Iatrogenic Iron Promotes Neurodegeneration and Activates Self-Protection of Neural Cells against Exogenous Iron Attacks.

Maosheng Xia,Manman Zhang,Shanshan Liang,Shuai Li,Xinyu Li,Wenliang Gong,Dawei Guan,Beina Chen,Yuefei Zhou,Alexei Verkhratsky,Xiaoni Zhan,Ming Ji,Gehua Wen,Baoman Li,Dianjun Zhang,Chengyi Dong,Binjie Chen

doi:10.1093/function/zqab003

Abstract

Metal implants are used worldwide, with millions of nails, plates, and fixtures grafted during orthopedic surgeries. Iron is the most common element of these metal implants. As time passes, implants can be corroded and iron can be released. Ionized iron permeates the surrounding tissues and enters circulation; importantly, iron ions pass through the blood–brain barrier. Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that patients with metal implants delivered through orthopedic surgeries have higher incidence of Parkinson’s disease or ischemic stroke compared to patients who underwent similar surgeries but did not have implants. Concentration of serum iron and ferritin was increased in subjects with metal implants. In experiments in vivo, we found that injection of iron dextran selectively decreased the presence of divalent metal transporter 1 (DMT1) in neurons through increasing the expression of Ndfip1, which degrades DMT1 and does not exist in glial cells. At the same time, excess of iron increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microgliosis. Facing the attack of excess iron, glial cells act as neuroprotectors to accumulate more extracellular iron by upregulating DMT1, whereas neurons limit iron uptake through increasing DMT1 degradation. Cerebral accumulation of iron in animals is associated with impaired cognition, locomotion, and mood. Excess iron from surgical implants thus can affect neural cells and may be regarded as a risk factor for neurodegeneration.

Highlights

Every year, millions of metal implants such as metal nails, metal plates, and other fixtures are used for orthopedic intervention
Iron is a necessary element in the human body, the iron deficiency is harmful for development and health, but the excessive iron can trigger pathology
According to our study, the insertion of iron-based metal implants in the orthopedic surgery may, in long-term, affect the nervous system and, as we found, may increase the risk of Parkinson’s disease (PD) and ischemic stroke

Summary

Introduction

Millions of metal implants such as metal nails, metal plates, and other fixtures are used for orthopedic intervention. Metal implants are mainly composed of pure iron or ironbased alloys, the latter being more widely adopted in clinical practice. The common metal alloys contain Mn, Ti, Mg, Al, Co, Si, etc., yet iron remains the primary element.[1] Iron-based implants in the body can be corroded and iron in the form of ferric or ferrous (Fe3þ or Fe2þ) may permeate in the surrounding tissues and enter circulation; of note Fe3þ and Fe2þ can be mutually converted by ferroxidase or ferrireductase.[2,3,4] Corrosion of metallic components in the tissues may trigger inflammation and accumulation of iron in macrophages in months or years following the implantation.[3,4] Manipulations with iron content in rodents through the diet, intraperitoneal (i.p.) injection, or subcutaneous infusion results in iron deposition in different tissues and in plasma.[5]

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