3', 4'-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (α2 subunit) receptors

Kavitha Ramasamy; Jaikumar Shanmugasundaram; Viswanathan Subramanian; Rajesh Manoharan; Parimala Kathirvelu; Rajagopalan Vijayaraghavan

doi:10.6026/97320630019754

3', 4'-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating K_ATP channel, adenosine (A₃) and GABA_A (α₂ subunit) receptors

Bioinformation. 2023 Jun 30;19(6):754-763. doi: 10.6026/97320630019754. eCollection 2023.

Authors

Kavitha Ramasamy¹, Jaikumar Shanmugasundaram², Viswanathan Subramanian³, Rajesh Manoharan⁴, Parimala Kathirvelu³, Rajagopalan Vijayaraghavan⁵

Affiliations

¹ Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai - 600116, India.
² Department of Pharmacology, Panimalar Medical College Hospital and Research Institute, Chennai - 600123, India.
³ Department of Pharmacology, Meenakshi Medical College Hospital and Research Institute, Meenakshi Academy of Higher Education and Research, Kanchipuram - 631552, India.
⁴ Department of Pharmacology, Sri Muthukumaran Medical College and Research Institute, Chennai - 600069, India.
⁵ Director Research, Saveetha Institute of Medical And Technical Sciences, Thandalam, Chennai - 602105, India.

Abstract

Paclitaxel is a widely used cancer chemotherapeutic agent for many solid tumors; but peripheral neuropathy is a major limitation for its clinical use. Studies have demonstrated the usefulness of flavone derivatives in chemotherapy induced peripheral neuropathy. The present study evaluates the anti-neuropathic effect of 3', 4'-dihydroxyflavone on paclitaxel-induced peripheral neuropathy and the underlying mechanisms. Paclitaxel was administered to mice in a single dose of 10 mg/kg, i.p.The neuropathic behavioural parameters such as mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later. The test compound 3', 4'-dihydroxyflavone (50,100 or 200 mg/kg,s.c) was administered 30 min prior to the assessment of behavioral parameters. The possible mechanisms involving K_ATP channels, adenosine and GABA_A receptors were explored by employing suitable interacting drugs. Molecular docking studies to predict the binding interactions of 3', 4'-dihydroxyflavone at the above targets were also carried out. The test compound 3', 4'-dihydroxyflavoneexhibited a significant reduction in paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. The anti-neuropathic effect of 3', 4'-dihydroxyflavonewas significantly reversed by pre-treatment with glibenclamide, caffeine or bicuculline revealing the involvement of K_ATP channels, adenosine and GABA_A receptors respectively. Furthermore, the molecular docking studies indicated a favourable binding affinity and good H-bond interaction of 3', 4'-dihydroxyflavone at these targets. The findings of the present study suggests that, 3', 4'-dihydroxyflavone has anti-neuropathic effect against paclitaxel-induced peripheral neuropathy through mechanisms that involve K_ATP channels, adenosine (A₃) and GABA_A (α₂ subunit) receptors.

Keywords: 3', 4'-dihydroxyflavone; CIPN; GABAA (α2 subunit); KATP channels; Paclitaxel; adenosine (A3).