Abstract
An increased risk of skin pressure ulcers (PUs) is common in patients with sensory neuropathies, including those caused by diabetes mellitus. Recombinant human erythropoietin (rhEPO) has been shown to protect the skin against PUs developed in animal models of long-term diabetes. The aim of this work was to determine whether rhEPO could prevent PU formation in a mouse model of drug-inducedSFN. Functional SFN was induced by systemic injection of resiniferatoxin (RTX, 50 µg/kg, i.p.). RhEPO (3000 UI/kg, i.p.) was given the day before RTX injection and then every other day. Seven days after RTX administration, PUs were induced by applying two magnetic plates on the dorsal skin. RTX-treated mice expressed thermal and mechanical hypoalgesia and showed calcitonin gene-related peptide (CGRP) and substance P (SP) depletion without nerve degeneration or vascular dysfunction. RTX mice developed significantly larger stage 2 PUs than Vehicle mice. RhEPO prevented thermal and mechanical hypoalgesia and neuropeptide depletion in small nerve fibers. RhEPO increased hematocrit and altered endothelium-dependent vasodilatation without any effect on PU formation in Vehicle mice. The characteristics of PUs in RTX mice treated with rhEPO and Vehicle mice were found similar. In conclusion, RTX appeared to increased PU development through depletion of CGRP and SP in small nerve fibers, whereas systemic rhEPO treatment had beneficial effect on peptidergic nerve fibers and restored skin protective capacities against ischemic pressure. Our findings support the evaluation of rhEPO and/or its non-hematopoietic analogs in preventing to prevent PUs in patients with SFN.
Highlights
Prolonged pressure and the resulting local ischemia are widely accepted as the primary etiologies of skin pressure ulcers (PUs) [1,2], but the precise mechanisms of their formation remain unclear
In order to further study the link between sensory nerve dysfunction and PUs, we developed a purely functional and reversible mouse model of small fiber neuropathy (SFN) induced by resiniferatoxin (RTX) [5]
The main findings of this report are that (1) Systemic recombinant human erythropoietin (rhEPO) treatment prevent RTX-induced neuropathy by its neuroprotective properties (2) A functional SFN induced by RTX with a calcitonin gene-related peptide (CGRP) and substance P (SP) depletion, promotes skin PU development, after a long ischemic pressure application (3) PU formation is increased independently by CGRP antagonist (CGRP8-37) and SP antagonist (SR140333) (4) Neuroprotective effect of rhEPO restores skin capacity to protect against ischemic pressure in RTX-induced neuropathy model
Summary
Prolonged pressure and the resulting local ischemia are widely accepted as the primary etiologies of skin pressure ulcers (PUs) [1,2], but the precise mechanisms of their formation remain unclear. In order to further study the link between sensory nerve dysfunction and PUs, we developed a purely functional and reversible mouse model of small fiber neuropathy (SFN) induced by resiniferatoxin (RTX) [5]. Peptidergic nerve fibers have been reported to have ischemic-protective properties [10,15], but have not been assessed for PU development, which combines pressure/loading and local ischemia. Stimulation of these nerve fibers mediates antidromic transport and CGRP/SP release by peripheral nerve endings; in addition, CGRP and SP are key players in skin homeostasis and have protective effects on ischemic injury in various tissues [16,17,18]. We hypothesized that CGRP and SP, released by epidermal nerve endings could be involved in cutaneous protection against PU formation
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