In vivo evaluation of a rat model for diabetic neuropathies

Abstract

Diabetic peripheral neuropathy is considered to be a long-term complication of Diabetes Mellitus. This neuropathy is the most common form of peripheral neuropathy in the Western world and develops in about 50% of diabetes patients affected with either type I or type II diabetes. Despite advances in understanding metabolic causes of diabetic peripheral neuropathy, specific treatments against this complications are far from being used in therapy options. In this study we have evaluated the diabetic peripheral neuropathy in the streptozotocin (STZ)-induced diabetic animal model. For years, this model has been used in an attempt to provide information of the underlying processes and to evaluate potential therapies. Therefore, as a primary objective of the present study, a quantification over time of the neuropathic behavior (sixteen weeks post STZ-injection) of diabetic rats was compared to normoglycemic controls. The neuropathy was assessed by quantifying mechanical hyperalgesia and allodynia and by evaluating the rat’s global clinical condition. Simultaneously, skin biopsies and dorsal root ganglions (DRGs) were taken at different time points after STZ-injection in order to create an idea of the histological alterations of nerves during diabetic peripheral neuropathy. This diabetes-associated neuropathic behavior and the comparison with the histological alterations of nerves during neuropathy can be important for the development of a disease modifying treatment for diabetic peripheral neuropathy. Therefore the second objective of this study was to evaluate the diabetic peripheral neuropathy after treatment with neurotrophic factors. After subplantar injection of GDNF and NGF in one hind paw of diabetic animals, the neuropathy was again evaluated by quantifying mechanical hyperalgesia and allodynia. While GDNF improved the hyperalgesic effect in rats resulting from diabetes, NGF increased the nociceptive responses. After evaluating skin biopsies of these rats, no difference in epidermal thickness was shown, but an increased inflammatory response resulted after growth factor injection compared to rats injected with vehicle. This study indicates that GDNF has an advantage effect on the neuropathic behavior observed in the in vivo model of diabetic peripheral neuropathy, while NGF increased the hyperalgesia and allodynia following injection. Therefore we can conclude that GDNF can be considered as a possible candidate for the treatment of diabetic peripheral neuropathy. Further research is necessary for improving the treatment options and to investigate whether GDNF could also be effective in the treatment of neuropathy in humans.