Endocrine Therapy for the Functional Recovery of Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is a major cause of physical disability and leads to patient dissatisfaction with their quality of life. Patients with SCI usually exhibit severe clinical symptoms, including sensory and motor dysfunction below the injured levels, paraplegia, quadriplegia and urinary retention, which can exacerbate the substantial medical and social burdens. The major pathological change observed in SCI is inflammatory reaction, which induces demyelination, axonal degeneration, and the apoptosis and necrosis of neurons. Traditional medical treatments are mainly focused on the recovery of motor function and prevention of complications. To date, numerous studies have been conducted to explore the cellular and molecular mechanism of SCI and have proposed lots of effective treatments, but the clinical applications are still limited due to the complex pathogenesis and poor prognosis after SCI. Endocrine hormones are kinds of molecules that are synthesized by specialized endocrine organs and can participate in the regulation of multiple physiological activities, and their protective effects on several disorders have been widely discussed. In addition, many studies have identified that endocrine hormones can promote nerve regeneration and functional recovery in individuals with central nervous system diseases. Therefore, studies investigating the clinical applications of endocrine hormones as treatments for SCI are necessary. In this review, we described the neuroprotective roles of several endocrine hormones in SCI; endocrine hormone administration reduces cell death and promotes functional repair after SCI. We also proposed novel therapies for SCI.

Keywords: basic fibroblast growth factor; endocrine hormone; erythropoietin; estrogen; spinal cord injury; testosterone; thyroid hormones.

FIGURE 1

Pathological process of SCI. Primary SCI is caused by a directed compression or contusion of the spinal cord, leading to acute ischaemia and oedema of the damaged tissue. Primary SCI is difficult to heal, and the pathological damage after the injury may persist for a long time, which eventually progresses into secondary SCI. Secondary SCI is caused by chronic inflammation and cytotoxic factors. In the chronic phase, inflammatory damage and cytotoxic effects induce extensive pathological damage in contused tissues, including axon degeneration, necrosis, microglial proliferation and the formation of a glial scar, which further exacerbates neuronal dysfunction and leads to adverse clinical outcomes.

FIGURE 2

The neuroprotective signaling pathways of estrogen and estrogen receptors. Estrogen exerts its neuroprotective effects mainly by binding to estrogen receptors ERα/β. Estrogen and ER ligands can enhance the expression of anti-apoptotic genes and brain-derived neurotrophic factors and suppressed the expression of pro-apoptotic genes and pro-inflammatory molecules. Estrogen can inhibit the expression of inflammatory factors TNF-α, IL-1β, IL-6, iNOS, PGE2, and COX-2 by reducing the levels of p-p38 MAPK, p-ERK and p-JNK, to ameliorate central and peripheral neuropathic pain. In addition, estrogen can also maintain membrane integrity and inhibit apoptosis by preventing cytochrome c and calpain influx into the injured area.

FIGURE 3

EPO-related neuroprotective effects in SCI. The secondary SCI induces abnormal microenvironment and deteriorates hypoxic and inflammatory condition in damaged tissues. Fortunately, neural precursor cells and astrocytes can spontaneously synthesize EPO under hypoxic conditions to alleviate neural insult and demyelination. In addition, EPO induces the recruitment of BMSCs to the injured spinal cord, leading to the increased expression of VEGF and BDNF, which can promote neurogenesis and vasculogenesis.