Effect of oxidative stress induced by intracranial iron overload on central pain after spinal cord injury

Abstract

BackgroundCentral pain (CP) is a common clinical problem in patients with spinal cord injury (SCI). Recent studies found the pathogenesis of CP was related to the remodeling of the brain. We investigate the roles of iron overload and subsequent oxidative stress in the remodeling of the brain after SCI.MethodsWe established a rat model of central pain after SCI. Rats were divided randomly into four groups: SCI, sham operation, SCI plus deferoxamine (DFX) intervention, and SCI plus nitric oxide synthase (NOS) inhibitor treatment. Pain behavior was observed and thermal pain threshold was measured regularly, and brain levels of iron, transferrin receptor 1 (TfR1), ferritin (Fn), and lactoferrin (Lf), were detected in the different groups 12 weeks after establishment of the model.ResultsRats demonstrated self-biting behavior after SCI. Furthermore, the latent period of thermal pain was reduced and iron levels in the hind limb sensory area, hippocampus, and thalamus increased after SCI. Iron-regulatory protein (IRP) 1 levels increased in the hind limb sensory area, while Fn levels decreased. TfR1 mRNA levels were also increased and oxidative stress was activated. Oxidative stress could be inhibited by ferric iron chelators and NOS inhibitors.ConclusionsSCI may cause intracranial iron overload through the NOS–iron-responsive element/IRP pathway, resulting in central pain mediated by the oxidative stress response. Iron chelators and oxidative stress inhibitors can effectively relieve SCI-associated central pain.

The microglial activation profile and associated factors after experimental spinal cord injury in rats

“…SCI may cause intracranial iron overload through the NOS–iron-responsive element/IRP pathway, resulting in central pain mediated by the oxidative stress response. 38 Other findings showed that high intracellular iron accumulation in macrophages had induced TNF expression. 17 Thus, iron accumulation after SCI may also contribute to the activation of microglial.…”

Lipoxin A4 protects primary spinal cord neurons from Erastin‐induced ferroptosis by activating the Akt/Nrf2/HO‐1 signaling pathway

“…Ferroptosis is different from apoptosis, necroptosis, autophagy and other reported cell death methods [4]. levels in the injured area, and iron overload further increases the accumulation of reactive oxygen species (ROS) [5]. In vivo study has demonstrated that ions play a very important role in the early stage of secondary SCI, and enhances production of hydroxyl radicals [6].…”

“…Although iron is necessary for normal nerve function, iron overload aggravates secondary damage after nerve injury. Local hemorrhage in the acute phase of SCI leads to a significant increase of iron levels in the injured area, and iron overload further increases the accumulation of reactive oxygen species (ROS) [ 5 ]. In vivo study has demonstrated that irons play a very important role in the early stage of secondary SCI and enhance production of hydroxyl radicals [ 6 ].…”

Dietary intake of GDF11 delays the onset of several biomarkers of aging in male mice through anti-oxidant system via Smad2/3 pathway

“…Another important point we have to point out is that although our study is limited to aged male mice, the anti-aging effects of GDF11 are expected similarly applicable for female mice. The “free radical damage theory” suggests that excess ROS can cause oxidative damage to the macromolecules of cells, including DNA, RNA, proteins, carbohydrates and lipids (Beckman and Ames 1998 ; Giordano et al 2013 ), thus it is applicable for all multicellular organisms at cellular level (Beckman and Ames 1998 ; Finkel and Holbrook 2000 ; Larsen 1993 ; Meng et al 2017 ). As mentioned above, rGDF11 exerts its rejuvenation and anti-aging activity through suppression of ROS production, which is thus believed to equally benefit to both male and female mice.…”