AUTHOR=Alolayan Salma A. , Alhowail Ahmad H. 

TITLE=Ineffectiveness of tirzepatide in mitigating Doxorubicin-induced oxidative stress and cognitive deficits in a rat model

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1638527

DOI=10.3389/fphar.2025.1638527

ISSN=1663-9812

ABSTRACT=Doxorubicin (DXN) is widely utilized for the treatment of various cancer types. However, prolonged DXN administration induces vascular impairment and neurological effects, including cognitive deficits. Here, we investigated the efficacy of tirzepatide (TIR), an antidiabetic agent that improve cognitive function in diabetic rats, in alleviating cognitive impairment in DXN-treated rats. Forty female Wistar rats were allocated to four experimental groups: Control, DXN (5 mg/kg body weight (BW)), TIR (1.35 mg/kg BW), and DXN + TIR (5 mg DXN/kg BW followed by 1.35 mg TIR/kg BW). The compounds were injected intraperitoneally over four cycles. Mortality rates, alterations in body weight (BW), behavior, and oxidative stress markers were evaluated. The mortality rates in the control and TIR groups remained 0%, whereas those in the DXN and DXN + TIR groups were 30% and 40%, respectively. A decline in body weight was detected in rats treated with DXN and DXN + TIR, significantly relative to those in the control and TIR groups. Behavioral assessments revealed that subjects administered with DXN showed impairments, as evidenced by their performance in the Y-maze, MORT, and EPMT tasks. Furthermore, the addition of TIR did not alleviate these impairments. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels were diminished in the DXN and DXN + TIR groups although not changes in catalase, whereas reactive oxygen species (ROS), lipid peroxidation, and malondialdehyde (MDA) levels were increased relative to those in the control group. Additionally, the functionality of mitochondrial complex-I was found to be compromised in DXN and DXN + TIR in comparison to the control group. In conclusion, the findings demonstrate that DXN induces neurotoxicity and cognitive impairments through the mechanism of increased oxidative stress. Furthermore, the concurrent administration of TIR did not mitigate the neurotoxic effects, as evidenced by persistent oxidative stress and cognitive deficits.