), good stability and reusability (at least 8 times), and abundant binding sites for AEDs. Under optimal extraction conditions, the proposed Fe3O4@CD-MON-PBA-MSPE-HPLC-UV method exhibited a wide linear range (0.5-1000 µg L-1), low limits of detection (0.1-0.5 µg L-1) and quantitation (0.3-2 µg L-1), good anti-interference ability, and large enrichment factors (92.2-104.3 to 92.3-98.0) for four typical AEDs. This work confirmed the feasibility of the thiol-yne click post-synthesis strategy for constructing novel and efficient multifunctional magnetic CD-MONs for sample pretreatment and elucidated the significance of B-N coordination between PBA and N-containing AEDs.
Assuntos
Anticonvulsivantes , Ácidos Borônicos , Química Click , Ciclodextrinas , Extração em Fase Sólida , Compostos de Sulfidrila , Ácidos Borônicos/química , Anticonvulsivantes/química , Anticonvulsivantes/isolamento & purificação , Anticonvulsivantes/síntese química , Extração em Fase Sólida/métodos , Ciclodextrinas/química , Porosidade , Compostos de Sulfidrila/química , Alcinos/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/isolamento & purificação , Limite de DetecçãoRESUMO
Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers' development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure-function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.