Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

Abstract

Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain.

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

“…Furthermore, the study showed antihyperalgesic activity of fisetin was abolished by co-administration of 5-HT7 receptor antagonist (SB-258719), indicating the involvement of 5-HT7 in the fisetin-induced antinociceptive activity. Fisetin also attenuated the co-morbid depressive and anxiety-like behaviors developed following 2-3 weeks CCI surgery, as shown by the increased immobility time in forced swim test, increased latency to feed in novelty suppressed feeding test, and deceased lit compartment time in light-dark test [99]. In another study, the significant antihyperalgesic effect induced by the combination of hesperidin with diosmin was abolished by the presence of naloxone (opioid receptor antagonist), bicuculline (GABA A receptor antagonist), and haloperidol (D2 receptor antagonist), indicating the involvement of the afore-mentioned receptors in hesperidin-diosmin-induced antihyperalgesia in CCI model of neuropathic pain [129].…”

“…The flavonoids catechin [89], naringenin [96], morin [97], kaempferol [98], luteolin [90], rutin [92], genistein [93], hesperidin, and fisetin [99] have been shown to decrease the level of ROS by increase the level of different antioxidative enzymes, such as SOD, CAT, reduced glutathione peroxidase (GSH), GPx and glutathione reductase (GR) in different tissues (brain, liver, sciatic nerve) of diabetic animals. Furthermore, luteolin, morin and rutin have shown to increase the expression of nuclear factor-E2-related factor-2 (Nrf2) Nrf2 and its downstream effectors heme oxygenase-1 (HO-1) in nerve tissues of diabetic animals.…”

“…Several flavonoids, such as naringenin [96], naringin [111], luteolin [90], baicalin [112], pelargonidin [91], rutin [92], hesperidin [113], and fisetin [99], attenuated diabetes-induced thermal hyperalgesia, whereas morin [97], naringenin [96], naringin [111], kaempferol [98], luteolin [90], epigallocatechin gallate [114], and rutin [92] reduced mechanical hyperalgesia. In addition to hyperalgesia, morin [97], baicalein [112], puerarin [115], hesperidin [113], and fisetin [99] reduced mechanical allodynia, whereas, genistein [93] and naringin [111] reduced mechano-tactile allodynia, and luteolin [90] and rutin [92] reduced cold allodynia. Studies have shown that short term diabetes induced thermal, chemical and mechanical hyperalgesia [116,117], whereas long term diabetes induces thermal and mechanical hypoalgesia [118].…”

“…Luteolin has been reported to reduce cold and mechanical hyperalgesia, but not thermal hyperalgesia [137]. On the other hand, fisetin reduced thermal hyperalgesia, but not nociceptive sensitivity to mechanical stimuli [99].…”

“…Zhao et al [99] explored the antinociceptive activity of fisetin, a 3,3 ,4 ,7-tetrahydroxyflavone, in a mouse neuropathic pain model after performing sciatic nerve CCI. The study found that fisetin exerted antihyperalgesic effect in CCI-induced animals by activating descending monoamine system with markedly increasing spinal monoamine (serotonin) levels and the ratio of 5-HT/5-HTP, and concomitantly decreasing spinal monoamine oxidase A (MAO-A).…”