The potential role of Tirzepatide as adjuvant therapy in countering colistin-induced nephro and neurotoxicity in rats via modulation of PI3K/p-Akt/GSK3-β/NF-kB p65 hub, shielding against oxidative and endoplasmic reticulum stress, and activation of p-CREB/BDNF/TrkB cascade

• Published in: International immunopharmacology Vol. 135; p. 112308
• Main Authors: Hassan, Noha F., Ragab, Diaa, Ibrahim, Shaimaa G., Abd El-Galil, Mona M., Hassan Abd-El-Hamid, Asmaa, Hamed, Dalia M., Magdy William, Mira, Salem, Maha A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.06.2024
• Subjects: Colistin; ER stress; Nephrotoxicity; Neurotoxicity; PI3K/p-Akt/GSK3-β; Tirzepatide; DCTs; PAS; Colistin; MDA; NF-κB; MRCs; SD; Neurotoxicity; CREB; PI3K; Nrf2; CHOP; GSH; GLP-1; BDNF; H&E; ER stress; Akt; ER; IL-6; GFAP; GIP; TrkB; TNF-α; PCTs; PI3K/p-Akt/GSK3-β; Bcl2; Bax; Tirze; Tirzepatide; Nephrotoxicity; ELISA
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2024.112308

•The potential role of Tirzepatide as adjuvant therapy in counteracting colistin-induced nephro and neurotoxicity through modulation of PI3K/p-Akt/GSk3-β/NF-kB p65 dependent signaling pathways that display the main role in the kidney and brain pathogenesis.•Tirzepatide shields against apoptosis, oxidative, and endoplasmic reticulum stress via upregulation of Nrf2/GSH and reversing of the ATF4/CHOP trajectories and regulation of apoptotic-related biomarkers.•Tirzepatide attenuated neuronal impairment evoked by colistin treatment through activation of p-CREB/BDNF/TrkB neuroprotective cascade and downregulation of GFAP- immunoreactivity. Although colistin has a crucial antibacterial activity in treating multidrug-resistant gram-negative bacteria strains; it exhibited renal and neuronal toxicities rendering its use a challenge. Previous studies investigated the incretin hormones either glucose-dependent insulinotropic polypeptide (GIP) or glucagonlike peptide-1 (GLP-1) for their neuroprotective and nephroprotective effectiveness. The present study focused on investigating Tirzepatide (Tirze), a dual GLP-1/GIP agonist, as an adjuvant therapy in the colistin treatment protocol for attenuating its renal and neuronal complications. Rats were divided into; The normal control group, the colistin-treated group received colistin (300,000 IU/kg/day for 7 days; i.p.). The Tirze-treated group received Tirze (1.35 mg/kg on the 1,4,7thdays; s.c.) and daily colistin. Tirze effectively enhanced histopathological alterations, renal function parameters, and locomotor activity in rats. Tirze mechanistically acted via modulating various signaling axes evolved under the insult of phosphatidylinositol 3-kinases (PI3K)/phosphorylated protein kinase-B (p-Akt)/ glycogen synthase kinase (GSK)3-β hub causing mitigation of nuclear factor (NF)-κB (NF-κB) / tumor necrosis factor-α (TNF-α), increment of nuclear factor erythroid 2-related factor 2 (Nrf2)/ glutathione (GSH), downregulation of ER stress-related biomarkers (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)), antiapoptotic effects coupling with reduction of glial fibrillary acidic protein (GFAP) immunoreactivity and enhancement of phosphorylated c-AMP response element-binding (p-CREB) / brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) neuroprotective pathway. Briefly, Tirze exerts a promising role as adjuvant therapy in the colistin treatment protocol for protection against colistin’s nephro- and neurotoxicity according to its anti-inflammatory, antioxidant, and antiapoptotic impacts besides its ability to suppress ER stress-related biomarkers.