# Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Ischemic stroke is a leading cause of death and long-term disability in elderly veterans. It is well established that
post-stroke immune responses have a substantial impact on the progression of ischemic brain injury and brain
recovery, but there are no clinical treatments that successfully harness the restorative power of the immune
system while also tempering inflammation-induced secondary injuries. The reasons for this gap are multifactorial,
but include a preclinical overemphasis on young adult animals, which simply do not display the same
pathophysiological mechanisms underlying brain ischemia as the aged, including the dynamic inflammatory
dialogue between glia and neurons. We propose to fill the critical gap in elderly veteran care by focusing on aged
animals and repurposing an FDA-approved drug at low doses to correct hyperactive immune responses and tip
the balance in favor of sustained tissue healing and long-term recovery of neurological functions.
 To commence this goal, we have conducted pilot studies on proteins that are highly enriched in microglia
and brain-infiltrating macrophages (Mi/MΦ)—including the retinoid X receptor (RXR). RXR binds to peroxisome
proliferator-activated receptor γ (PPARγ) to govern the transcription of genes critically involved in redox status,
inflammation resolution, trophic factor production, and metabolism. Thus, RXR/PPARγ activation lies at the apex
of a decision tree for arbitrating between polymorphic, often-opposing immune responses in Mi and MΦ. To
engage this important biological target, we have chosen a selective RXR agonist, bexarotene, an FDA-approved
antineoplastic agent lacking in pan-immunosuppressive effects and with excellent safety profiles. The scientific
premise underlying the engagement of the RXR/PPARγ axis as a superior biological target for stroke is its ability
to titrate immune balance toward anti-inflammatory/pro-repair phenotypes, while avoiding indiscriminate
suppression of immune function in the vulnerable elderly.
 The premise of this proposal is also strengthened by our new preliminary discoveries: 1) Mi/MΦ-specific
conditional knockout (mKO) of RXR or PPARγ worsens long-term outcomes after permanent distal middle
cerebral artery occlusion (dMCAO) in mice. 2) RXR or PPARγ mKO mice exhibit impairments in post-stroke
efferocytosis (Mi/MΦ phagocytosis of dying neurons) and resolution of neuroinflammation. 3) PPARγ mKO alters
the Mi/MΦ transcriptome, with heightened proinflammatory responses and impaired phagocytosis according to
RNA sequencing data. 4) Excitingly, intraperitoneal administration of low-dose bexarotene (10-20 times lower
than in clinical trials) improves long-term outcomes after dMCAO in aged mice (20 months old). Accordingly, our
research group is now in an excellent position to test the following core hypothesis: Activation of RXR improves
long-term outcomes after ischemic stroke by promoting efferocytosis and inflammation-resolving, pro-
repair microglial/macro...

## Key facts

- **NIH application ID:** 10768652
- **Project number:** 5I01BX005290-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Jun Chen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768652

## Citation

> US National Institutes of Health, RePORTER application 10768652, Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice (5I01BX005290-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10768652. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*