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

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 insulinresistant 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.

A novel rhein-huprine hybrid ameliorates disease-modifying properties in preclinical mice model of Alzheimer’s disease exacerbated with high fat diet

“…HFD consumption leads to metabolic alterations, including insulin resistance and T2DM [59,60], both conditions frequently associated with the development of dementia [41,61]. T2DM is a complex disorder that begins with a state of insulin resistance, leading to hyperinsulinemia and hyperglycemia, which is known to cause different alterations in the brain.…”

Seizure susceptibility to various convulsant stimuli in the BTBR mouse model of autism spectrum disorders

“…In experiment #2, we studied BTBR mice’s susceptibility to PTZ-kindling and its impact on animal behavior in a set of various tests evaluating different aspects spanning from sociability to anxiety and cognitive impairment (see Section Behavioral Tests). Regarding behavioral tests, for every single mice group, testing started 24 h after the last PTZ injection necessary to achieve the kindling criterion within the group ( Nesci et al, 2020 ). Likewise, testing for non-kindled mice started contemporarily with their respective kindled control groups.…”

Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

“…This enhances astrocytic glucose uptake and glycolysis and enables proper regulation of the astrocyte-neuron lactate shuttle (ANLS), which preserves neuronal metabolic functionality [74]. This could explain the beneficial effects of AMPK activation by metformin on PTZ-induced seizures in mice on a high-fat diet, since after treatment with metformin, a normalization in the expression levels of GLUT1 and GLUT3 was observed [75].…”