Geranylgeranyl Transferase Inhibitors Mitigate Intestinal Radiation Toxicity.

Area of Science:

• Radiation biology
• Gastroenterology
• Pharmacology

Background:

• Growing risk of large-volume radiation exposure necessitates medical countermeasures.
• Intestinal damage from partial-body irradiation (PBI) lacks effective post-exposure treatments.
• Radiation mitigators administered after exposure are currently unavailable.

Purpose of the Study:

• To investigate the efficacy of geranylgeranyl transferase inhibitors (GGTis) in mitigating intestinal radiation injury.
• To assess GGTi's potential as a medical countermeasure against PBI-induced damage.
• To evaluate GGTi's effects on various intestinal cell types and markers post-irradiation.

Main Methods:

• Mice exposed to 12 or 13 Gy gamma-rays with hind limbs shielded underwent partial-body irradiation (PBI).
• Geranylgeranyl transferase inhibitor (GGTi) or vehicle administered intraperitoneally starting 24 hours post-PBI.
• Intestinal tissues analyzed for structural damage, cell counts, marker expression, and organoid function.

Main Results:

• GGTi treatment increased surviving crypts and mitigated intestinal structural damage in both sexes.
• GGTi reduced PBI-induced alterations in mucus secretion, stem cell markers, immune cell infiltration, and endothelial cell markers.
• Ex vivo studies showed GGTi preserves beneficial molecules in endothelial cells and upregulates key molecules for intestinal homeostasis and stem cell maintenance.

Conclusions:

• Geranylgeranyl transferase inhibitors (GGTis) are potent mitigating agents against intestinal radiation toxicity.
• GGTi demonstrates efficacy by targeting multiple cell types within the intestine.
• This research highlights GGTi as a promising therapeutic strategy for radiation injury.