Paclitaxel is an anti-microtubule agent, most widely used chemotherapeutic agent for the treatment of malignant solid
tumors. However, it is associated with some severe side effects including painful neurotoxicity with reporting of
neuropathic pain and sensory abnormalities by patients during and after
paclitaxel therapy.
Peripheral neuropathy was induced by the administration of
paclitaxel (4 mg/kg on days 1, 3, 5, and 7). In this study, the anti-nociceptive and anti-inflammatory propensity of
3-Hydroxyflavone (3HF) in mice and the preventive effect of 3HF against
paclitaxel-induced
peripheral neuropathy in Sprague Dawley (SD) rats were investigated. Moreover, tactile and cold
allodynia, thermal and tail immersion
hyperalgesia, and effects on motor-coordination were also evaluated. Furthermore, the expression of proinflammatory
cytokines i.e.
Calcitonin gene-related peptide (CGRP), and
Substance P from the spinal cord was examined through RT-PCR. Additionally, a computational structural biology approach was applied to search the potential therapeutic targets and to predict the binding mechanism of 3HF. Treatment of 3HF alleviated the
nociceptive pain, paw
edema, development of tactile and cold
allodynia, and
hyperalgesia. Similarly, treatment with 3HF suppressed the
paclitaxel-induced increase in
mRNA expression of several inflammatory
cytokines including
tumor necrosis factor -α (TNF-α), interleukin-1β (IL-1β), and
interleukin-6 (IL-6), CGRP, and
Substance P. However, the daily treatment of 3HF did not affect the motor behaviors of rats. The inhibitory mechanism of 3HF in
neuropathic pain is predicted with extensive computational bioinformatics approach which indicates that the 3HF effectively interacts with the binding domains of
Nuclear factor-kappa B (NF-κB),
CGRP receptor and the receptor of
Substance P to exert its inhibitory activities. However, the computationally predicted binding affinities revealed that the potential of binding of the compound with
Substance P receptor (
Neurokinin 1 receptor) is higher than the other receptors; there NK1R could be the most possible binding target of 3HF. These findings indicate that 3HF has anti-nociceptive, anti-inflammatory, and anti-
neuropathic pain effects against
paclitaxel-induced
neuropathic pain.