Amelioration of gentamicin-induced acute kidney injury by trifluoperazine: in vivo mechanistic insights

Résumé

Acute kidney injury (AKI) is a serious risk associated with gentamicin. Therefore, the current study investigated whether pretreatment with the antipsychotic trifluoperazine could provide protective effects. Assessment of serum creatinine and blood urea nitrogen, in addition to histopathology analysis, demonstrated that trifluoperazine effectively protected the kidneys from functional and structural abnormalities induced by gentamicin. Several signaling pathways that were modulated by drug treatments were investigated in the kidney and showed that trifluoperazine mitigated gentamicin-triggered oxidative stress evidenced by the preservation of SOD activity, reduction of MDA levels, and inhibition of the transcription of stress-responsive genes, Chop and Ho-1. Moreover, trifluoperazine abrogated the increased protein levels of the p65 subunit of NF-κB and suppressed the transcription of NF-κB target genes, IL-1β, TNF-α, and Tsp-1, highlighting the inhibition of the aberrantly activated NF-κB signaling. Further, trifluoperazine attenuated the increased ERK1/2 phosphorylation by gentamicin. Notably, p62 and LC3B protein levels indicated that trifluoperazine alleviated the impaired autophagy by gentamicin. Additionally, NLRP3 and IL-1β protein levels suggested that trifluoperazine mitigated gentamicin-induced NLRP3 inflammasomes activation. Finally, trifluoperazine effectively suppressed apoptosis induction by gentamicin. In conclusion, our study provided the first in vivo preclinical evidence supporting further investigation of the potential of trifluoperazine to mitigate gentamicin-induced AKI.

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