Empagliflozin Dampens Doxorubicin-Induced Chemobrain in Rats: The Possible Involvement of Oxidative Stress and PI3K/Akt/mTOR/NF-κB/TNF-α Signaling Pathways

Chemobrain is a cognitive impairment observed in up to 75% of cancer patients treated with doxorubicin (DOX). Cognitive deficits associated with DOX are complex, and multiple interplay pathways contribute to memory impairment and the loss of concentration. Empagliflozin (EMPA), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor with neuroprotective potential, has recently been elucidated because of its regulatory effects on oxidative stress and neuroinflammation. Thus, this study aimed to explore the protective mechanisms of EMPA in DOX-induced chemobrain. Rats were allocated to four groups: normal (NC), EMPA, DOX, and EMPA + DOX. Chemobrain was induced in the third and fourth groups by DOX (2 mg/kg, IP) on the 0th, 7th, 14th, and 21st days of the study, while EMPA was administered (10 mg/kg, PO) for 28 consecutive days in both the EMPA and EMPA + DOX groups. Behavioral and biochemical assessments were then performed. Rats treated with DOX exhibited significant memory, learning, and muscle coordination dysfunctions. Moreover, DOX boosted oxidative stress in the brain, as evidenced by elevated malondialdehyde (MDA) content together with decreased levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and reduced glutathione (GSH). Neuroinflammation was also observed as an upsurge of tumor necrosis factor-alpha (TNF-alpha) and nuclear factor kappa B (NF-kappa B) (p65). Additionally, DOX diminished the expression of brain-derived neurotrophic factor (BDNF) and increased phosphoinositol-3-kinase (PI3K), phosphorylated-Akt (pAkt), and mammalian target of rapamycin (mTOR) content. EMPA exhibited potent neuroprotective potential in DOX-induced cognitive impairment, attributed to its antioxidant and neuroplasticity-enhancing properties and suppression of the PI3K/Akt/mTOR/NF-kappa B/TNF-alpha signaling pathway.Graphical AbstractDoxorubicin (DOX)-induced chemobrain may occur because of increased tumor necrosis factor-alpha (TNF-alpha) levels in the brain, which activates inhibitory-kappa B kinase (IKK), thus triggering the dissociation of nuclear factor kappa B (NF-kappa B) from its inhibitor protein. NF-kappa B, then, translocates into the nucleus and increases the transcription of TNF-alpha, which induces the production of reactive oxygen species (ROS). Enhanced lipid peroxidation (MDA) diminishes antioxidant defense mechanisms, such as reduced glutathione (GSH) brain content. It inhibits the production of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream ROS-detoxifying enzyme, heme oxygenase-1 (HO-1). Moreover, DOX enhanced the expression of phosphoinsitol-3-kinase (PI3K), phosphorylated-Akt (pAkt), and downstream kinase, the mammalian target of rapamycin (mTOR) pathway, which enhances the expression of NF-kappa B, TNF-alpha, and the resultant ROS production. Pre-treatment with empagliflozin (EMPA) successfully counteracted all the parameters above.