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

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Abstract 

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.

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Acknowledgements

Dr. Giovanni Politi is kindly acknowledged for his technical help with the experiments. We would like to thank to Dr. Luigi Francesco Iannone who has made the experimental scheme.

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Authors and Affiliations

  1. System and Applied Pharmacology@University Magna Grecia (FAS@UMG) Research Center, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy

    Martina Tallarico, Antonio Leo, Lorenza Guarnieri, Maria Caterina Zito, Carmen De Caro, Emilio Russo, Giovambattista De Sarro & Rita Citraro

  2. Department of Science of Health, School of Medicine and Surgery, University of Catanzaro, Viale Europa – Germaneto, 88100, Catanzaro, Italy

    Antonio Leo

  3. IRCCS Neuromed, Pozzilli, Italy

    Ferdinando Nicoletti

  4. Department of Physiology and Pharmacology, University Sapienza, Roma, Italy

    Ferdinando Nicoletti

  5. Department of Pharmacology, University College London School of Pharmacy, 29/39 Brunswick Square, London, WC1N 1AX, UK

    Andrew Constanti

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  1. Martina Tallarico
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  2. Antonio Leo
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  10. Rita Citraro
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Contributions

Rita Citraro, Antonio Leo, Giovambattista De Sarro, and Andrew Constanti contributed to conceptualization; Antonio Leo, Martina Tallarico, Emilio Russo, and Rita Citraro performed formal analysis and investigation; Martina Tallarico, Antonio Leo, Carmen De Caro, Maria Caterina Zito, and Lorenza Guarnieri provided methodology; Antonio Leo, Martina Tallarico, Andrew Constanti, and Emilio Russo performed writing—original draft preparation; Antonio Leo, Emilio Russo, and Rita Citraro performed writing—reviewing and editing.

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Correspondence to Antonio Leo or Andrew Constanti.

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The experimental protocols and the procedures reported here were approved (Authorization n° 491/2016-PR) by the Animal Care Committee of the University of Catanzaro, Italy.

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Tallarico, M., Leo, A., Guarnieri, L. et al. N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy. Mol Neurobiol 59, 2702–2714 (2022). https://doi.org/10.1007/s12035-021-02720-3

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