Neuroprotective effect of canagliflozin against cisplatin-induced cerebral cortex injury is mediated by regulation of HO-1/PPAR-γ, SIRT1/FOXO-3, JNK/AP-1, TLR4/iNOS, and Ang II/Ang 1–7 signals

Abstract

Objectives

Canagliflozin (CAN), a sodium-glucose co-transporter 2 inhibitor, is an anti-hyperglycemic drug that has been approved to treat diabetes. This study evaluated the beneficial effects of CAN on cerebral cortex intoxication induced by cisplatin (CIS).

Materials and methods

Rats were allocated into four groups: normal control, CAN (10 mg/kg, P.O.) for 10 days, CIS (8 mg/kg, i.p.) as a single dose on the 5th day of the experiment, and CAN + CIS group.

Results

In comparison with CIS control rats, CAN significantly mitigated CIS-induced cortical changes in rats’ behavior in the open field and forced swimming assessment as well as histological structure. Biochemically, CAN administration efficiently decreased lipid peroxidation biomarkers MDA and boosted the antioxidant status via a remarkable increase in the cortical reduced glutathione (GSH) content as well as enzymatic activities of antioxidant enzymes superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase (CAT), and glutathione peroxidase (GPx) mediated by up-regulation of heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptors (PPARγ), and silent information regulator (SIRT1)/forkhead box-O3 (FOXO-3) signals. Additionally, pretreatment with CAN significantly decreased cortical myeloperoxidase (MPO), nitrite (NO₂^–), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels. At the same time, it elevated the IL-10 level associated with the downregulation of Jun N-terminal kinase (JNK)/activator protein 1 (AP-1), TLR4/inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and Ang II/Ang 1–7 signals.

Conclusions

Due to the potent antioxidant and anti-inflammatory properties of CAN, our findings showed that CAN could be a good candidate for the protection against CIS-induced cortical intoxication in the patient receiving CIS.

Graphical Abstract

Keywords:

• Canagliflozin
• cisplatin
• cerebral cortex
• HO-1/PPAR-γ
• JNK/AP-1
• Ang II/Ang 1–7

Author contributions

Emad Hassanein: conceptualization, data curation, writing-original draft preparation, and formal analysis. Fayez Saleh: reviewing and editing, data curation, and resources. Fares Ali: conceptualization, methodology, writing-original draft preparation, reviewing, and editing. Eman K. Rashwan: reviewing and editing, data curation, and resources. Ahmed Atwa: validation, investigation, resources, reviewing, and editing. Omnia Abd El-Ghafar: validation, investigation, resources, writing-original draft preparation, reviewing, and editing.

Disclosure statement

The author declares that there are no conflicts of interest.

Data availability statement

All data generated or analyzed during this study are included in this article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.