6-Hydroxyflavanone treats anxiety and chemotherapy-induced neuropathy in Sprague-Dawley rats

Abstract

Background: Cancer remains a predominant cause of death worldwide. The advent of effective chemotherapy has enormously decreased the mortality rate and increased the life expectancy of cancer patients. However, the adverse effects allied with chemotherapy contribute to the development of neurotoxicity, anxiety, and depression.

Objective: The dual effects of a novel flavanone, 6-hydroxyflavanone (6-HF), were investigated in treating chemotherapy-induced neuropathy along with anxiolytic propensity.

Methods: The anti-neuropathy propensity of 6-HF was evaluated utilizing the cisplatin-induced neuropathy (CIN) model, whereas its anxiolytic activity was evaluated utilizing anxiety models, such as the elevated plus maze test (EPM), the staircase test, and the open-field paradigm.

Result: Cisplatin administration induced static and dynamic allodynia in the rats. Concomitant administration of 6-HF and cisplatin for four successive weeks remarkably reduced the chemotherapy-induced mechanical allodynia, evident from an elevation in the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The anxiolytic-like activity of 6-HF in the EPM apparatus was confirmed by the increased number of entries in the open arm and time spent at the central platform, which was further confirmed by the enhanced head-dipping frequency in the same assay. A decrease in rearing behavior of the mice without suppression of the steps ascended further assured the anxiolytic-like potential of 6-HF. Additionally, the animals under investigation spent more time at the intersection of the open-field apparatus, further confirming the anxiolytic potential of 6-HF.

Conclusion: 6-HF might be considered a potential therapeutic agent for counteracting two common adverse effects of chemotherapy, neurotoxicity and anxiety.

Keywords: 6-hydroxyflavanone; anxiety; cancer; chemotherapy; neurotoxicity.

FIGURE 1

Induction of peripheral neuropathy by weekly administration of cisplatin at a dose of 3.00 mg/kg for 4 weeks with respect to (A) paw withdrawal threshold (PWT; mean ± SEM) and (B) paw withdrawal latency (PWL; mean ± SEM) in male Sprague–Dawley rats. ***p < 0.001 compared to vehicle-treated control animals. Two-way repeated measure ANOVA post hoc Bonferroni’s analysis (n = 6 rats per group). Effect of co-administration of 6-HF at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg and the positive control gabapentin (GP) at a dose of 75 mg/kg on the expression of mechanical-static/dynamic allodynia induced by the administration of cisplatin (3.0 mg/kg; Cis-3) for four consecutive weeks in male Sprague–Dawley rats. (C) Effect of 6-HF and GP on the paw withdrawal threshold (PWT in g; static allodynia). (D) Effect of 6-HF and GP on the paw withdrawal latency (PWL in sec; dynamic allodynia). ^### p < 0.001 compared to vehicle (Veh)-treated animals. **p < 0.01 and ***p < 0.001 compared to cisplatin-treated control animals. Two-way repeated measure ANOVA post hoc Bonferroni’s analysis (n = 6 rats per group).

FIGURE 2

Effect of 6-HF at doses of 15 mg/kg (6-HF-15), 30 mg/kg (6-HF-30), and 60 mg/kg (6-HF-60) and diazepam (DPM) at a dose of 2 mg/kg in male Sprague–Dawley rats on the (A) open-arm entries, (B) time spent in the open arms, (C) frequency of wall-rearing, (D) frequency of head-dipping, (E) closed-arm entries, and (F) the time spent at the center of apparatus in the elevated plus maze model of anxiety. One-way ANOVA post hoc Dunnett’s analysis (n = 6 rats per group; mean ± SEM).

FIGURE 3

Effect of 6-HF at doses of 15 mg/kg (6-HF-15), 30 mg/kg (6-HF-30), and 60 mg/kg (6-HF-60) and diazepam (DPM) at a dose of 2 mg/kg in Sprague–Dawley rats on the (A) number of steps ascended, (B) number of wall-rearing instances in the staircase model, (C) number of lines crossed, and (D) time spent in center of the apparatus in the open-field model of anxiety. One-way ANOVA post hoc Dunnett’s analysis (n = 6 rats per group; mean ± SEM).