RESUMO

BACKGROUND: Diabetic neuropathy is a common cause of painful diabetic neuropathy (PDN). C-X-C chemokine receptor type 4 (CXCR4) expression is increased in peripheral nerve samples from diabetes patients, suggesting a role for CXCR4 in PDN. Therefore, we evaluated the effects of Phα1ß, ω-conotoxin MVIIA, and AMD3100 in a model of streptozotocin (STZ)-induced PDN in rodents and naïve model of rats with the activation of the CXCR4/stromal cell-derived factor 1 (SDF-1) signal. METHODS: Diabetic neuropathy was induced by intraperitoneal (ip) injection of STZ in Wistar rats. Naïve rats were intrathecally injected with SDF-1 to test the CXCR4/SDF-1 signal. The effects of Phα1ß intrathecal (it), ω-conotoxin MVIIA intrathecal (it), and AMD3100 intraperitoneal (ip) on rat hypersensitivity, IL-6, and the intracellular calcium [Ca2+]i content of diabetic synaptosomes were studied. RESULTS: The drugs reduced the hypersensitivity in diabetic rats. SDF-1 (1.0 µg/it) administration in naïve rats induced hypersensitivity. Phα1ß (100 pmol/it) or AMD3100 (2.5 µg/ip) reduced this hypersensitivity after 2 h treatments, while ω-conotoxin MVIIA did not have an effect. IL-6 and [Ca2+]i content increased in the spinal cord synaptosomes in diabetic rats. The drug treatments reduced IL-6 and the calcium influx in diabetic synaptosomes. CONCLUSIONS: Phα1ß, ω-conotoxin MVIIA, and AMD3100, after 2 h of treatment of STZ-induced PDN, reduced hypersensitivity in diabetic rats. In naïve rats with CXCR4/SDF-1 activation, the induced hypersensitivity decreased after 2 h treatments with Phα1ß or AMD-3100, while ω-conotoxin MVIIA did not affect. The inhibitory effects of Phα1ß on PDN may involve voltage-dependent calcium channels.

Assuntos

RESUMO

Background Diabetic neuropathy is a common cause of painful diabetic neuropathy (PDN). C-X-C chemokine receptor type 4 (CXCR4) expression is increased in peripheral nerve samples from diabetes patients, suggesting a role for CXCR4 in PDN. Therefore, we evaluated the effects of Pha1ß, Ômega-conotoxin MVIIA, and AMD3100 in a model of streptozotocin (STZ)-induced PDN in rodents and naïve model of rats with the activation of the CXCR4/stromal cell-derived factor 1 (SDF-1) signal. Methods Diabetic neuropathy was induced by intraperitoneal (ip) injection of STZ in Wistar rats. Naïve rats were intrathecally injected with SDF-1 to test the CXCR4/SDF-1 signal. The effects of Pha1ß intrathecal (it), Ômega-conotoxin MVIIA intrathecal (it), and AMD3100 intraperitoneal (ip) on rat hypersensitivity, IL-6, and the intracellular calcium [Ca2+]i content of diabetic synaptosomes were studied. Results The drugs reduced the hypersensitivity in diabetic rats. SDF-1 (1.0 µg/it) administration in naïve rats induced hypersensitivity. Pha1ß (100 pmol/it) or AMD3100 (2.5 µg/ip) reduced this hypersensitivity after 2 h treatments, while Ômega-conotoxin MVIIA did not have an effect. IL-6 and [Ca2+]i content increased in the spinal cord synaptosomes in diabetic rats. The drug treatments reduced IL-6 and the calcium influx in diabetic synaptosomes. Conclusions Pha1ß, Ômega-conotoxin MVIIA, and AMD3100, after 2 h of treatment of STZ-induced PDN, reduced hypersensitivity in diabetic rats. In naïve rats with CXCR4/SDF-1 activation, the induced hypersensitivity decreased after 2 h treatments with Pha1ß or AMD-3100, while Ômega-conotoxin MVIIA did not affect. The inhibitory effects of Pha1ß on PDN may involve voltage-dependent calcium channels.

RESUMO

Administration of streptozotocin (STZ) is one of the most used experimental models of diabetes (STZ-DT). STZ induces beta-cell damage in pancreatic islets. It is known that hematopoietic stem progenitor cells (HSPCs) are mobilized from bone marrow to damaged tissues. In this work, we evaluated the effects of the hematopoietic mobilizers G-CSF (250µg/kg; for five consecutive days) and AMD3100 (5mg/kg; single s.c injection) in mice treated with STZ (175mg/kg). Mice injected with STZ showed a significant reduction in the number and area of islets and in the number of beta- and alpha-cells. Concurrently, they had hyperglycemia (blood glucose over 300mg/dl) associated with very low levels of insulin in plasma. The number and area of islets from STZ-DT mice treated with G-CSF and/or AMD3100 were similar to the controls. However, these mice had neither a reduction of hyperglycemia nor an improvement in the insulin levels. Analysis of islet cellularity showed a large reduction in beta-cells with a significant expansion of alpha-cells. These results indicate that G-CSF and AMD3100 induce partial protection of islet tissues and expansion of alpha-cells in mice treated with STZ but do not protect beta-cells from the damage induced by this compound.

Assuntos

RESUMO

The stromal cell derived factor 1 (SDF-1/CXCL12) plays an essential role in the homing of hematopoietic stem and progenitor cells (HSPCs) to bone marrow (BM). It is not known whether SDF-1 may also regulate the homing of HSPCs to the liver during extramedullary hematopoiesis (EMH). Here, we investigated the possible role of SDF-1 in attracting HSPCs to the liver during experimental EMH induced by the hematopoietic mobilizers G-CSF, AMD3100 and phenylhydrazine (PHZ). Mice treated with G-CSF, AMD3100 and PHZ showed a significant increase in the expression of SDF-1 in the liver sinusoidal endothelial cells (LSECs) microenvironments. Liver from mice treated with the hematopoietic mobilizers showed HSPCs located adjacent to the LSEC microenvironments, expressing high levels of SDF-1. An inverse relationship was found between the hepatic SDF-1 levels and those in the BM. In vitro, LSEC monolayers induced the migration of HSPCs, and this effect was significantly reduced by AMD3100. In conclusion, our results provide the first evidence showing that SDF-1 expressed by LSEC can be a major player in the recruitment of HSPCs to the liver during EMH induced by hematopoietic mobilizers.

Assuntos