In 1959, the FDA approved colistin, a polymyxin antibiotic, for treating gram-negative bacteria [1]. Nevertheless, due to the documented neuro- and nephrotoxic effects of polymyxins, colistin has been discontinued for all uses except for topical applications in the eyes and ears [2]. By 1990, the introduction of multi-drug resistant (MDR) gram-negative bacteria, such as K. pneumonia, P. aeruginosa, and A. baumannii, re-introduced the colistin as a “last resort” for the treatment of these MDR strains [3]. Colistimethate sodium (CMS), which is administered in a sodium derivative form, is known to have possible toxic effects on the kidneys and neurons. This poses a challenge in its use [4].

The colistin-induced nephrotoxicity has been reported to be attributed to apoptotic and inflammatory pathways [5]. This was demonstrated by elevated renal B-cell lymphoma (Bcl)-2, Bcl-2 associated X (Bax) protein, C/EBP homologous protein (CHOP), caspase-1 and caspase-3 [5], [6], suggesting endoplasmic reticulum (ER) and mitochondrial stress pathways upon colistin exposure. In previous studies, colistin renal apoptosis engages overt oxidative stress that is perceived as a kickstart for renal apoptosis and injury [7], [8], [9]. Similarly, neurotoxicity of colistin involves increased oxidative stress [10], Bax/BCL-2 ratio[11], and phosphatidylinositol 3-kinases (PI3K)/protein kinase-B (Akt)/c-AMP response element-binding (CREB) pathways [12], in cascade to elicits apoptotic and oxidative neurological injuries.

Tirzepatide (Tirze) is a dual glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP) receptor agonist that has been recently approved by the FDA for the treatment of type 2 diabetes mellitus [13]. Besides its anti-diabetic effect, Tirze showed a nascent anti-inflammatory potential by reducing myriad inflammatory cytokines in obese asthmatic mice [14]. In addition, Tirze suppressed cardiac and cerebral tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and phosphorylation of nuclear factor (NF)-κB, and apoptosis in rat models of left ventricular dysfunction and diabetic memory impairment [15], [16]. Also, Tirze upregulated the cerebral expression of PI3K and glycogen synthase kinase (GSK)3-β, outletting neuroprotection in diabetic rats [16]. Overall, incretin receptor activation has positive effects on glycemic control, weight loss, and inflammation, as well as oxidative stress in many organs [17]. Daily administration of GIP in high-fat diet feed rats reduced phosphorylation of Akt, adiposal 5-adenosine monophosphate-activated protein kinase (AMPK), FS-7-associated surface antigen (FAS), TNF-α, IL-1, and c-Jun N-terminal kinases, highlighting an anti-apoptotic and anti-inflammatory resilience [18]. Further, renal GLP-1 receptor activation drives protein kinase A to inhibit renal oxidative injury in diabetic rats [19], and enhance renal blood perfusion by dilating glomerular blood vessels [20].

To our knowledge, several compounds have been studied and showed possible protection during colistin therapy in experimental animals [21]; however, only vitamin C was clinically trialed and did not offer any significant protection in those patients [22]. Therefore, and from the previously aforementioned studies, we aim to investigate the feasibility of Tirze as adjuvant therapy for protection against colistin-induced renal and neurological side effects, clarifying its targets on renal and cerebral PI3K/p-Akt/GSK3-β/NF-kB p65, nuclear factor erythroid 2-related factor 2 (Nrf2), and p-CREB /brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling pathways.