The 7-Hydroxyflavone attenuates chemotherapy-induced neuropathic pain by targeting inflammatory pathway

Vincristine and paclitaxel are widely used chemotherapeutic drugs for the treatment of brain tumors, breast cancer, leukemia, lymphomas, and malignant solid tumors. Though, these drugs are associated with some severe adverse effects including peripheral neuropathic pain. The anti-nociceptive and anti-inflammatory properties of the 7-Hydroxyflavone (7HF) were evaluated in the mice using thermally- and chemically-induced nociception, naloxone antagonistic test, and carrageenan-induced paw edema models. Initially, the in-vitro cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitory assays were carried out. Peripheral neuropathic pain was induced in the Sprague Dawley (SD) rats by administration of paclitaxel (4 mg/kg) and vincristine (200 µg/kg) on days 1, 3, 5, 7, and 9, respectively. The protective effect of 7HF was assessed against the chemotherapy-induced peripheral neuropathy in the rats. Moreover, the expression of the inflammatory mediators in the spinal cord was investigated through RT-PCR. In addition, a computational study was performed to find the potential therapeutic targets and the binding mechanism of 7HF. The 7HF caused concentration-dependent inhibition of COX-2 and 5-LOX, it attenuated the nociceptive pain, carrageenan-induced paw edema, and the development of mechanical and cold allodynia, and hyperalgesia dose-dependently without causing motor coordination deficit. Likewise, the 7HF decreased the vincristine-induced increased expression of different inflammatory mediators including COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and nuclear factor-kappa B (NF-κB). The computational study showed the effective interactions of 7HF with the binding sites of NF-κB, COX-2, and 5-LOX, exert its inhibitory activities. These findings reveal that the 7HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic potentials.