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

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2021 · —

## Abstract

Estrogen (E2) treatment is known to be neuroprotectant in spinal cord injury (SCI). This hormone is highly
pleiotropic and has been shown to decrease apoptosis, modulate calcium signaling, regulate growth factor
expression, act as an anti-inflammatory, and can drive angiogenesis. These beneficial effects were found at
the low dose of 10μg/kg E2 (multiple i.v. injections; previous grant), which helped in obtaining IND approval for
taking this into a small clinical safety trial. However, the dose remains non-physiologic and thereby poses a
safety hurdle 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 study is to investigate the effects
of nanoparticle delivery of lower doses of E2 (2.5-5.0µg, single dose) that may avoid the high systemic
exposures seen with traditional dose routes (i.v. or i.p.) and allow for enhanced protective and reparative
effects on lesioned tissue. Preliminary data show that a single administration of rapid release formulated
PLGA-PEG nanoparticles loaded with E2 can focally deliver E2 to the contused spinal cord with reduced
plasma concentrations when compared with i.v. dosing and can drive estrogenic changes. Additionally, this
approach has shown that a single 5.0µg dose of nanoparticle E2 (N-E2) can improve locomotor function
recovery. Pilot data suggest that E2 supports the survival of oligodendrocyte precursor cells (OPC) when
exposed to toxic factors from Th1 cells and microglia in vitro. Thus, using a cocktail of rapid and slow release
nanoparticle formulations, an entirely novel approach, enhanced efficacy may be achieved after SCI. This
approach may allow for rapid translation of this known neuroprotectant into clinical trials. We hypothesize
that focal delivery of estrogen via nanoparticles will minimize plasma exposure and increase tissue
concentrations thereby allowing for maximized therapeutic potential in SCI. To test the hypothesis, three
specific aims are proposed: (1) Examine N-E2 release profile and estrogenic effects on inflammation, gliosis,
and neuronal protection in acute SCI; (2) Determine the mechanisms of E2-driven protective effects on
epithelial, glial and neuronal cells following slow release N-E2 in acute and chronic SCI; and (3) Investigate the
potential additive effects of rapid and slow release N-E2 on reduced glial scarring, enhanced regeneration, and
improved locomotor function in chronic SCI. Completion of this study will identify the optimal dosing strategy of
E2 loaded nanoparticles for delivery of this therapeutic agent in SCI. Additionally, as novel targets of E2
signaling are explored, progress in understanding the mechanisms of estrogenic driven neuroprotection will be
made. These data should provide sufficient evidence to support the translation of E2 into clinical trials, with the
ultimate goal of providing a safe and effective therapeutic to treat both veterans...

## Key facts

- **NIH application ID:** 10045555
- **Project number:** 5I01BX001262-07
- **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:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045555

## Citation

> US National Institutes of Health, RePORTER application 10045555, Hormonal Intervention Protects Axon-myelin to Promote Functional Recovery in SCI (5I01BX001262-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10045555. Licensed CC0.

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