Diosmin reduces chronic constriction injury-induced neuropathic pain in mice

Abstract

Injury or dysfunction of somatosensory system induces a complex syndrome called neuropathic pain, which still needs adequate pharmacological control. The current pharmacological treatments were in part developed from natural compounds. Flavonoids are natural polyphenolic molecules presenting varied biological activities and low toxicity. The flavonoid diosmin is a safe compound with good tolerability and low toxicity. This study evaluated the antinociceptive effect of diosmin in the sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain model. Male Swiss mice were submitted to CCI and 7 days after, diosmin at 1 or 10 mg/kg was administrated intraperitoneally. Mechanical (electronic analgesimeter) and thermal (hot plate) hyperalgesia were evaluated 1-24 h after treatment. The role of the NO/cGMP/PKG/KATP channel signaling pathway in the analgesic effect of diosmin was evaluated using the pretreatment with L-NAME (an inhibitor of NOS), ODQ (an inhibitor of soluble guanylate cyclase), KT5823 (an inhibitor of PKG), or glibenclamide (an ATP-sensitive K+ channels blocker). Single treatment with diosmin inhibited in a dose-dependent manner CCI-induced mechanical and thermal hyperalgesia by activating the NO/cGMP/PKG/KATP channel signaling pathway and inhibiting spinal cord cytokine (Il-1β and Il-33/St2) and glial cells activation (microglia - Iba-1, oligodendrocytes - Olig2) mRNA expression markers. Daily treatment during 7 days with diosmin inhibited CCI-induced mechanical and thermal hyperalgesia by inhibiting spinal cord cytokine (Il-1β, Tnfα, and Il-33/St2) and glial cells activation (astrocytes - Gfap, Iba-1, and Olig2) markers mRNA expression. In conclusion, diosmin inhibits neuropathic spinal cord nociceptive mechanisms suggesting this flavonoid as a potential therapeutic molecule to reduce nerve lesion-induced neuropathic pain.

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

“…This flavonoid presents anti-inflammatory and anti-hyperalgesic mechanisms described in different models. Some of these effects have been attributed to the reduction of NF-κB activation [47], TNF-α in PC12 cell induced by LPS [117], Il-1β, Tnf-α, and Il-33/St2 mRNA expression in the spinal cord induced by CCI [118], TNF-α, IL-1β and IL-6 in the spinal cord and sciatic nerve tissues [119], NO, PGE 2 , IL-6, IL-12, TNF-α production by macrophages [120], COX-2 and MPO activity [121,122]. In addition, diosmin inhibited LTB 4 synthesis [121].…”

“…Diosmin reduced the levels of MDA and prevented the consumption of GSH [121,122]. Regarding the analgesic effects of diosmin, this flavonoid reduces neuropathic pain in the sciatic nerve chronic constriction injury (CCI) model by activating the analgesic NO/cGMP/PKG/ATP-sensitive potassium channels channel signaling pathway and blocking central sensitization [118]. Also, in a model of CCI in rats, diosmin acts at central level through opioid and dopaminergic receptors to inhibit mechanical and thermal hyperalgesia [119].…”

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

“…CCI-induced pain includes several symptoms, including spontaneous (tingling, burning, electric-shock like) pain, dysesthesia, paraesthesia, allodynia, and hyperalgesia [127]. Flavonoids diosmin [128], hesperidin [129], and grape seed proanthocyanidins [130] reduced both thermal and mechanical hyperalgesia, whereas isoorientin [131], morin [132], EGCG [133], epigallocatechin derivate compounds 23 and 30 [134], and genistein [135] reduced only thermal hyperalgesia. Quercetin has been reported to reduce thermal and mechanical hypersensitivities in a superior degree compared to gabapentin and morphine [136].…”

“…However, PARP activation leads to the activation of NF-κB, which in turn leads to the activation of pro-inflammatory markers, such as cyclooxygenase-2 (COX-2), iNOS, TNF-α, and IL-6, playing a major role in pain processing events [143,144]. The effects of flavonoids on different pro-inflammatory biomarkers have also been reported in CCI-induced neuropathic pain model [128]. Single treatment of diosmin reduced the mRNA expressions of IL-1β, IL-33, and St2, whereas prolonged treatment reduced the mRNA expression of TNFα along with IL-1β, IL-33, and St2.…”

Anti-Inflammatory and Anti-Nociceptive Effects of Cocoa: A Review on Future Perspectives in Treatment of Pain

“…Other polyphenolic compounds have been reported to exert beneficial effects on NP, such as hesperidin [51], diosmin [52], naringenin [53].…”