The flavonoid 6-methoxyflavone allays cisplatin-induced neuropathic allodynia and hypoalgesia

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side-effect of several commonly used chemotherapeutic agents (such as cisplatin) that profoundly impairs patient quality of life. Unfortunately, neither prophylactic strategies nor symptomatic treatments have proven useful in this condition. Flavonoids are found ubiquitously in fruits and vegetables and exert a multiplicity of beneficial effects. In this study, the antinociceptive activity of 6-methoxyflavone (6-MF) was investigated and evaluated in comparison with gabapentin in a rat model of CIPN. The effect on motor balance was also assessed using the rotarod and footprint analysis paradigms. 6-MF possessed both peripheral and central antinociceptive activities against tonic and phasic nociceptive stimuli. Cisplatin administration (3.0mg/kg/week, i.p.) for four consecutive weeks generated temporal mechanical allodynia (decreased paw withdrawal threshold; PWT) and thermal hypoalgesia (increased paw thermal threshold; PTT) in the bilateral hindpaws. Daily treatment with 6-MF (25, 50 and 75mg/kg/day, i.p) for four weeks attenuated the cisplatin-induced expression of nocifensive behaviors observed as a significant increase in PWT and alleviation of PTT during the third and fourth weeks of cisplatin administration. Accordingly, daily gabapentin (75mg/kg, i.p) suppressed the expression of CIPN by normalizing the PWT and hotplate response latency. However, these antinociceptive actions were associated with motor impairment exemplified by a significant decrease in rotarod endurance latency and a deficit in the uniformity of step alternation. In contrast, 6-MF was devoid of these adverse side-effects. These findings suggested that 6-MF afforded desirable neuropathic pain alleviating effects in CIPN and it was devoid of gabapentin-like unwanted motor side-effects.

Keywords: Antinociceptive; Chemotherapy-induced neuropathic pain; Flavone; Lack of motor incoordination; Natural product; Pharmacotherapy.