Title

3′, 4′-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating K_ATP channel, adenosine (A₃) and GABA_A (a₂ subunit) receptors

Authors

Kavitha Ramasamy^1,*, JaikumarShanmugasundaram², Viswanathan Subramanian ³, Rajesh Manoharan ⁴, ParimalaKathirvelu³ & Rajagopalan Vijayaraghavan⁵

Affiliation

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

Email

Kavitha Ramasamy – E-mail:  r.kavitha@sriramachandra.edu.in

Article Type

Research Article

Date

Received June 1, 2023; Revised June 30, 2023; Accepted June 30, 2023, Published June 30, 2023

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

Paclitaxel; 3′, 4′-dihydroxyflavone; CIPN; GABA_A (α₂ subunit); adenosine (A₃); K_ATP channels

Citation

Ramasamy et al. Bioinformation 19(6): 754-763 (2023)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.