L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration.

PURPOSE: Neuropathic pain is a common diabetic complication. It is characterized by symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. L-Arginine is a common precursor of many metabolites of biological interest, in particular, nitric oxide (NO), ornithine, and hence polyamines. In central nervous system, NO, glutamate, and polyamines share an N-methyl-D-aspartate (NMDA) receptor-mediated effect. We hypothesized that a variation in arginine metabolism caused by diabetes may contribute to development and maintenance of neuropathic pain and to the worsening of clinical and biological signs of diabetes. METHODS: We examined whether oral L-arginine supplementation (2.58 ± 0.13 g/l in drinking water for 3 weeks) could improve the development of neuropathic pain and the clinical, biological, and metabolic complications of diabetes in streptozocin (STZ)-induced diabetic (D) rats. RESULTS: STZ administration induced classical symptoms of type 1 diabetes. Diabetic rats also displayed mechanical hypersensitivity, tactile, and thermal allodynia. Plasma citrulline and NO levels were increased in diabetic hyperalgesic/allodynic rats. L-Arginine supplementation failed to reduce hyperglycaemia, polyphagia, and weight loss. Moreover, it abolished hyperalgesia and allodynia by normalizing NO plasma concentration and increasing plasma agmatine concentration. CONCLUSIONS: L-Arginine supplementation prevented the development of mechanical hyperalgesia, tactile, and thermal allodynia in painful diabetic neuropathy with concomitant reduction of NO and increased agmatine production, offering new therapeutic opportunities for the management of diabetic neuropathic pain.

TRPM7 is essential for Mg(2+) homeostasis in mammals.

Mg(2+) is the second-most abundant cation in animal cells and is an essential cofactor in numerous enzymatic reactions. The molecular mechanisms controlling Mg(2+) balance in the organism are not well understood. In this study, we report identification of TRPM7, a bifunctional protein containing a protein kinase fused to an ion channel, as a key regulator of whole body Mg(2+) homeostasis in mammals. We generated TRPM7-deficient mice with the deletion of the kinase domain. Homozygous TRPM7(Δkinase) mice demonstrated early embryonic lethality, whereas heterozygous mice were viable, but developed signs of hypomagnesaemia and revealed a defect in intestinal Mg(2+) absorption. Cells derived from heterozygous TRPM7(Δkinase) mice demonstrated reduced TRPM7 currents that had increased sensitivity to the inhibition by Mg(2+). Embryonic stem cells lacking TRPM7 kinase domain displayed a proliferation arrest phenotype that can be rescued by Mg(2+) supplementation. Our results demonstrate that TRPM7 is essential for the control of cellular and whole body Mg(2+) homeostasis.

Relationship between low magnesium status and TRPM6 expression in the kidney and large intestine.

The body maintains Mg(2+) homeostasis by renal and intestinal (re)absorption. However, the molecular mechanisms that mediate transepithelial Mg(2+) transport are largely unknown. Transient receptor potential melastatin 6 (TRPM6) was recently identified and shown to function in active epithelial Mg(2+) transport in intestine and kidney. To define the relationship between Mg(2+) status and TRPM6 expression, we used two models of hypomagnesemia: 1) C57BL/6J mice fed a mildly or severely Mg(2+)-deficient diet, and 2) mice selected for either low (MgL) or high (MgH) erythrocyte and plasma Mg(2+) status. In addition, the mice were subjected to a severely Mg(2+)-deficient diet. Our results show that C57BL/6J mice fed a severely Mg(2+)-deficient diet developed hypomagnesemia and hypomagnesuria and showed increased TRPM6 expression in kidney and intestine. When fed a Mg(2+)-adequate diet, MgL mice presented hypomagnesemia and hypermagnesuria, and lower kidney and intestinal TRPM6 expression, compared with MgH mice. A severely Mg(2+)-deficient diet led to hypomagnesemia and hypomagnesuria in both strains. Furthermore, this diet induced kidney TRPM6 expression in MgL mice, but not in MgH mice. In conclusion, as shown in C57BL/6J mice, dietary Mg(2+)-restriction results in increased Mg(2+) (re)absorption, which is correlated with increased TRPM6 expression. In MgL and MgH mice, the inherited Mg(2+) status is linked to different TRPM6 expression. The MgL and MgH mice respond differently to a low-Mg(2+) diet with regard to TRPM6 expression in the kidney, consistent with genetic factors contributing to the regulation of cellular Mg(2+) levels. Further studies of these mice strains could improve our understanding of the genetics of Mg(2+) homeostasis.

Dietary inulin in mice stimulates Mg2+ absorption and modulates TRPM6 and TRPM7 expression in large intestine and kidney.

Complex fermentable carbohydrates, such as inulin-type fructans have been shown to improve Mg2+ absorption in the hindgut and body stores. The mechanisms for this are not well understood. The newly identified transient receptor potential melastatin 6 and 7 (TRPM6 and TRPM7) channels have been shown to function in active epithelial Mg2+ transport in the apical membrane of epithelial cells, the kidney and intestine and to be regulated by dietary intake. To determine the modulation of TRPM6 and TRPM7 expression in kidney and large intestine by long-chain inulin ingestion, C57B16J mice were fed a control or a long-chain inulin enriched diet (65 g of inulin/kg diet) for two weeks. Our results show that the inulin-enriched diet ameliorated Mg2+ absorption and Mg2+ bone stores. These features were accompanied by increased TRPM6 and TRPM7 expression in the hindgut. Downregulation of TRPM6 in the kidney of inulin fed mice could be related to reduced Mg2+ reabsorption and supports the beneficial effect of dietary fibers on Mg2+ absorption and stores. Inulin ingestion also modulates TRPM6 and TRPM7 expression in the large intestine. The origin and role of this modulation is not known. Changes in Mg2+ fluxes, lower pH of the digestive content and increased cell proliferation may be involved.