Linezolid mitigates tissue injury in experimental model of pediatric testicular torsion: TLR-4/MAPK/NF-κB involvement

Testicular torsion is a urological emergency that requires prompt surgery to prevent orchiectomy. Pharmacological interventions may slow the progression of damage and reduce reperfusion injury after surgical correction.

This study evaluated the protective effects of linezolid against testicular torsion-detorsion (T/D) injury in rats by focusing on the mechanisms involving the Toll-like receptor 4 (TLR-4) pathway.

Eighty-four male Wistar rats were allocated into 8 groups; of them, one was subjected to a sham operation and another was subjected to 4-hour ischemia via 720° of torsion followed by 24-hour reperfusion. Linezolid (3-100 mg/kg) was assessed for its effects on T/D injury using histopathological evaluation, oxidative stress markers (malondialdehyde [MDA], superoxide dismutase [SOD]), and inflammatory biomarker tumor necrosis factor-alpha (TNF-α). Mechanistic investigations have focused on TLR-4 the mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. Molecular docking and in silico analyses were conducted to predict interactions with key inflammatory proteins.

Linezolid 25, 50, and 100 mg/kg significantly reduced the histopathological damage, with 50 mg/kg being the most effective dosage. Within the 6-50 mg/kg range, linezolid reduced MDA, increased SOD, decreased TNF-α, and suppressed TLR-4/NF-κB pathway activity, with maximal reductions in MDA, TNF-α, NF-κB, and TLR-4 of 64%, 77%, 56%, and 53%, respectively, and an enhancement in SOD of 47%. In silico docking predicted strong binding interactions with TLR-4 pathway proteins, including p38 MAPK and JNK, with affinities of -7.4 to -8.3 kcal/mol.

Linezolid protects against testicular torsion by reducing oxidative stress and inflammation via modulating the TLR-4/NF-κB pathway, suggesting its therapeutic potential and need for further study.