Oligodeoxynucleotide IMT504 induces a marked recovery in a streptozotocin-induced model of diabetes in rats: correlation with an early increase in the expression of nestin and neurogenin 3 progenitor cell markers

Abstract

Aims/hypothesis IMT504 is an oligonucleotide that promotes tissue repair in bone injury and neuropathic pain models by stimulating progenitor cells. Here we evaluated the effect of IMT504 on the recovery of islet function in a streptozotocin (STZ)-induced model of diabetes in the rat. Methods Male Sprague-Dawley rats were injected with STZ (60 mg/kg, i.p., day1) or citrate buffer (Control). Animals with glycaemia between 11 and 20 mmol/l on day 4 were injected with IMT504 (4 mg/animal in saline, s.c., STZ-IMT504) or with saline (STZ-Saline) for 10 days. Glycaemia and water and food intake were recorded for 33 days. Intraperitoneal glucose tolerance tests (IPGTTs) were performed on day30. On day35, overnight-fasted animals were killed and blood samples and pancreases collected for hormonal and histological studies. A second group of STZ-IMT504 rats was killed, together with Control and STZ-Saline rats, after two consecutive days of blood glucose decreases after the beginning of IMT504 treatment. Pancreases were collected and proliferating cell nuclear antigen (PCNA), nestin and neurogenin 3 (NGN3) detected by immunohistochemistry. Results IMT504 greatly improved blood glucose and food and water intakes in STZ-IMT504 rats by day8, as well as IPGTTs on day30. Significant increases in islet number and beta cell content were observed in STZ-IMT504 rats (day 33). Furthermore, after two to five IMT504 injections, blood glucose decreased, and an increase in pancreatic nestin (mainly in endothelial cells), PCNA and NGN3 production (in islets) was observed in STZ-IMT504 rats. Conclusions/interpretation IMT504 induced a marked recovery of STZ-induced diabetes that correlated with early production of progenitor cell markers, such as nestin and NGN3.

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

“…IMT504 also promoted marked improvement in rat models of bone injury (22), neuropathic pain (7), and sepsis (5). Regarding diabetes, streptozotocin-induced toxic diabetes in rats was reversed by IMT504, improving glycemia, increasing islet number, ␤-cell content, ␤-cell proliferation, and early expression of pancreatic progenitor markers (3). Although IMT504 is active in rat and human cells, we have not yet demonstrated its effects in mice.…”

Postnatal development of the endocrine pancreas in mice lacking functional GABABreceptors

“…5F), whereas Nes expression could not be determined. This may be due to the fact that nestin is expressed only during early development (74) or after islet damage (4,36,74). In addition, in adults, nestin-positive cells are found mainly in ductal and acinar cells (59,69,75), which would be scarce in our islet-rich samples.…”

Non-Clinical Safety Studies of IMT504, a Unique Non-CpG Oligonucleotide

“…These effects include in vitro activation, proliferation, and expression of costimulatory molecules on B cells (Elías et al, 2003;Rodriguez et al, 2006a); immune modulatory effect on mice, rats, and primates when combined with a variety of antigens Montaner et al, 2011Montaner et al, , 2012Gan et al, 2009) Statistically significant differences as compared with control (0 mg/kg/day). *p < 0.05; **p < 0.02. improvement of tissue damage or disease in animal models (Rodriguez et al, 2006b;Hernando-Insúa et al, 2007;Coronel et al, 2008;Bianchi et al, 2010). All of these studies contributed to the dose selection for the present non-clinical studies.…”

“…Also, IMT504, but not CpG ODNs, increases the number of adult mesenchymal stromal cells with multipotent differentiation capacity in vitro and in vivo (Hernando-Insúa et al, 2007). We have also found that treatment with IMT504 causes significant improvements in animal models of bone injury (Hernando-Insúa et al, 2007), neuropathic pain (Coronel et al, 2008), and type 1 diabetes (Bianchi et al, 2010). Furthermore, in human B cells from patients with chronic lymphocytic leukemia, IMT504 induces an immunogenic phenotype (up-regulation of CD25, CD40, CD80, and CD86 surface molecules) and stimulates apoptosis in vitro (Rodriguez et al, 2006b).…”

“…Taking into consideration the pharmacological effect described in tissue regeneration models (Hernando-Insúa et al, 2007;Coronel et al, 2008;Bianchi et al, 2010), the femoral bone, peripheral sciatic nerve, and pancreas of rats from the repeated-dose IV toxicity assay (0.35 and 3.5 mg/kg/day) were studied. Organ weight and gross pathology from samples taken at weeks 6 and 12were examined.…”