All-Trans Retinoic Acid Restores Hippocampal and Intestinal Function Following Intestinal Ischemia-Reperfusion Injury in Young Female Wistar Rats

Abstract

Background: The occurrence of intestinal ischemia-reperfusion injury (IIRI) can disrupt the gut–brain axis and potentially accelerate cognitive decline in females. This study investigated the protective role of all-trans retinoic acid (ATRA) against IIRI-induced intestinal and hippocampal dysfunction in young female Wistar rats.

Methods: Forty-two young female Wistar rats were divided into six groups (n = 7): Sham, IIRI, LDATRA + IIRI (pre-treatment; 10 mg/kg), HDATRA + IIRI (pre-treatment; 15 mg/kg), IIRI + LDATRA (post-treatment; 10 mg/kg), and IIRI + HDATRA (post-treatment; 15 mg/kg). ATRA was administered intraperitoneally for 14 days before or after ischemia induction. Neurobehavioural performance (Y-maze, open field, and novel object recognition tests) was assessed. Ileal and hippocampal tissues, along with serum samples, were analysed for oxidative stress (GSH, SOD, MDA, NO), inflammatory (IL-6, TNF-α, NF-κB, MPO), and apoptotic (Bax, BCL-2, caspase-3) markers. Histological evaluation (H&E staining) was performed on ileal and hippocampal sections.

Results: IIRI significantly reduced SOD and GSH, while elevating MDA, NO, IL-6, TNF-α, NF-κB, MPO, Bax, and caspase-3. These were accompanied by villus blunting, neuronal pyknosis, and cognitive deficits. Furthermore, the hippocampus showed secondary damage characterised by disrupted serotonin, dopamine, glutamate, Na+/K+-ATPase, acetylcholinesterase, and NADH levels. Pre-treatment with ATRA, particularly at a higher dose, produced stronger antioxidant recovery and inflammatory suppression than post-treatment, hence restoring near-normal histoarchitecture and cognitive indices. Post-treatment effects (high dose) were also significant compared with IIRI alone.

Conclusion: These findings suggest that ATRA administration effectively preserves the intestine and hippocampus following IIRI, potentially preventing long-term cognitive implications in young female subjects.