Fumaric acid protects rats from ciprofloxacin-provoked depression through modulating TLR4, Nrf-2, and p190-rho GTP

Abstract

Depression is a persistent illness affecting health, behavior, and performance in life. Worldwide morbidity and mortality are caused by depression. The current study intended to explore fumaric acid’s potential protective effect against ciprofloxacin-provoked depression in rats and to determine its mechanism of action by studying its antioxidant and anti-inflammatory properties. Five groups of male Wistar albino rats (120 g ± 20) were employed; the first group received physiological saline, the second group received fumaric acid (80 mg/kg/day; orally) for 3 weeks, the third group was administered ciprofloxacin (50 mg/kg/day; orally) for 3 weeks to induce depression, the fourth group received a daily low dose of fumaric acid (40 mg/kg; orally) concurrent with ciprofloxacin and the fifth group received a daily high dose of fumaric acid (80 mg/kg; orally) concurrent with ciprofloxacin for 21 days. Then, behavior tests, oxidative stress indicators, inflammatory biomarkers, neurotransmitters, p190 Rho GTP, and histopathological examination were evaluated. Ciprofloxacin significantly increased oxidative stress biomarkers [malondialdehyde (MDA) as a lipid peroxidation marker and nitric oxide (NO)] and biomarkers of inflammation [Toll-like receptor4 (TLR-4)] and tumor necrosis factor-alpha (TNF-α) with reduction in the activities of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and catalase as well as brain contents of neurotransmitters and P190-RHO GTP. In addition, it causes necrosis of neurons and mild loss of Purkinje cells. Fumaric acid eliminates these effects of ciprofloxacin. Fumaric acid has beneficial effects as an anti-depressant in Wistar albino male rats that received ciprofloxacin.

Keywords:

• Depression
• fumaric acid
• Nrf-2
• neuroprotection
• TLR-4
• rat

Acknowledgement

Thanks and gratitude to Dr. Seham Abd El-Raouf Abd El-Aleem, Professor of Pathology, Faculty of Medicine, Minia University, Egypt, for her assistance in performing the histopathological study and to Dr. Emad Hassanein Mohamed Hassanein, Lecturer of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University (Assiut Branch), Egypt for his kind help in the careful checking for language, grammar, and style.

Ethical approval

The ‘Research Ethical Committee’ of Faculty of Pharmacy, Beni-Suef University has reviewed and approved the research proposal and has given us the agreement on conducting the research under Serial No.: REC-A-PhBSU-20009.

Authors contributions

MM, AS and MA conceived and designed research. AS and AH conducted experiments. AS and MM analyzed data. MM, HM and AH wrote the manuscript. HM: the corresponding author. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

Data and materials are available with the corresponding author upon reasonable request.

Additional information

Funding

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