Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice

Toxicol Appl Pharmacol. 2017 Jul 1;326:43-53. doi: 10.1016/j.taap.2017.04.010. Epub 2017 Apr 13.

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 212.67mg/kg, while the TD50 value - at 191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (200mg/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 6Hz-induced psychomotor seizure. At doses of 10-200mg/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 100mg/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 150-300mg/kg), hypothermia (at 150-300mg/kg), impairment of motor coordination (at 200-300mg/kg), decrease in skeletal muscle strength (at 250-300mg/kg), and deaths (at 200-300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg/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: Antiepileptic drugs; Lethal dose; Proconvulsant; Sulforaphane; Toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / toxicity*
  • Body Temperature Regulation / drug effects
  • Brain / drug effects*
  • Brain / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Electroshock
  • Isothiocyanates / toxicity*
  • Lethal Dose 50
  • Male
  • Memory, Long-Term / drug effects
  • Mice
  • Motor Activity / drug effects
  • Muscle Strength / drug effects
  • Pentylenetetrazole
  • Psychomotor Performance / drug effects
  • Risk Assessment
  • Seizures / blood
  • Seizures / chemically induced*
  • Seizures / physiopathology
  • Seizures / prevention & control
  • Time Factors

Substances

  • Anticonvulsants
  • Isothiocyanates
  • sulforafan
  • Pentylenetetrazole