Mitigating cyclophosphamide-induced hepatorenal toxicity: Linalool's role in modulating oxidative stress, inflammation, and apoptosis

Cyclophosphamide (CP) is associated with detrimental side effect including hepatic and renal toxicities. Linalool (LIN), acyclic monoterpene alcohol, is acquired from several plants' essential oils. Rats were disseminated into four groups. Group 1: Normal and Cyclophosphamide (CP) groups in which rats were given normal saline or CP intraperitoneally (200 mg/kg, ip on 12nd). Group 3 and 4 (LIN 50 + CP and LIN 100 + CP) groups in which rats were administered LIN (50 or 100 mg/kg) orally for 14 days and CP (200 mg/kg, ip on 12nd). Assessment of hepatic and renal function tests and histopathological examination were performed. Oxidative stress indicators, inflammatory mediators, and apoptosis markers in hepatic and renal homogenates were assessed. JAK2/STAT3/NF kappa B gene expression was measured. The network pharmacology study suggests JAK2 as one the targets so molecular docking of LIN against JAK2 was accomplished. LIN administration with CP resulted in a significant reduction in liver function test including ALT, AST, LDL, bilirubin, and gamma GTT1 and in renal function markers including BUN, creatinine, uric acid, Kim-1, NGAL, and CysC. Also, LIN increases in antioxidant ability via enhancing GST, GSH-Px, GSH-R, SOD, and catalase as well as a declining NO, MDA levels. Furthermore, LIN significantly diminished JAK2/STAT3/NF kappa B gene expressions with subsequent reduction in the inflammatory markers including TNF-alpha, MPO, ICAM-1, IL-6, and IL-1 beta levels and the apoptotic markers Bax and cleavage caspase-3 and 9. LIN protected the hepatic and renal tissues from ROS damage and mitigated JAK2/STAT3/NF kappa B with subsequent anti-inflammatory and anti-apoptotic properties.