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1.
Epilepsy Res ; 181: 106873, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35180639

RESUMO

PURPOSE: Curcumin is known for its neuroprotective, anti-inflammatory and anti-oxidant properties and has been investigated as a potential therapeutic drug for Temporal Lobe Epilepsy (TLE). We previously found anti-epileptogenic properties of curcumin in an in vitro brain slice model for epileptogenesis, and inhibitory effects on the MAPK-pathway in vivo after intracerebrally applying curcumin in post-status epilepticus rats. Here, we investigated whether the intracerebral application of curcumin could be anti-epileptogenic in the rapid kindling rat model for TLE. METHODS: Curcumin or vehicle was injected directly into the brain through an intracerebral ventricular cannula at 5 consecutive days during the kindling process. Kindling consisted of repeated electrical stimulations of the angular bundle (12 times a day with a 30 min interval) every other day, until rats were fully kindled or until 36 stimulations were administered. One week after kindling acquisition, additional kindling stimulations were applied in a re-test in the absence of curcumin- or vehicle treatment. RESULTS: Curcumin-treated rats required more stimulations compared to vehicle-treated rats to reach Racine stage IV seizures, indicating that curcumin delayed seizure development. However, it did not prevent the fully kindled state as shown in the re-test. Increasing the dose of curcumin did not produce a delay in seizure development. Immunohistochemistry showed that kindling produced cell loss, astrogliosis, mossy fiber sprouting and neurogenesis in the dentate gyrus, which were not different between vehicle- and curcumin-treated groups. CONCLUSION: Although curcumin's effects on neuropathology were not detected and the delay of kindling development was transient, the data warrant further exploration of its anti-epileptogenic potential using formulations that further increase its bioavailability.


Assuntos
Curcumina , Epilepsia do Lobo Temporal , Excitação Neurológica , Estado Epiléptico , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/tratamento farmacológico , Ratos , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico
2.
Epilepsia ; 60(4): 605-614, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30747999

RESUMO

OBJECTIVE: Inhibition of the mammalian target of rapamycin (mTOR) pathway could be antiepileptogenic in temporal lobe epilepsy (TLE), possibly via anti-inflammatory actions. We studied effects of the mTOR inhibitor rapamycin and the anti-inflammatory compound curcumin-also reported to inhibit the mTOR pathway-on epileptogenesis and inflammation in an in vitro organotypic hippocampal-entorhinal cortex slice culture model. METHODS: Brain slices containing hippocampus and entorhinal cortex were obtained from 6-day-old rat pups and maintained in culture for up to 3 weeks. Rapamycin or curcumin was added to the culture medium from day 2 in vitro onward. Electrophysiological recordings revealed epileptiformlike activity that developed over 3 weeks. RESULTS: In week 3, spontaneous seizurelike events (SLEs) could be detected using whole cell recordings from CA1 principal neurons. The percentage of recorded CA1 neurons displaying SLEs was lower in curcumin-treated slice cultures compared to vehicle-treated slices (25.8% vs 72.5%), whereas rapamycin did not reduce SLE occurrence significantly (52%). Western blot for phosphorylated-S6 (pS6) and phosphorylated S6K confirmed that rapamycin inhibited the mTOR pathway, whereas curcumin only lowered pS6 expression at one phosphorylation site. Real-time quantitative polymerase chain reaction results indicated a trend toward lower expression of inflammatory markers IL-1ß and IL-6 and transforming growth factor ß after 3 weeks of treatment with rapamycin and curcumin compared to vehicle. SIGNIFICANCE: Our results show that curcumin suppresses SLEs in the combined hippocampal-entorhinal cortex slice culture model and suggest that its antiepileptogenic effects should be further investigated in experimental models of TLE.


Assuntos
Antioxidantes/farmacologia , Curcumina/farmacologia , Córtex Entorrinal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Convulsões/metabolismo , Animais , Córtex Entorrinal/metabolismo , Hipocampo/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/antagonistas & inibidores
3.
Epilepsia ; 57(5): 688-97, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26924447

RESUMO

OBJECTIVE: Inhibition of the mammalian target of rapamycin (mTOR) pathway has been suggested as a possible antiepileptogenic strategy in temporal lobe epilepsy (TLE). Here we aim to elucidate whether mTOR inhibition has antiepileptogenic and/or antiseizure effects using different treatment strategies in the electrogenic post-status epilepticus (SE) rat model. METHODS: Effects of mTOR inhibitor rapamycin were tested using the following three treatment protocols: (1) "stop-treatment"-post-SE treatment (6 mg/kg/day) was discontinued after 3 weeks; rats were monitored for 5 more weeks thereafter, (2) "pretreatment"-rapamycin (3 mg/kg/day) was applied during 3 days preceding SE; and (3) "chronic phase-treatment"-5 days rapamycin treatment (3 mg/kg/day) in the chronic phase. We also tested curcumin, an alternative mTOR inhibitor with antiinflammatory and antioxidant effects, using chronic phase treatment. Seizures were continuously monitored using video-electroencephalography (EEG) recordings; mossy fiber sprouting, cell death, and inflammation were studied using immunohistochemistry. Blood was withdrawn regularly to assess rapamycin and curcumin levels with high performance liquid chromatography (HPLC). RESULTS: Stop-treatment led to a strong reduction of seizures during the 3-week treatment and a gradual reappearance of seizures during the following 5 weeks. Three days pretreatment did not prevent seizure development, whereas 5-day rapamycin treatment in the chronic phase reduced seizure frequency. Washout of rapamycin was slow and associated with a gradual reappearance of seizures. Rapamycin treatment (both 3 and 6 mg/kg) led to body growth reduction. Curcumin treatment did not reduce seizure frequency or lead to a decrease in body weight. SIGNIFICANCE: The present study indicates that rapamycin cannot prevent epilepsy in the electrical stimulation post-SE rat model but has seizure-suppressing properties as long as rapamycin blood levels are sufficiently high. Oral curcumin treatment had no effect on chronic seizures, possibly because it did not reach the brain at adequate levels.


Assuntos
Anticonvulsivantes/uso terapêutico , Curcumina/uso terapêutico , Estimulação Elétrica/efeitos adversos , Sirolimo/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Análise de Variância , Animais , Anticonvulsivantes/sangue , Peso Corporal/efeitos dos fármacos , Curcumina/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletroencefalografia , Hipocampo/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Sirolimo/sangue , Estado Epiléptico/sangue , Estado Epiléptico/etiologia , Fatores de Tempo , Resultado do Tratamento
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