STZ treatment causes depletion of immune cells in sciatic nerve and dorsal root ganglion in mice

Introduction: Streptozotocin (STZ) treatment is an accepted pharmacological method for the induction of type 1 diabetes in rodent models. Recent publications have shown that STZ induces thermal hyperalgesia in mice, independently of hyperglycemia, and that STZ is neurotoxic in vitro. These findings bring into question the limitations of STZ-induced diabetes as a model for diabetic neuropathy. The aim of this study was to investigate effects of STZ treatment on nerve physiology in vivo.

Methods: Healthy, wild-type mice were treated with STZ (50 mg/kg) i.p. Mice were sacrificed at different timepoints and the changes in cell populations within the sciatic nerve (SN) and dorsal root ganglions (DRG) were investigated by FACS and immunofluorescence. Thermal hyperalgesia was measured by Hargreaves and Hotplate.

Results: Transient hyperalgesia was detected 4 days after initiation of treatment with STZ, before hyperglycemia had developed, but had subsided by three weeks of diabetes. The number of CD45+ leukocytes, CD11b+ monocytes and macrophages were decreased by STZ treatment, first in DRG and later in SN. The effects on immune cells were specific to peripheral nerve, since STZ treatment increased circulating CD11b+Ly6C+ monocytes and did not affect peritoneal macrophages. STZ-induced lymphopenia of peripheral nerve gradually normalized over the course of 12 weeks.

Conclusion: Our findings are consistent with an anti-inflammatory response to a toxic injury and apoptosis in peripheral nervous system induced by STZ. Diabetic neuropathy, observed during the first three months of STZ-induced diabetes, may therefore be due to direct toxic effects of STZ, independently of hyperglycemia.