Emerging role of copper in the pathophysiology of spinal cord injury

Copper is a trace element that plays an important role in neuronal development, maturation, and function. It also acts as a cofactor for various copper-binding proteins or serves as an active component of their structure. Acquired copper deficiency has been associated with numerous neurological diseases. Recent research has demonstrated that serum copper concentrations are elevated following spinal cord injury, similar to the elevated copper levels observed after ischemic insult in a rat model of myocardial infarction. This suggests that spinal cord damage may impair the effective utilization of copper due to local ischemia following spinal cord injury. Studies have shown that copper supplementation may form part of a therapeutic strategy for patients with spinal cord injury. It has been reported to promote T-cell differentiation and proliferation, reduce malondialdehyde levels, decrease myeloperoxidase activity and apoptotic cell numbers, and enhance superoxide dismutase activity and glutathione levels. Additionally, copper supplementation may stimulate the transcriptional activity of hypoxia-inducible factor and restore angiogenic capacity, thereby increasing capillary density. Furthermore, researchers have found that dihydrolipoamide dehydrogenase, an enzyme involved in inducing cuproptosis, can influence the immune microenvironment of spinal cord injury by promoting copper toxicity. This leads to increased peripheral M2 macrophage polarization and systemic immunosuppression. This led us to hypothesize that copper may influence three major pathological pathways after spinal cord injury, inflammation, oxidative stress, and cell death, which are critical targets for therapeutic intervention. On the one hand, copper deficiency can cause spinal cord tissue damage; on the other hand, elevated serum copper may induce copper toxicity, contributing to cell death. Therefore, in this review, we investigate the possible link between spinal cord injury and copper in the perspective of inflammation, oxidative stress, and cell death. Additionally, we review published studies on copper metabolism and explore potential therapeutic strategies by considering various sources and mechanisms of copper delivery.