Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy—The Effects of Treatment with a GPR39 Agonist and Knockout of the Gpr39 Gene

Abstract

Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated with an agonist of the GPR39 receptor (TC-G 1008) and underwent acute seizures (maximal electroshock (MES)- or 6-hertz-induced seizures) or a pentylenetetrazole (PTZ)-induced kindling model of epilepsy. MES seizures and PTZ kindling, unlike 6 Hz seizures, increased serum magnesium concentration. In turn, Gpr39-KO mice that underwent PTZ kindling displayed decreased concentrations of this element compared to WT mice subjected to this procedure. However, the levels of expression of TRPM7 and SlC41A1 proteins—which are responsible for magnesium transport into and out of cells, respectively—did not differ in the hippocampus between Gpr39-KO and WT mice. Furthermore, laser ablation inductively coupled plasma mass spectrometry applied to hippocampal slices did not reveal differences in magnesium levels between the groups. These data show the relationship between magnesium homeostasis and certain types of acute or chronic seizures (MES seizures or PTZ kindling, respectively), but do not explicitly support the role of GPR39 in mediating magnesium balance in the hippocampus in the latter model. However, decreased expression of TRPM7 and increased expression of SLC41A1—which were observed in the hippocampi of Gpr39-KO mice treated with TC-G 1008, in comparison to WT mice that received the same treatment—implicitly support the link between GPR39 and hippocampal magnesium homeostasis.

Dietary Zinc Differentially Regulates the Effects of the GPR39 Receptor Agonist, TC-G 1008, in the Maximal Electroshock Seizure Test and Pentylenetetrazole-Kindling Model of Epilepsy

“…It binds, however, to the serotonin 5-HT1A receptor [19]. We found non-selective effects of TC-G 1008 on the expression of p-CREB/CREB [16] and TRPM7 [39] proteins in the hippocampus. In the MEST test, we did not exclude the involvement of other targets such as 5-HT1A receptor in the activity of TC-G 1008 [16].…”

Signaling pathway mechanisms of neurological diseases induced by G protein‐coupled receptor 39

“…GPR39 may also play an important role in magnesium homeostasis. 67 Magnesium homeostasis is associated with epilepsy, and it may have synergistic effects with other antiepileptic agents. 68 , 69 …”

“…GPR39 may also play an important role in magnesium homeostasis. 67 Magnesium homeostasis is associated with epilepsy, and it may have synergistic effects with other antiepileptic agents. 68,69 As previously mentioned, the activation of KCC2 is closely related to intra-and extracellular chloride regulation and GABAergic inhibition, and the altered electrical activity of hippocampal cells is a key point for seizure suppression.…”

“…Recent studies have shown that in the hippocampus of GPR39‐KO mice, TC‐G 1008 treatment reduced the expression of TRPM7 and increased the expression of SLC41A1, which are important transport proteins for the movement of magnesium in and out of cells. GPR39 may also play an important role in magnesium homeostasis 67 . Magnesium homeostasis is associated with epilepsy, and it may have synergistic effects with other antiepileptic agents 68,69 …”

The impact of serum magnesium and calcium on the risk of epilepsy: A mendelian randomization study

“…A 22‐year follow‐up study also revealed that higher oral magnesium supplementation was related to a lower risk of adult epilepsy 12 . Recently, animal research showed a certain relationship between magnesium homeostasis and acute or chronic seizures 13 . Likewise, lower serum calcium concentrations was reported to be associated with a higher risk of epilepsy 9,10,14 .…”