BackgroundThe anti - nociceptive effect of 7, 2′, 3′ – trimethoxy flavone, 7, 2′, 4′ – trimethoxy flavone, 7, 3′, 4′ – trimethoxy flavone and 7, 5, 4′ – trimethoxy flavone against inflammatory, neurogenic and thermal pain in mice was reported earlier. The present study was designed to investigate the effect of the above trimethoxy flavones in amelioration of peripheral neuropathy induced by paclitaxel.MethodsPeripheral neuropathy was induced in mice by administration of a single i.p. dose (10 mg/kg) of paclitaxel. The manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later by employing hair aesthesiometer test, acetone bubble test and hot water tail immersion test respectively. Further, the role of inflammatory cytokines like TNF – α, IL - 1β and free radicals in the action of trimethoxy flavones was investigated using in vitro assays.ResultsThe test compounds dose dependently attenuated paclitaxel - induced tactile allodynia, cold allodynia and thermal hyperalgesia in mice. The test compounds inhibited TNF – α, IL - 1β and free radicals in a concentration dependent manner.ConclusionThe investigated trimethoxy flavones attenuated paclitaxel – induced peripheral neuropathy in mice. The inhibition of cytokines and free radicals in addition to many neuronal mechanisms reported earlier may contribute to this beneficial effect.

The investigated trimethoxy flavones exhibited promising anti-nociceptive activity in various nociceptive models, and multiple mechanisms are involved in the anti-nociceptive activity of these compounds.

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Background:Peripheral neuropathy is the dose limiting side effect of many anticancer drugs. Flavonoids exhibit good antinociceptive effect in animal models. Their efficacy against different types of nociception has been documented. The present study investigated the effect of flavonol (3-hydroxy flavone), 3′,4′-dimethoxy flavonol, 6,3′-dimethoxy flavonol, 7,2′-dimethoxy flavonol and 7,3′-dimethoxy flavonol against paclitaxel-induced peripheral neuropathy in mice.Methods:A single dose of paclitaxel (10 mg/kg, i.p.) was administered to induce peripheral neuropathy in mice and the manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later by employing Von Frey hair aesthesiometer test, acetone bubble test and hot water tail immersion test, respectively. The test compounds were prepared as a suspension in 0.5% carboxymethyl cellulose and were administered s.c. in various doses (25, 50, 100 and 200 mg/kg). The above behavioral responses were assessed prior to and 30 min after drug treatment. In addition, the effect of test compounds on proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β) and free radicals was investigated by using suitablein vitroassays.Results:A dose-dependent attenuation of tactile allodynia, cold allodynia and thermal hyperalgesia was evidenced in mice treated with flavonol derivatives. The test compounds inhibited TNF-α, IL-1β and free radicals in a concentration-dependent manner.Conclusions:These results revealed that flavonol and its dimethoxy derivatives ameliorated the manifestations of paclitaxel-induced peripheral neuropathy in mice. The inhibition of proinflammatory cytokines and free radicals could contribute to this beneficial effect.

Flavonoids have been shown to possess central nervous system (CNS) depressant effect mediated through the ionotropic GABA receptors. In the present study, 5-methoxyflavone was evaluated for sedative-hypnotic like activity in mice and the mechanisms involved by employing a battery of tests including molecular docking studies. In the open field test, 5-methoxyflavone in various doses (50, 100 and 150 mg/kg, i.p) exhibited a significant and dose-dependent reduction in the spontaneous locomotor activity (F (530) = 87.17 P < 0.001). Pretreatment with 5-methoxyflavone decreased the latency to sleep induction after pentobarbitone or ether administration and also significantly increased the duration of sleep (p < 0.001). A significant and dose-dependent myorelaxant effect was observed with 5-methoxyflavone in the inclined plane, horizontal wire test and rota rod test. Pretreatment with picrotoxin, bicuculline, glycine, caffeine or NMDA either decreased or completely abolished the hypnotic effect of 5-methoxyflavone in mice. The above results revealed the involvement of GABA, adenosine, glycine and NMDA receptors in the hypnotic effect of 5-methoxyflavone. The results of in silico studies indicated that, 5-methoxyflavone exhibits good binding affinity towards these receptors by H-bond interactions. In conclusion, the present study identified a novel and potential sedative-hypnotic like effect of 5-methoxyflavone involving multiple mechanisms.