Related Experiment Video
Updated: Mar 30, 2026
Assessing Neuroprotective Effects of Glycyrrhizae Radix et Rhizoma Extract Using a Transient Middle Cerebral Artery Occlusion Mouse Model
Published on: December 9, 2018
Activation of RXR/PPARγ underlies neuroprotection by bexarotene in ischemic stroke
Michelangelo Certo1, Yasuyuki Endo2, Kiminori Ohta2
1Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, CS, Italy.
Abstract:
The identification of novel drug targets for the treatment of ischemic stroke is currently an urgent challenge. Recent experimental findings have highlighted the neuroprotective potential of immunomodulatory strategies, based on polarization of myeloid cells toward non-inflammatory, beneficial phenotypes. Given the role of retinoid X receptors (RXR) in myeloid cells differentiation and polarization, here we have explored the neuroprotective potential of the RXR agonist bexarotene in mice subjected to focal cerebral ischemia. Acute administration of bexarotene significantly reduced blood brain barrier leakage, brain infarct damage and neurological deficit produced by transient middle cerebral artery occlusion in mice, without affecting cerebral blood flow. The rexinoid exerted neuroprotection with a wide time-window, being effective when administered up to 4.5h after the insult. The amelioration of histological outcome, as well as the ability of bexarotene to revert middle cerebral artery occlusion (MCAo)-induced spleen atrophy, was antagonised by BR1211, a pan-RXR antagonist, or by the selective peroxisome proliferator-activated receptor (PPAR)γ antagonist bisphenol A diglycidyl ether (BADGE), highlighting the involvement of the RXR/PPARγ heterodimer in the beneficial effects exerted by the drug. Immunofluorescence analysis revealed that bexarotene elevates Ym1-immunopositive N2 neutrophils both in the ipsilateral hemisphere and in the spleen of mice subjected to transient middle cerebral artery occlusion, pointing to a major role for peripheral neutrophil polarization in neuroprotection. Thus, our findings suggest that the RXR agonist bexarotene exerts peripheral immunomodulatory effects under ischemic conditions to be effectively repurposed for the acute therapy of ischemic stroke.
Insights
The retinoid X receptor (RXR) agonist bexarotene shows neuroprotective effects against ischemic stroke in mice. Bexarotene reduces brain damage and neurological deficits by modulating peripheral immune cells, suggesting its potential for stroke therapy.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Ischemic stroke treatment urgently requires novel drug targets.
- Immunomodulatory strategies, particularly myeloid cell polarization, show neuroprotective potential.
- Retinoid X receptors (RXRs) are key regulators of myeloid cell differentiation and polarization.
Purpose of the Study:
- To investigate the neuroprotective potential of the RXR agonist bexarotene in a mouse model of focal cerebral ischemia.
- To elucidate the mechanisms underlying bexarotene's effects, including its impact on the blood-brain barrier, infarct size, and neurological deficits.
Main Methods:
- Transient middle cerebral artery occlusion (MCAo) model in mice.
- Acute administration of bexarotene and assessment of neurological deficits, infarct volume, and blood-brain barrier integrity.
- Pharmacological antagonism of RXR and peroxisome proliferator-activated receptor gamma (PPARγ) to investigate signaling pathways.
- Immunofluorescence analysis to evaluate neutrophil polarization in the brain and spleen.
Main Results:
- Bexarotene significantly reduced blood-brain barrier leakage, brain infarct damage, and neurological deficits following MCAo.
- Neuroprotection was observed within a wide time-window (up to 4.5 hours post-insult) and did not affect cerebral blood flow.
- The beneficial effects of bexarotene were antagonized by RXR and PPARγ antagonists, indicating the involvement of the RXR/PPARγ heterodimer.
- Bexarotene increased Ym1-immunopositive N2 neutrophils in the brain and spleen, suggesting a role for peripheral neutrophil polarization.
Conclusions:
- The RXR agonist bexarotene demonstrates significant neuroprotective effects in a mouse model of ischemic stroke.
- Bexarotene's mechanism involves peripheral immunomodulation, specifically promoting beneficial neutrophil polarization via the RXR/PPARγ heterodimer.
- Bexarotene holds promise for repurposing as an acute therapy for ischemic stroke.
