Peripheral nerve pathology in sickle cell disease mice

INTRODUCTION: Many patients with sickle cell disease (SCD) suffer from chronic pain, which is often described as neuropathic in nature. Although vascular and inflammatory pathology undoubtedly contribute to the SCD pain experience, the nociceptive signals that ultimately drive symptoms are detected and transmitted by peripheral sensory neurons. To date, no systematic histological examination of peripheral nerves has been completed in patients or mouse models of SCD to diagnose disease-related neuropathy. OBJECTIVES: In this brief report, we compared peripheral nerve morphology in tissues obtained from Berkeley transgenic SCD mice and control animals. METHODS: Sciatic nerves were visualized using light and transmission electron microscopy. Myelin basic protein expression was assessed through Western blot. Blood–nerve barrier permeability was measured using Evan's blue plasma extravasation. RESULTS: Peripheral fibers from SCD mice have thinner myelin sheaths than control mice and widespread myelin instability as evidenced by myelin sheath infolding and unwrapping. Deficits are also observed in nonmyelinating Schwann cell structures; Remak bundles from SCD nerves contain fewer C fibers, some of which are not fully ensheathed by the corresponding Schwann cell. Increased blood–nerve barrier permeability and expression of myelin basic protein are noted in SCD tissue. CONCLUSIONS: These data are the first to characterize Berkeley SCD mice as a naturally occurring model of peripheral neuropathy. Widespread myelin instability is observed in nerves from SCD mice. This pathology may be explained by increased permeability of the blood–nerve barrier and, thus, increased access to circulating demyelinating agents at the level of primary sensory afferents.