Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5558546 | Toxicology and Applied Pharmacology | 2017 | 49 Pages |
Abstract
Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD50 value of sulforaphane in mice was estimated at 212.67Â mg/kg, while the TD50 value - at 191.58Â mg/kg. In seizure tests, sulforaphane at the highest dose tested (200Â mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Â Hz-induced psychomotor seizure. At doses of 10-200Â mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100Â mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150-300Â mg/kg), hypothermia (at 150-300Â mg/kg), impairment of motor coordination (at 200-300Â mg/kg), decrease in skeletal muscle strength (at 250-300Â mg/kg), and deaths (at 200-300Â mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200Â mg/kg. In conclusion, since sulforaphane was proconvulsant at a toxic dose, the safety profile and the risk-to-benefit ratio of sulforaphane usage in epileptic patients should be further evaluated.
Keywords
TD50ProconvulsantLD50ED50PTZNrf2DMSOmaximal electroshock seizure thresholdinternal standardMESTMaximal electroshock seizureconfidence limitstandard error of the meanIntraperitoneallyintravenouslyantiepileptic drugslethal doseDimethyl sulfoxideToxicitySulforaphaneantioxidant response elementnuclear factor erythroid 2-related factor 2median effective doseMeSmedian lethal doseNewtonAREPentylenetetrazole
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Authors
Katarzyna SocaÅa, Dorota Nieoczym, Edyta Kowalczuk-Vasilev, Elżbieta Wyska, Piotr Wlaź,