Normalization of magnesium deficiency with magnesium-L-Threonate alleviates bladder overactivity in cyclophosphamide-induced cystitis: Mechanisms of inflammatory modulation and barrier restoration.

Abstract

Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a chronic urological syndrome predominantly affecting women, with an incidence of 2.7-6.5%. It is characterized by bladder-related pain and lower urinary tract symptoms, with inflammation and urothelial barrier disruption as primary mechanisms. Our previous research demonstrated that normalization of magnesium deficiency with Magnesium-L-Threonate (L-TAMS) alleviates mechanical allodynia, depressive-like behaviors, and memory deficits in cyclophosphamide (CYP)-induced cystitis by suppressing neuroinflammatory responses. In the present study, we established a rat BPS/IC model through intraperitoneal CYP injections (50 mg/kg every 3 days for three doses) and administered L-TAMS via drinking water at 604 mg/kg/day. Micturition frequency was assessed using cystometry, and bladder tissue was evaluated through hematoxylin and eosin staining, TUNEL assay, toluidine blue staining, and Western blotting. L-TAMS restored magnesium homeostasis and ameliorated bladder overactivity by prolonging intercontractile intervals. Histopathological alterations including epithelial defects, edema, and vascular congestion were alleviated. Increased apoptosis and mast cell infiltration were reversed. Additionally, TNF-α/NF-κB signaling and IL-1β expression were suppressed, and the integrity of bladder tight junction proteins was restored. These findings suggest that oral L-TAMS effectively reduces bladder overactivity in CYP-induced cystitis by inhibiting inflammatory signaling pathways and restoring bladder barrier integrity, supporting its therapeutic potential for BPS/IC management.