The roles of streptozotocin neurotoxicity and neutral endopeptidase in murine experimental diabetic neuropathy

Abstract

We demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuroactive peptides, improves vascular and neural function in diabetic animal models. In this study we explored the role of NEP in neuropathy related to either insulin-deficient diabetes or diet-induced obesity using NEP deficient (-/-) mice. Initial studies showed that streptozotocin, in the absence of subsequent hyperglycemia, did not induce nerve conduction slowing or paw thermal hypoalgesia. Glucose disposal was impaired in both C57Bl/6 and NEP -/- mice fed a high fat diet. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and high fat fed C57Bl/6 mice but not in NEP -/- mice exposed to either streptozotocin-induced diabetes or a high fat diet. These studies suggest that streptozotocin does not induce neurotoxicity in mice and that NEP plays a role in regulating nerve function in insulin-deficient diabetes and diet-induced obesity.

Figure 1

Glucose utilization curve for C57Bl/6 (a) and neutral endopeptidase (NEP −/−) deficient mice (b) fed a normal or high fat containing diet for 12 weeks. Data are the mean ± standard error of the mean. The numbers of animals for each group are indicated in parenthesis. *P < .05 versus control.

Figure 2

Motor and sensory nerve conduction velocity for C57Bl/6 (a) and neutral endopeptidase (NEP −/−) deficient mice (b). Study groups included mice fed a normal diet for 12 weeks (control), streptozotocin-induced diabetes duration 12 weeks, or fed a high fat containing diet for 12 weeks. Data are the mean ± standard error of the mean. The numbers of animals for each group are indicated in parenthesis. *P < .05 versus control, ⁺ P < .05 versus C57Bl/6 mice.

Figure 3

Thermal response latency in the hindpaw for C57Bl/6 and neutral endopeptidase (NEP −/−) deficient mice. Study groups included mice fed a normal diet for 12 weeks (control), streptozotocin-induced diabetes duration 12 weeks, or fed a high fat containing diet for 12 weeks. Data are the mean ± standard error of the mean. The numbers of animals for each group are the same as described in Table 1. *P < .05 versus control C57Bl/6, ⁺ P < .05 C57Bl/6 mice versus NEP −/− mice, respectively.