Metformin Induced Cognitive Impairment and Neuroinflammation in CMF-Treated Rats

Ahmad H. Alhowail, Yasser Almogbel, Ahmed A.H. Abdellatif, Maha A. Aldubayan, Hani A. Alfheeaid, Shatha G. Felemban, Sridevi Chigurupati, Ibrahim F. Alharbi and Hindi S. Alharbi

Background and Objective: Metformin (MET) has been shown to reduce the toxicity and memory dysfunction caused by chemotherapeutic agents, thereby improving patient survival and quality of life. The current study aimed to evaluate the effects of MET treatment on the survival and cognitive function of rats receiving CMF chemotherapy (cyclophosphamide [CYP], methotrexate [MTX] and 5-fluorouracil [5-FU], a regimen for breast cancer treatment) for 2 weeks. Materials and Methods: Forty male rats were divided into four groups (n = 10 per group): control (saline); CMF group (2 mg kg^–1 MTX, 50 mg kg^–1 CYP and 50 mg kg^–1 5-FU weekly); MET group (2.5 mg mL^–1 MET daily); and CMF+MET group (CMF [2 mg kg^–1 MTX, 50 mg kg^–1 CYP and 50 mg kg^–1 5-FU weekly] and 2.5 mg mL^–1 MET daily). Animals were monitored daily to assess survival and their body weights were measured every 3 days. After treatment, cognitive function was evaluated via behavioural tests. CMF and CMF+MET treatment resulted in decreased survival and body weight compared with control and MET-treated rats, as well as impaired memory function as assessed by the Y-maze test. Results: Co-administration of MET alleviated the effect of CMF on survival, but it appeared to increase memory impairment according to the elevated plus-maze test. CMF+MET-treated rats showed significantly decreased blood glucose levels compared with controls. Rats treated with CMF+MET showed increased interleukin-6 expression in brain tissue compared with MET-only and CMF-only treated animals. Conclusion: While MET may improve survival during CMF treatment, it may harm cognitive function and increase neuroinflammation.

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