Fluoxetine and Curcumin Prevent the Alterations in Locomotor and Exploratory Activities and Social Interaction Elicited by Immunoinflammatory Activation in Zebrafish: Involvement of BDNF and Proinflammatory Cytokines.

The increase in proinflammatory cytokine expression causes behavioral changes consistent with sickness behavior, and this led to the suggestion that depression might be a psychoneuroimmunological phenomenon. Here, we evaluated the effects of the pretreatment with fluoxetine (10 mg/kg, i.p.) and curcumin (0.5 mg/kg, i.p.) on the immune response elicited by the inoculation of an Aeromonas hydrophila bacterin in zebrafish. Non-pretreated but A. hydrophila-inoculated and sham-inoculated groups of fish served as controls. The social preference, locomotor, exploratory activities, and cerebral expression of il1b, il6, tnfa, and bdnf mRNA were compared among the groups. Behavioral changes characteristic of sickness behavior and a significant increase in the expression of il1b and il6 cytokines were found in fish from the immunostimulated group. The behavioral alterations caused by the inflammatory process were different between males and females, which was coincident with the increased expression of cerebral BDNF. Fluoxetine and curcumin prevented the sickness behavior induced by A. hydrophila and the increased expression of proinflammatory cytokines. Our results point to the potential of zebrafish as a translational model in studies related to neuroinflammation and demonstrate for the first time the effects of fluoxetine and curcumin on zebrafish sickness behavior.

Micronized Resveratrol Shows Anticonvulsant Properties in Pentylenetetrazole-Induced Seizure Model in Adult Zebrafish.

Epilepsy affects 50 million people around the world, and the patients experience cognitive, psychological and social consequences. Despite the considerable quantity of antiepileptic drugs available, 30% of patients still suffer in seizure. Therefore, the advance in therapeutic alternatives is mandatory. Resveratrol has been attracting the attention of many researchers because of its pharmacological potential. However, despite its neuroprotective and anti-epileptic effects, clinical resveratrol use is impaired by its low bioavailability. Here, we applied the supercritical fluid micronization technology (SEDS) to overcome this deficit, and investigated the anticonvulsant potential of micronized resveratrol in a PTZ-induced seizure model in adult zebrafish (Danio rerio). SEDS permits obtaining significantly reduced particle size with a fine size distribution in comparison with the starting material. It can improve the pharmacotherapeutic efficacy. Our data showed that micronized resveratrol decreased the occurrence of the tonic-clonic seizure stage and slowed the development of the seizures in a similar manner of diazepam. Non-processed resveratrol was not able to protect the animals. Furthermore, diazepam decreased the locomotion and exploratory behavior. Differently from diazepam, the micronized resveratrol did not induce behavioral adverse events. In addition, our data showed that the PTZ-induced seizures increased the c-fos transcript levels following the neural excitability. However, the increase in c-fos levels was prevented by micronized resveratrol. In conclusion, our results demonstrate that the micronized resveratrol shows anticonvulsant effect, like the classical antiepileptic drug diazepam in a PTZ-induced seizure model. Excitingly, different from diazepam, micronized resveratrol did not provoke behavioral adverse events.

Micronized resveratrol shows promising effects in a seizure model in zebrafish and signalizes an important advance in epilepsy treatment.

Resveratrol is a natural non-flavonoid polyphenolic that has been emerging in epilepsy treatment. Despite its pharmacological properties, the poor bioavailability of resveratrol has been an important barrier that hinders its application as an anticonvulsant. The aim of this work was to improve resveratrol's anticonvulsant effects by micronizing this compound through supercritical fluid micronization technology, which promotes an increase of the particles' surface area and allows significantly reduced particle size to be obtained. We obtained commercial and micronized resveratrol and investigated the anticonvulsant effects of resveratrol as commercially found and micronized resveratrol in a pentylenetetrazole-induced seizure model in zebrafish (Danio rerio) larvae. Diazepam was used as the positive control. Also, animals had their locomotor and exploratory activity analyzed 24 h after the seizure occurrence. The occurrence of the tonic-clonic seizure stage was only prevented by diazepam and micronized resveratrol, unlike the non-processed compound. The seizure development was significantly slowed by diazepam and micronized resveratrol, while non-micronized resveratrol was not able to increase the latency of seizure stages. In addition, diazepam and micronized resveratrol prevented the deleterious effects of pentylenetetrazole-induced seizures on animals' locomotor and exploratory behaviour. Obtained data demonstrates that the micronization process potentiates the anticonvulsant effect of resveratrol. Micronized resveratrol achieved a similar effect to the classical drug diazepam, with the benefit that it may be a safe drug candidate to be used during the neurodevelopmental stage.