# Diosmetin as an Effective Treatment for Cisplatin-Induced Neuropathic Pain in Mice which does not Cause Hepatic or Renal Biomarker Alterations

## TL;DR

Diosmetin, a natural compound, effectively reduces cisplatin-induced neuropathic pain in mice without harming the liver or kidneys.

## Contribution

Diosmetin shows antinociceptive effects comparable to duloxetine and TRPV1 antagonists in a mouse model of chemotherapy-induced neuropathy.

## Key findings

- Diosmetin reduced mechanical allodynia and affective-motivational behaviors in mice.
- Diosmetin at 0.15 mg/kg decreased heat hyperalgesia and muscle strength loss.
- Diosmetin did not alter hepatic or renal biomarkers, indicating safety.

## Abstract

Although cancer incidence is increasing globally, early detection and antineoplastic treatment ensure high patient survival rates. Among the chemotherapeutic agents widely used clinically, cisplatin is associated with the development of painful and non-painful peripheral neuropathy symptoms, compromising patient treatment continuity. Preclinical studies have indicated that the transient receptor potential vanilloid 1 (TRPV1) ion channels play a crucial role in chemotherapy-induced neuropathic pain. Currently, only duloxetine is recommended for treating chemotherapy-induced peripheral neuropathy, highlighting the urgent need for novel therapies. Natural products such as diosmetin have shown promising pharmacological potential. Here, we evaluated the effects of diosmetin in a mouse model of cisplatin-induced neuropathic pain (0.23 mg/kg, intraperitoneal). Nociceptive parameters included mechanical allodynia, affective-motivational behaviour, heat hyperalgesia, and muscle strength loss, along with hepatic [aspartate aminotransferase (AST), alanine aminotransferase (ALT)] and renal (urea and creatinine) biomarkers. Diosmetin (0.015, 0.15, and 1.5 mg/kg) administered orally by gavage (p.o.) resulted in antinociceptive effects, reduced mechanical allodynia, and decreased affective motivational behaviours in mice. Diosmetin (0.15 mg/kg) also reduced cisplatin-induced heat hyperalgesia and muscle strength loss, showing an efficacy comparable to that of duloxetine (30 mg/kg, p.o., positive control) and SB-366791 (1 mg/kg p.o., TRPV1 channel antagonist). Additionally, prior desensitisation of TRPV1-positive fibres with subcutaneous resiniferatoxin (RTX) prevents the development of mechanical allodynia and thermal hyperalgesia. Diosmetin (0.15 mg/kg) did not alter hepatic or renal biomarkers. Diosmetin has therapeutic potential for treating pain in patients with neuropathy, and the TRPV1 channel plays a crucial role in cisplatin-induced peripheral neuropathy.