N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy.

N-acetylcysteine (NAC) is an antioxidant with some demonstrated efficacy in a range of neuropsychiatric disorders. NAC has shown anticonvulsant effects in animal models. NAC effects on absence seizures are still not uncovered, and considering its clinical use as a mucolytic in patients with lung diseases, people with epilepsy are also likely to be exposed to the drug. Therefore, we aimed to study the effects of NAC on absence seizures in the WAG/Rij rat model of absence epilepsy with neuropsychiatric comorbidities. The effects of NAC chronic treatment in WAG/Rij rats were evaluated on: absence seizures at 15 and 30 days by EEG recordings and animal behaviour at 30 days on neuropsychiatric comorbidities. Furthermore, the mechanism of action of NAC was evaluated by analysing brain expression levels of some possible key targets: the excitatory amino acid transporter 2, cystine-glutamate antiporter, metabotropic glutamate receptor 2, the mechanistic target of rapamycin and p70S6K as well as levels of total glutathione. Our results demonstrate that in WAG/Rij rats, NAC treatment significantly increased the number and duration of SWDs, aggravating absence epilepsy while ameliorating neuropsychiatric comorbidities. NAC treatment was linked to an increase in brain mGlu2 receptor expression with this being likely responsible for the observed absence seizure-promoting effects. In conclusion, while confirming the positive effects on animal behaviour induced by NAC also in epileptic animals, we report the aggravating effects of NAC on absence seizures which could have some serious consequences for epilepsy patients with the possible wider use of NAC in clinical therapeutics.