Inhibition of sodium glucose cotransporters following status epilepticus induced by intrahippocampal pilocarpine affects neurodegeneration process in hippocampus

Melo, Igor Santana de; Santos, Yngrid Mickaelli Oliveira dos; Costa, Mariana Ivo; Pacheco, Amanda Larissa Dias; Silva, Nívea K.G.T.; Cardoso-Sousa, Léia; Pereira, Ulises; Goulart, Luíz Ricardo; García-Cairasco, Norberto; Duzzioni, Marcelo; Gitaí, Daniel Leite Góes; Tilelli, Cristiane Queixa; Sabino-Silva, Robinson; Castro, Olagide Wagner de

doi:10.1016/j.yebeh.2016.05.026

Cited by 21 publications

(15 citation statements)

References 55 publications

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“…At the time in which this study was initiated, there were limited published studies that investigated the effects of SGLT inhibition on epilepsy. In one study published in 2016, Melo et al observed [ 12 ] that phlorizin, a specific SGLT inhibitor, increased the severity of limbic seizures induced by pilocarpine during status epilepticus and also worsened the severity of neurodegeneration in the hippocampus at 24 h after status epilepticus in mice. The results of this study appeared to contradict a study we conducted, in which phlorizin demonstrated anticonvulsant effects in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Given these early conflicting results, we were motivated to do this study to further investigate the potential effects of SGLT inhibition on seizure activity. Instead of doing another study on phlorizin, we selected dapagliflozin as the study drug since, as far as we know, the effects of SGLT2 inhibitors on seizure activity remained unknown, whether in rats or other mammals [ 12 ], and in addition dapagliflozin is becoming widely use around the world as a leading diabetic drug.…”

Section: Discussionmentioning

confidence: 99%

“…In one recent study [ 12 ], Melo et al demonstrated that phlorizin, a specific SGLT inhibitor, increased the severity of limbic seizures induced by pilocarpine during status epilepticus (SE) in mice, and in addition, caused more extensive neurodegeneration in the hippocampus 24 h after SE. However, yet other studies with the same compound and similar methodologies yielded opposite results.…”

Section: Introductionmentioning

confidence: 99%

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Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy

et al. 2018

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BackgroundWorldwide, over 10 million individuals suffer from drug-resistant epilepsy. New therapeutic strategies are needed to address this debilitating disease. Inhibition of sodium-glucose linked transporters (SGLTs), which are variably expressed in the brain, has been demonstrated to reduce seizure activity in murine models of epilepsy. Here we investigated the effects of dapagliflozin, a highly competitive SGLT2 inhibitor currently used as a drug for diabetes mellitus, on seizure activity in rats with pentylenetetrazol (PTZ) induced seizures.MethodsLaboratory rats (n = 48) were evenly randomized into two experiments, each with four study arms: (1) a vehicle-treated (placebo) arm infused with saline; (2) a control arm infused with PTZ; (3) a treatment arm with PTZ and dapagliflozin at 75 mg/kg, and (4) another treatment arm with PTZ and dapagliflozin at 150 mg/kg. Study subjects were assessed for seizures either via EEG as measured by spike wave percentage (SWP), or clinically via Racine’s scales scores (RSS) and time to first myoclonic jerk (TFMJ).ResultsRats treated with dapagliflozin had lower mean SWP on EEG (20.4% versus 75.3% for untreated rats). Behaviorally, treatment with dapagliflozin improved means RSS (2.33 versus 5.5) and mean TFMJ (68.3 versus 196.7 s). All of these findings were statistically significant with p-values of < 0.0001. There was a trend towards even better seizure control with the higher dose of dapagliflozin at 150 mg/kg, however this was not consistently statistically significant.ConclusionsDapagliflozin decreased seizure activity in rats with PTZ–induced seizures. This may be explained by the anti-seizure effects of decreased glucose availability and a reduction in sodium transport across neuronal membranes which can confer a stabilizing effect against excitability and unwanted depolarization. The potential clinical role of dapagliflozin and other SGLT2 inhibitors as anti-seizure medications should be further explored.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy

et al. 2018

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“…In turn, Wright et al suggested that SGLT2 (and SGLT1) expressed in the heart and brain may behave as glucose receptors [ 42 , 64 ], and the possibility that SGLT inhibitors may act in brain regions governing appetite and satiety to induce SGLT inhibitor-induced hyperphagia has not been conclusively ruled out [ 46 ]. SGLT2 in the brain may also affect the pathophysiology of epilepsy; however, the effects of SGLT2 inhibitors on murine epilepsy models are conflicting [ 65 , 66 ]. Brain SGLT2 and SGLT1 expressions are increased upon traumatic brain injury [ 67 ].…”

Section: Glucose Transporters In Choroid Plexus Epithelial Cellsmentioning

confidence: 99%

Glucose, Fructose, and Urate Transporters in the Choroid Plexus Epithelium

Chiba

Murakami

Matsumoto

et al. 2020

IJMS

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The choroid plexus plays a central role in the regulation of the microenvironment of the central nervous system by secreting the majority of the cerebrospinal fluid and controlling its composition, despite that it only represents approximately 1% of the total brain weight. In addition to a variety of transporter and channel proteins for solutes and water, the choroid plexus epithelial cells are equipped with glucose, fructose, and urate transporters that are used as energy sources or antioxidative neuroprotective substrates. This review focuses on the recent advances in the understanding of the transporters of the SLC2A and SLC5A families (GLUT1, SGLT2, GLUT5, GLUT8, and GLUT9), as well as on the urate-transporting URAT1 and BCRP/ABCG2, which are expressed in choroid plexus epithelial cells. The glucose, fructose, and urate transporters repertoire in the choroid plexus epithelium share similar features with the renal proximal tubular epithelium, although some of these transporters exhibit inversely polarized submembrane localization. Since choroid plexus epithelial cells have high energy demands for proper functioning, a decline in the expression and function of these transporters can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases.

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“…Inhibiting sodium glucose co transporter 2 (SGLT2) has been proven to increase the level of ZAG via activating PPARγ [ 11 ], while activating PPARγ was confirmed to increase AZGP1 mRNA [ 12 ]. Interestingly, both SGLT2 and PPARγ are known to participate in epileptogenesis, especially PPARγ was considered as a promising therapeutic target of epilepsy [ 13 – 15 ]. ZAG can also increase the level of mitochondrial uncoupling proteins (UCP) [ 16 ], and PPARγ-upregulated mitochondrial UCP2 expression can ameliorate neuronal death in the hippocampus following status epilepticus [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of zinc-α2-glycoprotein suppressed seizures and seizure-related neuroflammation in pentylenetetrazol-kindled rats

Liu

Wang

Liu

et al. 2018

J Neuroinflammation

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BackgroundZinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFβ and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation.MethodsWe overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFβ, ERK, and ERK phosphorylation were determined.ResultsThe overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFβ, and ERK phosphorylaton in PTZ-kindled rats.ConclusionsZAG may inhibit TGFβ-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy.

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Inhibition of sodium glucose cotransporters following status epilepticus induced by intrahippocampal pilocarpine affects neurodegeneration process in hippocampus

Cited by 21 publications

References 55 publications

Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy

Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy

Glucose, Fructose, and Urate Transporters in the Choroid Plexus Epithelium

Overexpression of zinc-α2-glycoprotein suppressed seizures and seizure-related neuroflammation in pentylenetetrazol-kindled rats

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