Work

Neuroprotective Effects of Dapagliflozin on Hippocampal Adult Neurogenesis and Synaptic Integrity in Rats with Doxorubicin‐induced Chemobrain

Year: 2025

Type: article

Abstract: BACKGROUND: Doxorubicin, a chemotherapeutic agent, frequently causes debilitating neurological deficits known as chemobrain, as indicated by impaired neurogenesis and synaptic dysplasticity (1). Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including dapagliflozin, also have neuroprotective properties beyond their anti-diabetic activity (2). However, the effects of dapagliflozin on chemobrain following doxorubicin treatment remain unexplored. Therefore, this study aimed to investigate the neuroprotective effects of dapagliflozin in rats with doxorubicin-induced chemobrain. METHOD: Adult male Wistar rats were divided into three groups: (1) Control (NSS), (2) DOX (doxorubicin; 3 mg/kg/day administered intraperitoneally for 6 doses over 30 days), and (3) DOX-DAPA (combined treatment with 3 mg/kg/day doxorubicin administered intraperitoneally for 6 doses and 1 mg/kg dapagliflozin administered orally for 30 days). At the end of the experiment, the rats were euthanized for molecular analysis in the hippocampus. The experimental protocol is summarized in Figures A and B. RESULT: We found that DOX-treated rats developed chemobrain in the hippocampus, including abnormal adult neurogenesis, as indicated by decreased BDNF, SOX2, DCX, NeuN, and PSD-95 protein expression, and synaptic dysplasticity, as shown by a reduction in dendritic spine density, compared to the control group (Figures C-I). Interestingly, dapagliflozin co-treatment exhibited neuroprotective effects in DOX-treated rats, as shown by increased DCX and PSD-95 protein expression and dendritic spine density in the hippocampus, compared with DOX-treated rats (Figures C-I). CONCLUSION: Our findings indicate that doxorubicin induces chemobrain, as shown by impairments in adult neurogenesis and synaptic integrity. Dapagliflozin mitigates the chemobrain induced by doxorubicin. Thus, dapagliflozin may serve as a therapeutic approach to alleviate chemobrain induced by doxorubicin.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70855_100062