Metformin Exerted Neuroprotective Effects on Cognition in Rats with Trastuzumap‐Induced Brain Toxicity

Abstract Background Trastuzumap (Trz) is effectively used for breast cancer patients to improve health status and reduce mortality rate. Nevertheless, several studies reported its adverse effect on brain toxicity. To date, the mechanisms of Trz‐induced brain toxicity are not fully understood. Metformin is a generic prescribed drug for type 2 diabetes mellitus, while in the past decade it also used for attenuating the adverse effects of chemotherapy. However, the effects of metformin on brain mitochondrial function, hippocampal microglial function, hippocampal synaptic plasticity, and cognitive function in Trz‐induced brain toxicity have never been investigated. Method Eighteen male Wistar rats were randomly divided into two groups; control group (0.9% NSS, intraperitoneal (i.p.) injection, n = 8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n = 16). Then, Trz‐treated rats were divided into two subgroups (n = 6/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or metformin (250 mg/kg/day for 7 days, daily via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation. Result Trz‐treated rats demonstrated an increase of mitochondrial ROS production, increased mean fluorescence intensity of ionized calcium binding adaptor molecule 1 (Iba1), decreased hippocampal dendritic spine density, decreased preferent index in novel object location (NOL) and novel object recognition (NOR) test (p<0.05, Figure 1A‐F). Metformin‐treated in Trz‐rats reversed the adverse effect of Trz by attenuated mitochondrial ROS production, decreased mean fluorescence intensity of Iba1, increased hippocampal dendritic spine density, as well as increased preferent index in NOL and NOR test (p<0.05, Figure 1A‐F). Conclusion Trz‐induced brain toxicity as indicated by brain mitochondrial dysfunction, decreased hippocampal microglial function, impaired hippocampal synaptic plasticity, and cognitive dysfunction, while metformin alleviated those deleterious effects. The findings in this study emphasize the roles of metformin against Trz‐induced brain toxicity and strengthen