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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References
Cramer JA, Wang ZJ, Chang E et al (2014) Healthcare utilization and costs in adults with stable and uncontrolled epilepsy. Epilepsy Behav 31:356–362. https://doi.org/10.1016/j.yebeh.2013.09.046
Mastrangelo M, Tromba V, Silvestri F, Costantino F (2019) Epilepsy in children with type 1 diabetes mellitus: Pathophysiological basis and clinical hallmarks. Eur J Paediatr Neurol 23:240–247
Chou IC, Wang CH, De Lin W et al (2016) Risk of epilepsy in type 1 diabetes mellitus: a population-based cohort study. Diabetologia 59:1196–1203. https://doi.org/10.1007/s00125-016-3929-0
Shlobin NA, Sander JW (2020) Drivers for the comorbidity of type 2 diabetes mellitus and epilepsy: a scoping review. Epilepsy Behav 106:107043. https://doi.org/10.1016/j.yebeh.2020.107043
Harden CL, Rosenbaum DH, Daras M (1991) Hyperglycemia presenting with occipital seizures. Epilepsia 32:215–220. https://doi.org/10.1111/j.1528-1157.1991.tb05247.x
Berkovic SF, Johns JA, Bladin PF (1982) Focal seizures and systemic metabolic disorders. Aust N Z J Med 12:620–623. https://doi.org/10.1111/j.1445-5994.1982.tb02650.x
Schwechter EM, Velíšková J, Velíšek L (2003) Correlation between extracellular glucose and seizure susceptibility in adult rats. Ann Neurol 53:91–101. https://doi.org/10.1002/ana.10415
Koltai M, Minker E (1975) Changes of electro-shock seizure threshold in alloxan diabetic rats. Experientia 31:1369. https://doi.org/10.1007/BF01945833
Tutka P, Sawiniec J, Kleinrok Z (1998) Experimental diabetes sensitizes mice to electrical- and bicuculline- induced convulsions. In: Polish Journal of Pharmacology. pp. 92–93
Leo A, De Caro C, Nesci V et al (2020) Modeling poststroke epilepsy and preclinical development of drugs for poststroke epilepsy. Epilepsy Behav 104:106472
Gasparini S, Ferlazzo E, Sueri C et al (2019) Hypertension, seizures, and epilepsy: A review on pathophysiology and management. Neurol Sci 40:1775–1783. https://doi.org/10.1007/s10072-019-03913-4
Ferlazzo E, Gasparini S, Beghi E et al (2016) Epilepsy in cerebrovascular diseases: Review of experimental and clinical data with meta-analysis of risk factors. Epilepsia 57:1205–1214. https://doi.org/10.1111/epi.13448
Palleria C, Leporini C, Maida F et al (2016) Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes. Front Neuroendocrinol 42:76–92. https://doi.org/10.1016/j.yfrne.2016.07.002
Kanner AM (2016) Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol 12:106–116. https://doi.org/10.1038/nrneurol.2015.243
Moulton CD, Pickup JC, Ismail K (2015) The link between depression and diabetes: The search for shared mechanisms. Lancet Diabetes Endocrinol 3:461–471
Hamed SA (2014) Antiepileptic drugs influences on body weight in people with epilepsy. Expert Rev Clin Pharmacol 8:103–114
Nisha Y, Bobby Z, Wadwekar V (2018) Biochemical derangements related to metabolic syndrome in epileptic patients on treatment with valproic acid. Seizure 60:57–60. https://doi.org/10.1016/j.seizure.2018.06.003
Ben-Menachem E (2007) Weight issues for people with epilepsy - a review. In: Epilepsia. pp. 42–45
Pearson-Smith JN, Patel M (2017) Metabolic dysfunction and oxidative stress in epilepsy. Int J Mol Sci 18:2365. https://doi.org/10.3390/ijms18112365
Mohamed S, El Melegy EM, Talaat I et al (2015) Neurometabolic disorders-related early childhood epilepsy: a single-center experience in Saudi Arabia. Pediatr Neonatol 56:393–401. https://doi.org/10.1016/j.pedneo.2015.02.004
Citraro R, Iannone M, Leo A et al (2019) Evaluation of the effects of liraglutide on the development of epilepsy and behavioural alterations in two animal models of epileptogenesis. Brain Res Bull 153:133–142. https://doi.org/10.1016/j.brainresbull.2019.08.001
Erdogan MA, Yusuf D, Christy J et al (2018) Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy. BMC Neurol 18. https://doi.org/10.1186/s12883-018-1086-4
Mehrabi S, Sanadgol N, Barati M et al (2018) Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy. Metab Brain Dis 33:107–114. https://doi.org/10.1007/s11011-017-0132-z
Zhao RR, Xu XC, Xu F et al (2014) Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun 448:414–417. https://doi.org/10.1016/j.bbrc.2014.04.130
Holman GD (2018) Chemical biology probes of mammalian GLUT structure and function. Biochem J 475:3511–3534. https://doi.org/10.1042/BCJ20170677
Simpson IA, Appel NM, Hokari M et al (1999) Blood-brain barrier glucose transporter: Effects of hypo- and hyperglycemia revisited. J Neurochem 72:238–247. https://doi.org/10.1046/j.1471-4159.1999.0720238.x
Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8:1003–1011. https://doi.org/10.1096/fasebj.8.13.7926364
Joost HG, Bell GI, Best JD et al (2002) Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol - Endocrinol Metab 282. https://doi.org/10.1152/ajpendo.00407.2001
Siracusa R, Fusco R, Cuzzocrea S (2019) Astrocytes: Role and functions in brain pathologies. Front Pharmacol. https://doi.org/10.3389/fphar.2019.01114
Vannucci SJ, Clark RR, Koehler-Stec E, et al (1998) Glucose transporter expression in brain: Relationship to cerebral glucose utilization. In: Developmental Neuroscience. pp. 369–379
Garcia-Serrano AM, Duarte JMN (2020) Brain metabolism alterations in type 2 diabetes: what did we learn from diet-induced diabetes models? Front Neurosci 14. https://doi.org/10.3389/fnins.2020.00229
Panandikar GA, Ravat SH, Ansari RR, Desai KM (2018) Rare and treatable cause of early-onset refractory absence seizures. J Pediatr Neurosci 13:358–361. https://doi.org/10.4103/JPN.JPN_146_17
Nathan DM, Buse JB, Davidson MB et al (2009) Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 32:193–203. https://doi.org/10.2337/dc08-9025
Mirabelli M, Chiefari E, Caroleo P, et al (2019) Long-term effectiveness of liraglutide for weight management and glycemic control in type 2 diabetes. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph17010207
Morales DR, Morris AD (2015) Metformin in cancer treatment and prevention. Annu Rev Med 66:17–29. https://doi.org/10.1146/annurev-med-062613-093128
Fan H, Yu X, Zou Z et al (2019) Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway. Carcinogenesis 40:669–679. https://doi.org/10.1093/carcin/bgy160
Rubio Osornio M d C, Custodio Ramírez V, Calderón Gámez D et al (2018) Metformin plus caloric restriction show anti-epileptic effects mediated by mTOR pathway inhibition. Cell Mol Neurobiol 38:1425–1438. https://doi.org/10.1007/s10571-018-0611-8
Brueggeman L, Sturgeon ML, Martin RM, Grossbach AJ, Nagahama Y, Zhang A, Howard MA 3rd, Kawasaki H et al (2019) Drug repositioning in epilepsy reveals novel antiseizure candidates. Ann Clin Transl Neurol 6:295–309
Yimer EM, Surur A, Wondafrash DZ, Gebre AK (2019) The effect of metformin in experimentally induced animal models of epileptic seizure. Behav Neurol 2019:1–13
Russo E, Leo A, Scicchitano F et al (2017) Cerebral small vessel disease predisposes to temporal lobe epilepsy in spontaneously hypertensive rats. Brain Res Bull 130:245–250. https://doi.org/10.1016/j.brainresbull.2017.02.003
Cassano V, Leo A, Tallarico M, et al (2020) Metabolic and cognitive effects of ranolazine in type 2 diabetes mellitus: data from an in vivo model. Nutrients 12: https://doi.org/10.3390/nu12020382
Russo E, Chimirri S, Aiello R et al (2013) Lamotrigine positively affects the development of psychiatric comorbidity in epileptic animals, while psychiatric comorbidity aggravates seizures. Epilepsy Behav 28:232–240. https://doi.org/10.1016/j.yebeh.2013.05.002
Lombardo GE, Arcidiacono B, De Rose RF, et al (2016) Normocaloric diet restores weight gain and insulin sensitivity in obese mice. Front Endocrinol (Lausanne) 7: https://doi.org/10.3389/fendo.2016.00049
De Sarro G, Ibbadu GF, Marra R et al (2004) Seizure susceptibility to various convulsant stimuli in dystrophin-deficient mdx mice. Neurosci Res 50:37–44. https://doi.org/10.1016/j.neures.2004.05.007
Leo A, Citraro R, Amodio N et al (2017) Fingolimod exerts only temporary antiepileptogenic effects but longer-lasting positive effects on behavior in the WAG/Rij rat absence epilepsy model. Neurotherapeutics 14:1134–1147. https://doi.org/10.1007/s13311-017-0550-y
Leo A, De Caro C, Nesci V et al (2019) Antiepileptogenic effects of ethosuximide and levetiracetam in WAG/Rij rats are only temporary. Pharmacol Reports 71:833–838. https://doi.org/10.1016/j.pharep.2019.04.017
Russo E, Leo A, Crupi R et al (2016) Everolimus improves memory and learning while worsening depressive- and anxiety-like behavior in an animal model of depression. J Psychiatr Res 78:1–10. https://doi.org/10.1016/j.jpsychires.2016.03.008
Leo A, Citraro R, Tallarico M et al (2019) Cognitive impairment in the WAG/Rij rat absence model is secondary to absence seizures and depressive-like behavior. Prog Neuro-psychopharmacology. Biol Psychiatry 94:109652. https://doi.org/10.1016/j.pnpbp.2019.109652
Citraro R, Leo A, Franco V et al (2017) Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive-like behavior. Epilepsia 58:231–238. https://doi.org/10.1111/epi.13629
Palleria C, Leo A, Andreozzi F et al (2017) Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects. Behav Brain Res 321:157–169. https://doi.org/10.1016/j.bbr.2017.01.004
Bax EN, Cochran KE, Mao J et al (2019) Opposing effects of S-equol supplementation on metabolic and behavioral parameters in mice fed a high-fat diet. Nutr Res 64:39–48. https://doi.org/10.1016/j.nutres.2018.12.008
Arcidiacono B, Chiefari E, Messineo S et al (2018) HMGA1 is a novel transcriptional regulator of the FoxO1 gene. Endocrine 60:56–64. https://doi.org/10.1007/s12020-017-1445-8
Wang D, Pascual JM, Yang H et al (2005) Glut-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol 57:111–118. https://doi.org/10.1002/ana.20331
Almeida-Suhett CP, Graham A, Chen Y, Deuster P (2017) Behavioral changes in male mice fed a high-fat diet are associated with IL-1β expression in specific brain regions. Physiol Behav. https://doi.org/10.1016/j.physbeh.2016.11.016
Dutheil S, Ota KT, Wohleb ES, et al (2016) High-fat diet induced anxiety and anhedonia: impact on brain homeostasis and inflammation. Neuropsychopharmacology. https://doi.org/10.1038/npp.2015.357
Rossmeisl M, Rim JS, Koza RA, Kozak LP (2003) Variation in type 2 diabetes - related traits in mouse strains susceptible to diet-induced obesity. Diabetes 52:1958–1966. https://doi.org/10.2337/diabetes.52.8.1958
Montgomery MK, Hallahan NL, Brown SH, et al (2013) Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia. https://doi.org/10.1007/s00125-013-2846-8
Wong SK, Chin KY, Suhaimi FH et al (2016) Animal models of metabolic syndrome: a review. Nutr Metab 13:1–12. https://doi.org/10.1186/s12986-016-0123-9
Takechi R, Lam V, Brook E, et al (2017) Blood-brain barrier dysfunction precedes cognitive decline and neurodegeneration in diabetic insulin resistant mouse model: an implication for causal link. Front Aging Neurosci 9:. https://doi.org/10.3389/fnagi.2017.00399
Thaler JP, Yi CX, Schur EA et al (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153–162. https://doi.org/10.1172/JCI59660
Vannucci SJ, Maher F, Koehler E, Simpson IA (1994) Altered expression of GLUT-1 and GLUT-3 glucose transporters in neurohypophysis of water-deprived or diabetic rats. Am J Physiol - Endocrinol Metab 267: https://doi.org/10.1152/ajpendo.1994.267.4.e605
Schüler R, Seebeck N, Osterhoff MA et al (2018) VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: consequences for cognitive function in humans. Mol Metab 11:129–136. https://doi.org/10.1016/j.molmet.2018.02.004
Mooradian AD, Chung HC, Shah GN (1997) GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging 18:469–474. https://doi.org/10.1016/S0197-4580(97)00111-5
Szablewski L (2017) Glucose transporters in brain: In health and in Alzheimer’s disease. J Alzheimers Dis 55:1307–1320
Liu Y, Liu F, Iqbal K et al (2008) Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett 582:359–364. https://doi.org/10.1016/j.febslet.2007.12.035
Kahl KG, Georgi K, Bleich S et al (2016) Altered DNA methylation of glucose transporter 1 and glucose transporter 4 in patients with major depressive disorder. J Psychiatr Res 76:66–73. https://doi.org/10.1016/j.jpsychires.2016.02.002
Hildebrand MS, Damiano JA, Mullen SA, et al (2014) Glucose metabolism transporters and epilepsy: only GLUT1 has an established role. Epilepsia 55:. https://doi.org/10.1111/epi.12519
Chapman AG, Meldrum BS, Siesiö BK (1977) Cerebral metabolic changes during prolonged epileptic seizures in rats. J Neurochem 28:1025–1035. https://doi.org/10.1111/j.1471-4159.1977.tb10665.x
Meldrum BS (1983) Metabolic factors during prolonged seizures and their relation to nerve cell death. Adv Neurol 34:261–275
Mantis JG, Centeno NA, Todorova MT, et al (2004) Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: Role of glucose and ketone bodies. Nutr Metab 1: https://doi.org/10.1186/1743-7075-1-11
Alzoubi KH, Hasan ZA, Khabour OF et al (2018) The effect of high-fat diet on seizure threshold in rats: Role of oxidative stress. Physiol Behav 196:1–7. https://doi.org/10.1016/j.physbeh.2018.08.011
Gronlund KM, Gerhart DZ, Leino RL et al (1996) Chronic seizures increase glucose transporter abundance in rat brain. J Neuropathol Exp Neurol 55:832–840. https://doi.org/10.1097/00005072-199607000-00008
Zemdegs J, Martin H, Pintana H et al (2019) Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci 39:5935–5948. https://doi.org/10.1523/JNEUROSCI.2904-18.2019
Caroleo M, Carbone EA, Greco M, et al (2019) Brain-behavior-immune interaction: Serum cytokines and growth factors in patients with eating disorders at extremes of the body mass index (bmi) spectrum. Nutrients. https://doi.org/10.3390/nu11091995
Yang Y, Zhu B, Zheng F et al (2017) Chronic metformin treatment facilitates seizure termination. Biochem Biophys Res Commun 484:450–455. https://doi.org/10.1016/j.bbrc.2017.01.157
H S N, Paudel YN, KL K (2019) Envisioning the neuroprotective effect of metformin in experimental epilepsy: a portrait of molecular crosstalk. Life Sci 233. https://doi.org/10.1016/j.lfs.2019.116686
Wang YW, He SJ, Feng X et al (2017) Metformin: a review of its potential indications. Drug Des Devel Ther 11:2421–2429. https://doi.org/10.2147/DDDT.S141675
Liu Y, Hou B, Zhang Y et al (2018) Anticonvulsant agent DPP4 inhibitor sitagliptin downregulates CXCR3/RAGE pathway on seizure models. Exp Neurol 307:90–98. https://doi.org/10.1016/j.expneurol.2018.06.004
Langenberg C, Lotta LA (2018) Genomic insights into the causes of type 2 diabetes. Lancet 391:2463–2474
Devinsky O, Vezzani A, O’Brien TJ, et al (2018) Epilepsy
Cordaro M, Scuto M, Siracusa R, et al (2020) Effect of N-palmitoylethanolamine-oxazoline on comorbid neuropsychiatric disturbance associated with inflammatory bowel disease. FASEB J. https://doi.org/10.1096/fj.201901584RR
De Caro C, Leo A, Nesci V, et al (2019) Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy. Sci Rep. https://doi.org/10.1038/s41598-019-50542-0
De Caro C, Iannone LF, Citraro R et al (2019) Can we ‘seize’ the gut microbiota to treat epilepsy? Neurosci Biobehav Rev 107:750–764. https://doi.org/10.1016/j.neubiorev.2019.10.002
Acknowledgments
We would like to thank to Dr. Giovanni Bosco Politi for providing technical help.
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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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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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DOI: https://doi.org/10.1007/s12035-020-02062-6