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Metabolic Alterations Predispose to Seizure Development in High-Fat Diet-Treated Mice: the Role of Metformin

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Abstract

The link between epilepsy and type 2 diabetes (T2DM) and/or metabolic syndrome (MetS) has been poorly investigated. Therefore, we tested whether a high-fat diet (HFD), inducing insulin-resistant diabetes and obesity in mice, would increase susceptibility to develop generalized seizures induced by pentylentetrazole (PTZ) kindling. Furthermore, molecular mechanisms linked to glucose brain transport and the effects of the T2DM antidiabetic drug metformin were also studied along with neuropsychiatric comorbidities. To this aim, two sets of experiments were performed in CD1 mice, in which we firstly evaluated the HFD effects on some metabolic and behavioral parameters in order to have a baseline reference for kindling experiments assessed in the second section of our protocol. We detected that HFD predisposes towards seizure development in the PTZ-kindling model and this was linked to a reduction in glucose transporter-1 (GLUT-1) expression as observed in GLUT-1 deficiency syndrome in humans but accompanied by a compensatory increase in expression of GLUT-3. While we confirmed that HFD induced neuropsychiatric alterations in the treated mice, it did not change the development of kindling comorbidities. Furthermore, we propose that the beneficial effects of metformin we observed towards seizure development are related to a normalization of both GLUT-1 and GLUT-3 expression levels. Overall, our results support the hypothesis that an altered glycometabolic profile could play a pro-epileptic role in human patients. We therefore recommend that MetS or T2DM should be constantly monitored and possibly avoided in patients with epilepsy, since they could further aggravate this latter condition.

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Acknowledgments

We would like to thank to Dr. Giovanni Bosco Politi for providing technical help.

Funding

This work was partly supported by the Italian Ministry of Health (Grant No. GR-2013-02355028). This work was partly supported by the Italian Ministry of University and Research (MIUR) (Prot. 2017YZF7MA).

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Conceived and designed the experiments: ER, AL, and AB. Performed the experiments: VN, AL, MT, and BA. Analyzed the data and wrote the paper: AL, ER, VN, and AC. Commented on the paper and provided feedback on the discussion: GDS and RC. Corrected and modified the manuscript: all authors.

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Correspondence to Emilio Russo.

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The experimental protocols and the procedures reported here were approved (Authorization n° 177/2019-PR) by the Animal Care Committee of the University of Catanzaro, Italy.

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Nesci, V., Russo, E., Arcidiacono, B. et al. Metabolic Alterations Predispose to Seizure Development in High-Fat Diet-Treated Mice: the Role of Metformin. Mol Neurobiol 57, 4778–4789 (2020). https://doi.org/10.1007/s12035-020-02062-6

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