Effect of flavonol and its dimethoxy derivatives on paclitaxel-induced peripheral neuropathy in mice

Abstract

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.

In Vitro and In Vivo Effects of Flavonoids on Peripheral Neuropathic Pain

“…Therefore, the antinociceptive activities of trimethoxy flavones against paclitaxel-induced peripheral neuropathy could be attributed to the structure-activity relationship of flavonoids, which might enhance their antinociceptive properties. In a similar study, flavonol and its dimethoxy derivatives does-dependently attenuated paclitaxel-induced tactile allodynia, cold allodynia and thermal hyperalgesia in mice along with decrease in pro-inflammatory cytokines TNFα and IL-1β and free radicals, such as DPPH and NO in a dose-dependent manner [73].…”

“…Flavonoids have also been reported in ameliorating neuropathic manifestation induced by paclitaxel [71][72][73]. Gao et al [71] reported that quercetin significantly increased thermal hyperalgesia and mechanical allodynia in both paclitaxel treated rats and mice.…”

“…The present review also focuses on the effects of flavonoids in combating oxidative stress either by increasing the levels of antioxidant enzymes or by decreasing the levels of ROS or other oxidative stress biomarkers in different peripheral neuropathic conditions [72,73,89,[91][92][93][96][97][98][99]111,114,[130][131][132]135]. Furthermore, studies have demonstrated that the antioxidant properties of flavonoids could be attributed to the increase in phenolic hydroxyls, replacement of C-3 ,4 positions in the B ring of flavonoids by hydroxyls, and the presence of a methoxyl group at the ortho position of phenolic hydroxyl [182].…”

Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy

“…Among the approved drugs, duloxetine, lacosamide, pregabalin, and rosuvastatin have also been reported to reverse PIPN via their antioxidant effects [23,28,32]. Moreover, many agents, which have antioxidant effects, inhibit PIPN in preclinical studies [19,22,[24][25][26][29][30][31]33,34].…”

“…Inflammatory cytokines (e.g., interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)) and chemokines (e.g., chemokine (C-X-C motif) ligand (CXCL) family) were elevated in the peripheral sites, spinal cord, and of paclitaxeltreated animals, and many agents reduced the peripheral neuropathy symptoms via their anti-inflammatory effects [19,21,22,24,25,27,28,[32][33][34][35][36][37][38][39]41,42,[44][45][46][47][49][50][51][52][53][54]56]. Activations of astrocytes and microglia were also observed in the spinal dorsal horn after paclitaxel administrations, and many agents including minocycline attenuated PIPN via the inhibition of these spinal changes and prevented neurological damage [40,43,44,48].…”