Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue

Abstract

Persons with spinal cord injury (SCI) are in need of effective therapeutics. Estrogen (E2), as a steroid hormone, is a highly pleiotropic agent; with anti-inflammatory, anti-apoptotic, and neurotrophic properties, it is ideal for use in treatment of patients with SCI. Safety concerns around the use of high doses of E2 have limited clinical application, however. To address these concerns, low doses of E2 (25 μg and 2.5 μg) were focally delivered to the injured spinal cord using nanoparticles. A per-acute model (6 h after injury) was used to assess nanoparticle release of E2 into damaged spinal cord tissue; in addition, E2 was evaluated as a rapid anti-inflammatory. To assess inflammation, 27-plex cytokine/chemokine arrays were conducted in plasma, cerebrospinal fluid (CSF), and spinal cord tissue. A particular focus was placed on IL-6, GRO-KC, and MCP-1 as these have been identified from CSF in human studies as potential biomarkers in SCI. S100β, an additional proposed biomarker, was also assessed in spinal cord tissue only. Tissue concentrations of E2 were double those found in the plasma, indicating focal release. E2 showed rapid anti-inflammatory effects, significantly reducing interleukin (IL)-6, GRO-KC, MCP-1, and S100β in one or all compartments. Numerous additional targets of rapid E2 modulation were identified including: leptin, MIP-1α, IL-4, IL-2, IL-10, IFNγ, tumor necrosis factor-α, etc. These data further elucidate the rapid anti-inflammatory effects E2 exerts in an acute rat SCI model, have identified additional targets of estrogen efficacy, and suggest nanoparticle delivered estrogen may provide a safe and efficacious treatment option in persons with acute SCI.

Spontaneous Recovery of Reflex Voiding Following Spinal Cord Injury Mediated by Anti-inflammatory and Neuroprotective Factors

“…A recent study was unable to quantitate the levels of CXCL2 ( MIP2), CXCL-5 ( LIX), TNF-α, CCL5( RANTES), G-CSF and GM-CSF at 6h time point after SCI in spinal cord tissue and plasma 30 . On the contrary, the quantitative measurement of the bladder tissue levels of CXCL2 ( MIP2), CXCL-5 ( LIX), TNF-α, CCL5( RANTES), G-CSF and GM-CSF in bladder tissue at the time point of 4, 8 and 12 weeks after SCI indicates a role temporal differences in paracrine signaling from spinal cord to bladder.…”

Electrospun Fibers for Drug Delivery after Spinal Cord Injury and the Effects of Drug Incorporation on Fiber Properties

“…[Taylor et al, 2004]. Results from Cox et al provide additional validation that drug inclusion within hydrogels is necessary for the hydrogel approach to robustly change the injury environment [Cox et al, 2015]. Like the study presented by Donaghue and colleagues [Elliott Donaghue et al, 2015a], Cox and colleagues also used polymer spheres to extend the release of drug from a polysaccharide hydrogel.…”

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

“…Recent studies also evaluated the potential beneficial effects of estrogen, which could be a neuroprotective agent in the treatment of SCI and TBI (40–43). Using a novel strategy of nanoparticle delivery of estrogen showed promising results with induction of anti-Inflammatory effects after SCI in rats (44). In spite of these studies, there is currently no FDA approved pharmacotherapeutic available for the effective treatment of acute SCI.…”