Effect of Metformin on Doxorubicin-Induced Cognitive Deficit in Rats

Abstract

Doxorubicin (DOX) is frequently used to treat a wide range of cancers. It is linked to chemotherapy-related side effects such as cognitive impairments called “chemobrain”. Chemobrain affects many cancer survivors, and there are currently no treatments. This study aimed to see if metformin (MET) protects against DOX-induced neurotoxicity. Forty male rats were equally divided into four groups: control, DOX-treated, DOX+MET-treated, and MET-treated. Rats treated with DOX received 4 mg/kg DOX weekly for five weeks (cumulative dose 20 mg/kg). MET (3 mg/mL) was added to the drinking water of the DOX-MET and MET groups. The survival rate and body weight were evaluated throughout all duration of the study. In control, DOX, MET groups the rats were survived to the end of the study, whereas the DOX+MET 10% were died in the day nine and more 10% died in the day 27, which last to the end of the study 80%. The body weight was significantly reduced in the DOX and DOX+MET groups compared to the control, whereas MET group reveals increased the body weight versus all the other three groups. In addition, one day after therapy completed, behavioral tests and biochemical assays were conducted. In the Y-maze, novel object recognition (NOR), and elevated plus maze (EPM) behavioral tests, we found that DOX treatment induced learning and memory dysfunction in the rats. These dysfunctions were not alleviated by MET. Surprisingly, MET alone was induced the memory impairment. In enzyme-linked immunosorbent assays (ELISA), the DOX-treated rats showed significantly decreased interleukin-1 (IL-1α) and insulin receptor substrate-1 (IRS-1) expression in the brain, and the expression of these proteins was rescued by MET administration. The expression of interleukin-6 (IL-6), protein kinase B (PkB/Akt), and tumor necrosis factor-alpha (TNF-alpha) was not altered in the brain of DOX- and MET-treated rats. The brain glucose level did not show a significant change in treated groups versus the control group. In conclusion, DOX therapy induces the cognitive impairment in rats chemobrain models; however, MET did not reverse this cognitive impairment caused by DOX. Also, the potential mechanism of these memory dysfunction caused by DOX could be a result of reduction of IL-1α and IRS- 1 expression in the brain. Moreover, Akt-a, TNF-alpha and IL-6 expressions were not altered in DOX, MET or combined groups in compared to the control group.