Abstract
This research aimed to assess the effect of perillyl alcohol (PA) on convulsive behavior in vivo using adult zebrafish (Danio rerio, both sexes). The seizures were induced with pentylenetetrazole (PTZ) intraperitoneally at 170 mg/kg, and diazepam (DZP) was used as the control anticonvulsant (2 mg/kg, oral); PA was tested at 10, 50, and 100 mg/kg orally. The groups had ten animals per group (total n = 60), observed for 10 minutes after seizure induction. We manually appraised typical seizure phenotypes for quantification and used an animal tracking software (Toxtrac) to assess the motor parameters. Next, we sought to find a mechanism of action for PA anticonvulsant activity in silico using a structure-based activity prediction server and molecular docking. The results show that PTZ induced seizure-like behavior in all untreated animals with hyperlocomotion episodes, seizure itself, posture loss, and immobility. DZP inhibited the seizures in all animals of the positive control group. PA, in turn, inhibited the occurrence of seizures in a dose-dependent manner, with frequencies of 90%, 70%, and 40% (for 10, 50, and 100 mg/kg, respectively). The PA treatments also decreased several seizure endpoints in a dose-dependent manner. Also, the difference of the group treated with highest dose of PA was statistically significant compared with the negative control group for all the endpoints assessed (p < 0.05, Kruskal-Wallis). The in silico analyses suggested that PA can affect the GABAergic system, which might be involved in its anticonvulsant activity, but other mechanisms cannot be ruled out. Overall, our results suggest an anticonvulsant potential in perillyl alcohol.
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Abbreviations
- CNS:
-
Central nervous system
- DNA:
-
Deoxyribonucleic acid
- DZP:
-
Diazepam
- GABA-AT:
-
Gamma aminobutyric acid
- mTOR:
-
Mammalian target of rapamycin
- PA:
-
Perillyl alcohol
- PTZ:
-
Pentylenetetrazole
- ROS:
-
Reactive oxygen species
- Toxtrac:
-
animal tracking software
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Funding
This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES). Process Number 88882.430015/2019-2019-01 and 88887.478228/2020-00.
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ACMP designed the study, performed the in vivo experiments, was one of the blind evaluators of manual assessment of seizure behavior, performed the software-assisted automated video analysis, analyzed the results, and wrote the manuscript. BLSO, ELM, and RSB helped with the in vivo experiments and were the other blind evaluators. LIDSHM performed the in silico experiments and analysis. XU and JCTC was the supervisor of the project.
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Matias Pereira, A.C., Sánchez-Ortíz, B.L., de Melo, E.L. et al. Perillyl alcohol decreases the frequency and severity of convulsive-like behavior in the adult zebrafish model of acute seizures. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1177–1190 (2021). https://doi.org/10.1007/s00210-021-02050-0
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DOI: https://doi.org/10.1007/s00210-021-02050-0