The lack of efficacy of tirzepatide in mitigating cisplatin-induced neurotoxicity and cognitive impairment in rats.

Introduction: Cisplatin (CIS) is a commonly utilized chemotherapeutic agent, but its use is often accompanied by adverse effects such as neurotoxicity and cognitive impairments, collectively referred to as chemobrain. This condition impacts over 70% of cancer survivors, and currently, there are no established therapeutic interventions. This study aimed to evaluate the efficacy of tirzepatide in mitigating the neuropathy effects induced by cisplatin therapy. Methods: Forty female Wistar albino rats were divided into four groups of ten: control (untreated), cisplatin (CIS), tirzepatide (TIRZ), and CIS/TIRZ. Treatments were administered intraperitoneally in two injections. The CIS group received cisplatin at a dosage of 5 mg/kg, while tirzepatide was administered at 1.35 mg/kg. In the CIS/TIRZ group, tirzepatide (1.35 mg/kg) was administered prior to cisplatin (5 mg/kg), with a 3-h interval between the two treatments. Post-treatment, behavioral assessments (Y-maze) and oxidative stress biomarkers were evaluated, including enzymatic antioxidants catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx-1), as well as oxidative damage markers such as reactive oxygen species (ROS) and malondialdehyde (MDA). Results: Survival rates were 90% in both the TIRZ and CIS groups, and 70% in the CIS/TIRZ group, whereas all rats in the control group survived. All treatment groups experienced a reduction in body weight compared to the control group. Cisplatin administration resulted in impaired learning and memory in the Y-maze test, which was linked to decreased levels of the antioxidants GPx-1 and catalase, with no alteration in SOD levels. Additionally, ROS and MDA levels were slightly elevated in the CIS and TIRZ groups individually. Although tirzepatide did not ameliorate the memory deficits or antioxidant reductions caused by cisplatin, it did lead to a reduction in ROS and MDA levels. Discussion: CIS therapy accelerates memory deficits in female rats by increasing oxidative stress. However, TRIZ did not alleviate the memory deficits or antioxidant reductions, although it did reduce ROS levels.