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1.
Epilepsy Behav ; 122: 108166, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34343958

RESUMO

Electrical Stimulation (ES) of the nervous system is a promising alternative to treat refractory epilepsy. Recent developments in the area have led to a novel method involving a non-standard form of electrical stimulation with randomized inter-pulse intervals called non-periodic stimulation (NPS). Although it is an interesting approach, there is limited statistical proof to confirm its effectiveness. Therefore this brief communication presents a survival analysis of a pre-clinical trial to assess the significance of NPS therapy. The experiment comprised four groups of rats that have been compared: two with and two without NPS treatment. ES was applied bilaterally to the amygdala in animals subjected to the pentylenetetrazole continuous infusion (10 mg/ml/min) model, myoclonic or tonic-clonic generalized seizures were triggered. The Kaplan-Meier estimator was used to develop survival functions and the Logrank test was carried out to check the differences among groups. The first comparison was made between two groups of rats that developed generalized tonic-clonic seizures (GTC groups), those who received NPS treatment took longer to develop epileptic seizures. The logrank test proved statistical difference due to reaching a p-value of 7%. The second comparison was performed between two groups of rats that developed myoclonic seizures (MYO groups), and once again better survival probabilities were observed for the NPS group. The Logrank test revealed a p-value of 0.5% thereof. Thus, a survival analysis of NPS treatment proved effectiveness against seizures by promoting an anticonvulsant effect. By comparing the groups selected for this study, it was found that the NPS treatment yielded better results, mainly against myoclonic seizures.


Assuntos
Epilepsia Resistente a Medicamentos , Pentilenotetrazol , Animais , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Pentilenotetrazol/toxicidade , Ratos , Convulsões/tratamento farmacológico , Análise de Sobrevida
2.
Eur J Pharm Sci ; 166: 105974, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34390829

RESUMO

In continuation of our research to find strong and safe anticonvulsant agents, a number of (arylalkyl)azoles (AAAs) containing naphthylthiazole and naphthyloxazole scaffolds were designed and synthesized. The in vivo anticonvulsant evaluations in BALB/c mice revealed that some of them had significant anticonvulsant activity in both maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy. The best profile of activity was observed with compounds containing imidazole and triazole rings (C1, C6, G1, and G6). In particular, imidazolylmethyl-thiazole C1 with median effective dose (ED50)= 7.9 mg/kg in the MES test, ED50= 27.9 mg/kg in PTZ test, and without any sign of neurotoxicity (in the rotarod test, 100 mg/kg) was the most promising compound. The patch-clamp recording was performed to study the mechanism of action of the representative compound C1 on hippocampal dentate gyrus (DG) cells. The results did not confirm any modulatory effect of C1 on the voltage-gated ion channels (VGICs) or GABAA agonism, but suggested a significant reduction of excitatory postsynaptic currents (EPSCs) frequency on hippocampal DG neurons. Sub-acute toxicity studies revealed that administration of the most active compounds (C1, C6, G1, and G6) at 100 mg/kg bw/day for two weeks did not result in any mortality or significant toxicity as evaluated by assessment of biochemical markers such as lipid peroxidation, intracellular glutathione, total antioxidant capacity, histopathological changes, and mitochondrial functions. Other pharmacological aspects of compounds including mechanistic and ADME properties were investigated computationally and/or experimentally. Molecular docking on the NMDA and AMPA targets suggested that the introduction of the heterocyclic ring in the middle of AAAs significantly affects the affinity of the compounds. The obtained results totally demonstrated that the prototype compound C1 can be considered as a new lead for the development of anticonvulsant agents.


Assuntos
Anticonvulsivantes , Convulsões , Animais , Anticonvulsivantes/uso terapêutico , Azóis/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naftalenos , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade
3.
Eur J Pharm Sci ; 166: 105978, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34418574

RESUMO

The current research article focused on formulating an easily applied, water-based buccal film loaded with the antiepileptic drug, lamotrigine (LTG). The designed film can be comfortably administered by epileptic patients to ensure a controllable therapeutic efficacy against seizures. The solubility of LTG in water was significantly improved by micellar solubilization. Upon testing several surfactants, three of them (Synperonic PE/P84, Brij L23, and Brij 78) achieved maximum possible solubility for LTG and were characterized for their micellar size, cloud point, and % transmittance. Selected micellar systems were incorporated within a buccal film prepared using solvent casting method based on either gelatin or polyvinylpyrrolidone (3%w/v) with 1.5%w/v propylene glycol as a plasticizer. Different micellar films were characterized for their physicochemical characteristics, swelling index, folding endurance, drug content uniformity, and in vitro LTG release. From the tested formulations, one formulation; LTG-BF1 (in which Brij 78 was used for the micellar solubilization and gelatin as the matrix former), was selected as the optimum and extensively studied for mucoadhesion, ex vivo permeation studies by Franz diffusion cells and confocal laser scanning microscopy. Results showed superior enhanced permeation of micellar film. LTG-BF1 was evaluated for the in vivo performance using rats. Status epilepticus was induced in rats by injecting Pentylenetetrazol (PTZ) i.p. at an initial dose of 30 mg/kg, followed by 10 mg/kg every10 min till 60 min. A group of rats receiving the designed buccal formulation (20 mg/kg) was compared with a group receiving the same dose of the oral market product and the normal control and PTZ groups. Rats receiving LTG-BF1 recorded reduced seizure scores at all stages, longer latency time, and higher threshold PTZ dose compared to PTZ and market product groups. In addition, LTG-BF1 reduced brain concentrations of TNF-α and TGF-ß with an elevation of EAAT2 and GABA brain contents compared to PTZ and market product groups and ameliorated neuronal damage. In conclusion, LTG-loaded buccal micellar film proved a superior antiepileptic effect in PTZ induced acute epileptic model.


Assuntos
Micelas , Convulsões , Animais , Anticonvulsivantes/uso terapêutico , Humanos , Lamotrigina , Pentilenotetrazol , Ratos , Convulsões/tratamento farmacológico
4.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443428

RESUMO

Ellagic acid (EA) is a natural dietary polyphenol that has many beneficial properties, including anti-inflammatory, antioxidant, antiviral, antibacterial, and neuroprotective effects. Studies have revealed that EA may modulate seizure activity in chemically induced animal models of seizures. Therefore, the aim of the present study was to investigate the effect of EA on the seizure threshold in two acute seizure tests in male mice, i.e., in the intravenous (i.v.) pentylenetetrazole (PTZ) seizure test and in the maximal electroshock seizure threshold (MEST) test. The obtained results showed that EA (100 mg/kg) significantly elevated the threshold for both the first myoclonic twitch and generalized clonic seizure in the i.v. PTZ seizure test. At the highest dose tested (200 mg/kg), EA increased the threshold for tonic hindlimb extension in the MEST test. EA did not produce any significant changes in motor coordination (assessed in the chimney test) or muscular strength (investigated in the grip-strength test). The plasma and total brain concentration-time profiles of EA after intraperitoneal and oral administration were also determined. Although further studies are necessary to confirm the anticonvulsant activity of EA, our findings suggest that it may modulate seizure susceptibility in animal models.


Assuntos
Ácido Elágico/uso terapêutico , Convulsões/tratamento farmacológico , Doença Aguda , Animais , Encéfalo/metabolismo , Ácido Elágico/sangue , Ácido Elágico/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Pentilenotetrazol , Convulsões/sangue , Convulsões/induzido quimicamente
5.
Andrologia ; 53(10): e14130, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34414592

RESUMO

In this study, it was aimed to investigate possible ameliorating effects of thymoquinone on testicular damage in an epilepsy model. Adult male Wistar rats were divided into 4 groups. The animals in sham-operated groups were given saline or thymoquinone (s.c.); and the animals in pentylenetetrazole (PTZ) group were applied PTZ. The animals in PTZ+thymoquinone group were given thymoquinone (i.p) for 6 days after applying PTZ. Hematoxylin-eosin, periodic acid-Schiff and TUNEL staining and PCNA, StAR, inhibin ß-B immunohistochemistry and ZO-1 immunofluorescence methods were applied. Staining intensity and cell numbers were determined. Degeneration of seminiferous tubules was observed in PTZ group. Most of the tubules showed normal morphology in the PTZ+thymoquinone group. Apoptotic cell index was found to be increased and proliferative index decreased in PTZ group. Thymoquinone administration decreased apoptotic index and increased proliferation index. In PTZ group, ZO-1, StAR and inhibin ß-B immunohistochemical staining intensity was observed to be decreased and after thymoquinone application, ZO-1 was increased. StAR and inhibin ß-B-positive cell numbers were decreased in PTZ group and increased in the PTZ +thymoquinone group. In this study, it was observed that PTZ-induced epileptic seizures caused testicular damage in the rat and thymoquinone ameliorated these effects.


Assuntos
Epilepsia do Lobo Temporal , Pentilenotetrazol , Animais , Benzoquinonas/farmacologia , Masculino , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar
6.
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
7.
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
8.
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
9.
ACS Chem Neurosci ; 12(13): 2542-2552, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34128378

RESUMO

The lack of disease-modifying therapeutic strategies against epileptic seizures has caused a surge in preclinical research focused on exploring and developing novel therapeutic candidates for epilepsy. Compounds from traditional Chinese medicines (TCMs) have gained much attention for a plethora of neurological diseases, including epilepsy. Herein, for the first time, we evaluated the anticonvulsive effects of schaftoside (SS), a TCM, on pentylenetetrazol (PTZ)-induced epileptic seizures in zebrafish and examined the underlying mechanisms. We observed that SS pretreatments significantly suppressed seizure-like behavior and prolonged the onset of seizures. Zebrafish larvae pretreated with SS demonstrated downregulation of c-fos expression during seizures. PTZ-induced upregulation of apoptotic cells was decreased upon pretreatment with SS. Inflammatory phenomena during seizure progression including the upregulation of interleukin 6 (IL-6), interleukin 1 beta (IL-1ß), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were downregulated upon pretreatment with SS. The PTZ-induced recruitment of immunocytes was in turn reduced upon SS pretreatment. Moreover, SS pretreatment modulated oxidative stress, as demonstrated by decreased levels of catalase (CAT) and increased levels of glutathione peroxidase-1a (GPx1a) and manganese superoxide dismutase (Mn-SOD). However, pretreatment with SS modulated the PTZ-induced downregulation of the relative enzyme activity of CAT, GPx, and SOD. Hence, our findings suggest that SS pretreatment ameliorates PTZ-induced seizures, suppresses apoptosis, and downregulates the inflammatory response and oxidative stress, which potentially protect against further seizures in zebrafish.


Assuntos
Pentilenotetrazol , Peixe-Zebra , Animais , Apoptose , Glicosídeos , Inflamação/tratamento farmacológico , Estresse Oxidativo , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
10.
Neuroscience ; 468: 1-15, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102267

RESUMO

Acute seizures can severely affect brain function and development. However, the underlying pathophysiological mechanisms are still poorly understood. Disturbances of the glutamatergic system are considered one of the critical mechanisms of neurological abnormalities. In the present study, we analyzed changes in the expression of NMDA and AMPA receptor subunits in the different brain regions (dorsal hippocampus, amygdala, and the medial prefrontal, temporal, and entorhinal cortex) using a pentylenetetrazole (PTZ) model of seizures in 3-week-old rats. A distinctive feature of this model is that the administration of PTZ causes severe acute seizures, which are not followed by the development of spontaneous recurrent seizures later on. Subunit expression was analyzed using qRT-PCR and Western blotting during the first week after seizures. The most pronounced alterations of mRNA and protein levels were observed in the dorsal hippocampus. We found decreased expression of the GluA2 mRNA 7 days after seizures (PSE7), as well as reduced GluN2a protein levels on PSE7. Significant alterations in the expression of different receptor subunits in the mRNA but not protein levels were observed in the entorhinal cortex and amygdala. In contrast, in the medial prefrontal and temporal cortex, we found almost no changes in the expression of the studied genes. The identified changes deepen our understanding of post-seizure disturbances in the developing brain and confirm that although various brain structures are involved in seizures, the hippocampus is the most vulnerable.


Assuntos
Pentilenotetrazol , Convulsões , Animais , Hipocampo/metabolismo , Pentilenotetrazol/toxicidade , RNA Mensageiro , Ratos , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de Glutamato/metabolismo , Convulsões/induzido quimicamente
11.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083383

RESUMO

Collybistin (CB) is a rho guanine exchange factor found at GABAergic and glycinergic postsynapses that interacts with the inhibitory scaffold protein, gephyrin, and induces accumulation of gephyrin and GABA type-A receptors (GABAARs) to the postsynapse. We have previously reported that the isoform without the src homology 3 (SH3) domain, CBSH3-, is particularly active in enhancing the GABAergic postsynapse in both cultured hippocampal neurons as well as in cortical pyramidal neurons after chronic in vivo expression in in utero electroporated (IUE) rats. Deficiency of CB in knock-out (KO) mice results in absence of gephyrin and gephyrin-dependent GABAARs at postsynaptic sites in several brain regions, including hippocampus. In the present study, we have generated an adeno-associated virus (AAV) that expresses CBSH3- in a cre-dependent manner. Using male and female VGLUT1-IRES-cre or VGAT-IRES-cre mice, we explore the effect of overexpression of CBSH3- in hippocampal pyramidal cells or hippocampal interneurons. The results show that: (1) the accumulation of gephyrin and GABAARs at inhibitory postsynapses in hippocampal pyramidal neurons or interneurons can be enhanced by CBSH3- overexpression; (2) overexpression of CBSH3- in hippocampal pyramidal cells can enhance the strength of inhibitory neurotransmission; and (3) these enhanced inhibitory synapses provide protection against pentylenetetrazole (PTZ)-induced seizures. The results indicate that this AAV vector carrying CBSH3- can be used for in vivo enhancement of GABAergic synaptic transmission in selected target neurons in the brain.


Assuntos
Proteínas de Transporte , Pentilenotetrazol , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Pentilenotetrazol/toxicidade , Células Piramidais/metabolismo , Ratos , Receptores de GABA-A/metabolismo , Convulsões/induzido quimicamente , Sinapses/metabolismo , Transmissão Sináptica
12.
Neuroscience ; 466: 235-247, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33961962

RESUMO

Convulsive status epilepticus (SE) in immature life is often associated with lasting neurobiological changes. We provoked SE by pentylenetetrazole in postnatal day 20 rat pups and examined communication modalities between the temporal hippocampus and medial entorhinal cortex (mEC) in vitro. After a minimum of 40 days post-SE, we prepared combined temporal hippocampal - medial entorhinal cortex (mEC) slices from conditioned (SE) and naïve (N) adult rats and recorded 4-aminopyridine-induced spontaneous epileptiform interictal-like discharges (IED) simultaneously from CA3 and mEC layer V-VI. We analyzed IED frequency and high frequency oscillations (HFOs) in intact slices and after surgical separation of hippocampus from mEC, by two successive incisions (Schaffer collateral cut, Parasubiculum cut). In all slices, IED frequency was higher in CA3 vs mEC (5N, 4SE) and Raster plots indicated no temporal coincidence between them either in intact or in CA1-cut slices (4N, 4SE). IED frequency was significantly higher in SE mEC, but similar in SE and N CA3, independently of connectivity state. Ripples (R) and Fast Ripples (FR) coincided with IEDs and their power differed between SE and N intact slices (22N, 12SE), both in CA3 and mEC. CA3 FR/R ratios were higher in the absence of mEC (14N, 8SE). Moreover, SE (vs N) slices showed significantly higher FR/R ratios independently of the presence of mEC. Taken together, these findings suggest lasting effects of immature SE in network dynamics governing hippocampal-entorhinal communication which may impact adult cognitive, behavioral, and/or seizure threshold sequalae.


Assuntos
Córtex Entorrinal , Estado Epiléptico , 4-Aminopiridina , Animais , Hipocampo , Pentilenotetrazol , Ratos , Estado Epiléptico/induzido quimicamente
13.
Eur J Pharmacol ; 902: 174099, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33910036

RESUMO

Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. To induce kindling in mice, pentylenetetrazol at a dose of 40 mg/kg was administered once every 48 h. Valacyclovir was orally administered 30 min before antiepileptic drug injection in kindled mice, and behavioral seizures were monitored for 20 min following pentylenetetrazol administration. Additionally, c-Fos expression in the hippocampal dentate gyrus was measured in kindled mice. Valacyclovir showed inhibitory effects on pentylenetetrazol-induced kindled seizures. In addition, simultaneous use of levetiracetam and valacyclovir caused more potent inhibition of seizure activity, and neither valproic acid nor diazepam augmented the anti-seizure effect in kindled mice. Furthermore, kindled mice showed increased c-Fos levels in the dentate gyrus. The increase in c-Fos expression was significantly inhibited by the simultaneous use of levetiracetam and valacyclovir. The findings of the present study indicate that a combination of levetiracetam and valacyclovir had possible anticonvulsive effects on pentylenetetrazol-induced kindled epileptic seizures. These results suggest that valacyclovir may have an antiseizure effect in patients with epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Excitação Neurológica/efeitos dos fármacos , Convulsões/tratamento farmacológico , Valaciclovir/farmacologia , Animais , Anticonvulsivantes/uso terapêutico , Cefepima/efeitos adversos , Bases de Dados Factuais , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Humanos , Levetiracetam/farmacologia , Levetiracetam/uso terapêutico , Masculino , Camundongos , Pentilenotetrazol/toxicidade , Proteínas Proto-Oncogênicas c-fos/metabolismo , Convulsões/induzido quimicamente , Valaciclovir/uso terapêutico
14.
Int J Pharm ; 602: 120604, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33862132

RESUMO

In the present study, gabapentin (GBP)-loaded chitosan nanosized particles were fabricated applying the nanospray drying technique. Different preparation parameters (spray mesh diameter, chitosan concentration and presence of D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) were studied while fixing other parameters (spraying rate, inlet temperature and gas flow rate). An optimized formulation with a particle size 107 ± 13 nm was obtained upon spraying 0.1% (w/v) chitosan solution containing 0.05% (w/v) of TPGS utilizing the small nozzle (4 µm spray mesh hole size). Drug entrapment efficiency and yield were as high as 95% and 83%, respectively. A 98.1 ± 6.1% (w/w) cumulative drug release was recorded after 2 h. Confocal laser scanning microscopy showed higher fluorescent dye penetration into brain tissue following intranasal administration of Rhodamine B labeled spray dried chitosan nanoparticles (NPs) as compared to Rhodamine B solution. Pentylenetetrazole (PTZ) was used to induce convulsions in rats through elevating seizure stages, releasing neuroinflammatory mediators and reducing excitatory amino acid transporter 2 (EAAT 2) and γ-aminobutyric acid (GABA) brain contents. Nanospray dried GBP-loaded chitosan NPs reduced seizure score, neuroinflammation; TNF-α and TGF-ß, elevated EAAT 2 and GABA as well as decreased degeneration in pyramidal neurons compared to marketed product Conventin® capsules. Thus, it can be concluded from the aforementioned data that nanospray dried GBP-loaded chitosan NPs could comprise an appropriate treatment of epilepsy.


Assuntos
Quitosana , Nanopartículas , Animais , Encéfalo , Portadores de Fármacos , Gabapentina , Tamanho da Partícula , Pentilenotetrazol , Ratos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
15.
Biochim Biophys Acta Mol Basis Dis ; 1867(6): 166128, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33722745

RESUMO

Neural precursor cell expressed developmentally down-regulated gene 4-like (NEDD4-2) encodes a ubiquitin E3 ligase that is involved in epileptogenesis with mechanisms needing further investigation. We constructed a novel Nedd4-2+/- mouse model with half level of both Nedd4-2 long and short isoforms in the brain. Nedd4-2 haploinsufficiency caused increased susceptibility and severity of pentylenetetrazole (PTZ)-induced seizures. Of the 3379 proteins identified by the hippocampal proteomic analysis, 55 were considered altered in Nedd4-2+/- mice compared with wild-type control, among which the inwardly rectifying K+ channel Kir4.1 was up-regulated by 1.83-fold. Kir4.1 was subsequently confirmed to be less ubiquitinated in response to comprised Nedd4-2 in mouse brains and C6 cells. Kir4.1 associated with Nedd4-2 through the threonine312-proline motif in the intracellular domain by target mutagenesis. Adaptor protein 14-3-3 facilitated Nedd4-2-mediated ubiquitination of Kir4.1. Our data consolidate the detailed molecular mechanism of Nedd4-2-mediated Kir4.1 ubiquitination, and provide a possible relationship between increased seizure susceptibility and impaired Kir4.1 ubiquitination in the brain.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Haploinsuficiência , Ubiquitina-Proteína Ligases Nedd4/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Proteoma/metabolismo , Convulsões/etiologia , Ubiquitinação , Animais , Convulsivantes/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pentilenotetrazol/toxicidade , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteoma/análise , Convulsões/metabolismo , Convulsões/patologia
16.
Biochim Biophys Acta Mol Basis Dis ; 1867(6): 166124, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33727197

RESUMO

With an associated 20% death risk, epilepsy mainly involves seizures of an unpredictable and recurrent nature. This study was designed to evaluate the neuroprotective effects and underlying mechanisms of insulin on mitochondrial disruption, oxidative stress, cell apoptosis and neurological deficits after epilepsy seizures. Mice were exposed to repetitive injections of pentylenetetrazol at a dose of 37 mg per kg. The influence of insulin was assessed by many biochemical assays, histopathological studies and neurobehavioral experiments. The administration of insulin was proven to increase the latency of seizures while also decreasing their intensity. It also caused a reversal of mitochondrial dysfunction and ameliorated oxidative stress. Additionally, insulin pretreatment upregulated Bcl-2, downregulated Bax, and then played a neuroprotective role against hippocampal neuron apoptosis. Furthermore, when insulin was administered, SIRT1/PGC-1α/SIRT3 signals were activated, possibly due to the fact that insulin's neuroprotective and anti-mitochondrial damage characteristics added to its observed antiepileptic functions. Finally, insulin treatment is thus extremely valuable for effecting improvements in neurological functions, as has been estimated in a series of functional tests. In conclude, the results of this study consequently demonstrate insulin to have significant potential for future application in epilepsy management.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Convulsões/tratamento farmacológico , Animais , Convulsivantes/toxicidade , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Insulina/administração & dosagem , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Convulsões/induzido quimicamente , Convulsões/patologia , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo
17.
Chem Biol Interact ; 340: 109447, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33771525

RESUMO

Accumulating evidences indicate that thiamine plays a vital role in the nervous system. However, questions exist as to how it causes epilepsy, neuronal damage, and antiepileptic mechanisms. The study looked at how the thiamine supplement impacted pentylenetetrazole (PTZ)-induced seizures in rats and pentylenetetrazole-induced neurotoxicity in the SH-SY5Y cell line. We used twenty-four male rats and they were randomly divided into 4 groups as control, saline (1 mL/kg/day serum physiologic) + PTZ, thiamine (50 mg/kg/day) + PTZ, and thiamine (50 mg/kg/day) for 10 days. PTZ (45 mg/kg) was given to activate the seizure on day 10. Memory efficiency was measured by using passive avoidance. The brain levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, nitric oxide (NO), and cyclic guanosine monophosphate (cGMP) were analyzed by using ELISA kits. SH-SY5Y cells were treated with/without thiamine for 1 h, followed by PTZ (30 µm) at a medium level to trigger neurotoxicity. Cell viability, total antioxidant status, total oxidant status, and apoptosis were assayed in the SH-SY5Y cells. Thiamine delayed the initiation of epileptic seizures and increased memory damage. In addition, 8-OHdG, caspase-3, NO, and cGMP levels were significantly reduced in the brain and prevented pentylenetetrazole-induced neurotoxicity, apoptosis, enhanced antioxidant, and reduced oxidant in SH-SY5Y cells. Thiamine dramatically altered seizures, memory loss, oxidative stress, and apoptosis. Thiamine has a preventative effect on PTZ-induced seizures in rats and PTZ-induced neurotoxicity in SH-SY5Y neuroblastoma cells. It could prevent oxidative stress and signaling of NO/cGMP. Thiamine supplement could be used as an additional therapeutic agent in epilepsy.


Assuntos
Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Convulsões/tratamento farmacológico , Tiamina/farmacologia , Animais , Anticonvulsivantes/farmacologia , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Masculino , Memória/efeitos dos fármacos , Neurônios/metabolismo , Pentilenotetrazol/farmacologia , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo
18.
Epilepsy Behav ; 118: 107915, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33743341

RESUMO

Epileptogenesis is a process that includes molecular and cellular events that foster the establishment of hyperexcitable neuronal networks in the brain. Pentylenetetrazole (PTZ)-induced kindling model in rodents has added new information to the knowledge about the pathogenesis of epilepsy and potential targets of novel antiepileptic agents. Evidence from animal and human studies suggests that oxidative and inflammatory events may play important roles in the initiation and maintaining seizure activities. Vitamin B12 has beneficial effects on the nervous system and presents pleiotropic effects with antioxidant and anti-inflammatory aspects. In the present study, we aimed to test the hypothesis that vitamin B12 and their combination with lamotrigine prevents behavioral deficits, hippocampal damage, oxidation, and proinflammatory state during epileptogenesis. Male rats were subjected to PTZ-induced epileptogenesis and pretreated with vitamin B12 (50 µg/kg) or Lamotrigine (LTG) (25 mg/kg) or B12 (50 µg/kg) + LTG (25 mg/kg). Vitamin B12 and its combination with LTG suppressed epileptogenesis and improved the performance of rats in the passive avoidance test. In addition, Vitamin B12 and its combination with LTG decreased levels of total oxidative status (TOS), oxidative stress index (OSI), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and increased total antioxidant status (TAS) levels in the hippocampus and cerebral cortex. Furthermore, it reduced hippocampal neuronal damage. Current findings support the beneficial actions of vitamin B12 due to its antioxidative and anti-inflammatory properties during the course of disease.


Assuntos
Excitação Neurológica , Pentilenotetrazol , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Hipocampo , Lamotrigina/uso terapêutico , Masculino , Estresse Oxidativo , Pentilenotetrazol/toxicidade , Ratos , Vitamina B 12/farmacologia
19.
Biomed Pharmacother ; 137: 111354, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33561642

RESUMO

Following the high treatment gap and massive impact of epilepsy on global health particularly in low- and middle-income countries, our study aims to investigate cryptolepine, the major alkaloid of Cryptolepis sanguinolenta as well as its solid-lipid nanoparticle formulation for potential antiseizure activity. Cryptolepine was isolated and a solid-lipid formulation was prepared. Antiseizure activity of Solid-Lipid Nanoparticle formulation of cryptolepine (SLN-CRYP) was investigated using Pentylenetetrazole (PTZ)-induced model of seizure-like behaviors in Zebrafish with 2.5 and 5 mg/kg each of cryptolepine and SLN-CRYP. Drug receptor binding and permeability of the compound across the Blood Brain Barrier (BBB) were also assessed. SLN formulation of cryptolepine increased its permeability to the BBB from 0.32 × 10-6 cm/s to 10.81 × 10-6 cm/s. 2.5 and 5 mg/kg of SLN-CRYP significantly reduced mean seizure score (P = 0.0018; F(6, 63) = 23.52) and significantly increased (P < 0.0001; F(6, 63) = 65.41) latency to onset of seizures. The total distance swam by fish administered with 2.5 and 5 mg/kg of SLN-CRYP was significantly (P < 0.000; F(6, 63) = 161.9) decreased. 5 mg/kg of cryptolepine also significantly decreased swimming distance. Cryptolepine exhibited inhibitory modulation of human voltage-gated calcium channels (Cav1.2), H1-receptor, Peripheral Benzodiazepine Receptor and Sigma 2 receptor with a high Ki values of 6133.38 nM and 2945.0 nM, indicating less potent antagonism on Cav1.2 and Sigma 2 receptors compared to Nifedipine and Haloperidol respectively. This study reveals that the solid-lipid nanoparticle formulation of cryptolepine improves its BBB permeability and hence antiseizure activity.


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Nanopartículas , Quinolinas/química , Quinolinas/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Barreira Hematoencefálica , Convulsivantes , Cryptolepis/química , Composição de Medicamentos , Alcaloides Indólicos/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Pentilenotetrazol , Quinolinas/administração & dosagem , Receptores de Droga/metabolismo , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Natação , Peixe-Zebra
20.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525453

RESUMO

Epilepsy is one of the most common neurological disorders, and it is characterized by spontaneous seizures. In a previous study, we identified 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as a novel anti-epileptic agent in chemically- or genetically-induced epileptic zebrafish and mouse models. In this study, we investigated the anti-epileptic effects of GM-90432 through neurochemical profiling-based approach to understand the neuroprotective mechanism in a pentylenetetrazole (PTZ)-induced epileptic seizure zebrafish model. GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-ß-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents.


Assuntos
Anticonvulsivantes/farmacologia , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/síntese química , Antioxidantes/síntese química , Encéfalo/metabolismo , Química Encefálica , Di-Hidrotestosterona/metabolismo , Modelos Animais de Doenças , Estradiol/metabolismo , Hidrocortisona/metabolismo , Masculino , Fármacos Neuroprotetores/síntese química , Normetanefrina/metabolismo , Estresse Oxidativo , Pentilenotetrazol/administração & dosagem , Pregnanolona/metabolismo , Progesterona/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/fisiopatologia , Serotonina/metabolismo , Peixe-Zebra , Ácido gama-Aminobutírico/metabolismo
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