Linezolid mitigates tissue injury in experimental model of pediatric testicular torsion: TLR-4/MAPK/NF-κB involvement.
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BACKGROUND: 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. PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.