Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models.

Jasmine Siew Min Chia,Enoch Kumar Perimal,Mohd Roslan Sulaiman,Ahmad Akira Omar Farouk,Hanis Zakaria,Tengku Azam Shah Tengku Mohamad,Nurul Izzaty Hassan

doi:10.3390/molecules26133849

Abstract

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.

Highlights

Neuropathic pain is a chronic pain disease known worldwide as a debilitating and challenging condition to treat
The pre-treatment with CB1 receptor antagonist (SR141716, 1 mg/kg) prior to zerumbone (10 mg/kg) abolished both the anti-allodynic and antihyperalgesic effects typically observed in the chronic constriction injury animal model of neuropathic pain
The current study found that the antagonism of CB1 receptors by SR141716 counteracted the antineuropathic effects of zerumbone, whereas SR144528 (CB2 receptor antagonist) produced no significant changes, implying that only CB1 receptors participate in zerumbone-induced antiallodynia and antihyperalgesia

Summary

Introduction

Neuropathic pain is a chronic pain disease known worldwide as a debilitating and challenging condition to treat. Neuropathic pain persistence lasts from months to years, affecting almost 10% of the population worldwide [1]. There are no specific medications to treat neuropathic pain. Natural products have been used for centuries for their medicinal properties. The readily consumable ginger plant, Zingiber zerumbet, has been documented as a folklore medicine, as it was used to treat stomachache, wounds and fever, typically in Asian countries. The primary active component of Z. zerumbet rhizomes, has been widely studied to assess its pharmacological properties (for a review of previous studies, see [3]). Zerumbone has shown prominent analgesic properties in acute and chronic pain animal models [4,5]. Zerumbone has displayed no toxicity at low to moderate dosages in acute toxicity studies, indicating oral consumption safety [6,7,8]

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