# Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

Severe spinal cord injury (SCI) is a complex, debilitating condition leading to permanent life-long neurological
deficits. In addition to neurological dysfunction, individuals with SCI experience neurogenic muscle loss due to
immobility. Amelioration of neurological deficits and prevention of skeletal muscle loss are intricately related to
recovery of function following SCI. Molecular mechanisms causing neuronal impairment and skeletal muscle
loss resulting from SCI, remain incompletely understood. Our laboratory is among the first to demonstrate steroid
hormone estrogen (E2) driven neuroprotection in experimental SCI in rats, suggesting E2 warrants clinical
evaluation in individuals with neurotrauma. The beneficial effect in SCI was found at a low dose of 10μg/kg E2,
but the dose remains at a non-physiologic for human use, and thereby poses a safety concern for clinical use.
The emergence of smart drug delivery techniques, such as nanoparticles, may allow for increased drug safety
and improved efficacy. Thus, the goal of this proposal is to examine the effects of novel fast and slow release
E2-loaded nanoparticles (NP) on neuronal dysfunction and skeletal muscle loss in a rat contusion model of SCI.
Since muscle loss may occur as a result of damage to motoneurons in the spinal cord, focal delivery of E2 may
reverse denervation and promote nerve sprouting in partially denervated muscle fibers. Preliminary studies
suggest that a single administration of a combined fast-release (FNP-E2) and slow-release (SNP-E2) formulation
to the contused spinal cord attenuates inflammatory cytokines/chemokines, gliosis, glial scarring, and neurogenic
muscle loss. The focal delivery of E2 promotes microglial and astroglial differentiation to subpopulations of anti-
inflammatory microglia/astrocytes which inhibit inflammation, axonal damage, and neuronal loss. Preliminary
studies also suggest that NP-mediated delivery of E2 gel patch therapy reduces insult-induced muscle RING
finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) proteins in vitro in myoblast cells and in vivo following mild
to moderate SCI (40g/cm injury) in rats. However, whether NP-E2 gel patch therapy alters neuronal impairment
and skeletal muscle loss in severe SCI (60g/cm injury) remains unknown. Thus, using a novel combined FNP-
E2 and SNP-E2, may allow for suppression of acute inflammation by FNP-E2 and modulation of the inflammatory
response by SNP-E2 thereafter. We hypothesize that focal delivery of combined FNP-E2 and SNP-E2 will
minimize plasma E2 levels and increase local spinal cord concentrations - thereby reducing acute and subacute
inflammation to promote recovery from neurogenic muscle loss in severe SCI. To test the hypothesis, three
specific aims are proposed: (Aim 1) Determine the delivery of a combined FNP-E2 and SNP-E2 gel patch
therapy and evaluate its kinetics, bio-distribution, toxicity, and effects in severe SCI model in rats; (Aim 2)
Investigate the effects of a combined FNP-...

## Key facts

- **NIH application ID:** 10903735
- **Project number:** 5I01BX001262-10
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** NAREN L BANIK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903735

## Citation

> US National Institutes of Health, RePORTER application 10903735, Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI (5I01BX001262-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10903735. Licensed CC0.

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