Antinociceptive and Anti-Inflammatory Activities of Zerumbone from Zingiber Zerumbet (l.) Roscoe ex sm., and its Possible Mechanisms of Action

The present study was conducted to investigate the antinociceptive and antiinflammatory activities of zerumbone and its possible mechanism of action in animals. Zerumbone is a sesquiterpene isolated and purified from the rhizomes of the Z. zerumbet plant, locally known as ‘lempoyang’. Z. zerumbet is one of the most important species of cultivated ginger, used in food flavoring and commonly used in traditional medicine to treat stomach aches, toothaches, muscle sprain and as a cure for swelling, sores and cuts. Zerumbone was obtained from the rhizomes through a sequence of isolation processes involving hydro-distillation, column chromatography and followed by recrystallization. The compound was subjected to thin layer chromatography (TLC), gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) to identify the chemical structure and ensure its purity. Zerumbone was optimally isolated using the hexane and ethyl acetate solvent system at a ratio of 8:2 with a total yield of 0.07%. Toxicological analysis comprising of acute, sub-acute and sub-chronis tests showed that oral and intraperitoneal administration of zerumbone at doses of 10 - 1000 mg/kg did not show any signs of toxicity in terms of behavioral changes, weights of body, liver and kidneys, hematological and liver function parameters. The findings were further supported by the histopathological observations of the liver that demonstrated normal histological architecture. Zerumbone (10 - 100 mg/kg, p.o.) was also found to possess significant gastroprotective effects on the ethanol-induced ulcer model, with the higher doses showing promising results in comparison with ranitidine (100 mg/kg, p.o), a commercially available gastric ulcer medication. The determination of the antinociceptive profile of zerumbone using the acetic acid-induced abdominal writhing test and hot plate test showed significant pain inhibition, suggesting the possible involvement of zerumbone in both peripheral and central systems of the pain pathway. The rota-rod evaluation confirmed that the antinociceptive effects of zerumbone were not in relation to any sedative or nervous system suppression. Further experiments demonstrated that zerumbone interacts with both the δ- and κ-opioid receptors coupled to Ca2+ channels but not through the μ-opioid receptors.The study continued to demonstrate the ability of zerumbone to inhibit pain through the nitric oxide pathway inactivating a series of event involving the L-Arginine-NOcGMP-PKC-K+-ATP channel pathways in the acetic acid-induced abdominal writhing test. The interaction of zerumbone with three other receptors mainly the NMDA receptor, TRPV1 and B2 receptors were elucidated. The involvement of other prominent receptors involved in antinociception including GABAergic,cholinergic, dopaminergic, noradrenergic, serotonergic and adenosinergic systems in zerumbone-induced antinociception were investigated, with results demonstrating that zerumbone induces antinociception through the involvement of the mentioned systems except for the cholinergic system. The Ca2+ activated potassium channels were investigated, eventually confirming the involvement of the small and large conductance calcium-gated K+ channels, voltage-gated K+ and ATP-gated K+channels. To conclude the antinociceptive study, the activation of the spinal cord nociresponsive neurons was evaluated using the expression of the c-fos protein in the spinal cords of rats through the formalin test. The use of immunohistochemistry to identify c-fos-like immunoreactivity (c-fos-LI) showed significant reduction in the expression of c-fos proteins reaffirming the central and more crucially, the involvement of the spinal cord in zerumbone’s antinociception, a significant step before pain signals are transmitted to the brain. The anti-inflammatory study was conducted using both the carrageenan-induced paw oedema test and the cottonpellet-induced granulomatous test. The findings in both the experiments showed that zerumbone possesses anti-inflammatory effect against both exudative and proliferative phases of inflammation. The mechanism of action of the antiinflammatory activity of zerumbone was evaluated using various inflammatory chemical mediators that act as inducers, mainly bradykinin, histamine, serotonin,prostaglandin E2, substance P, phospholipase A2 and arachidonic acid, of which zerumbone (100 mg/kg, i.p.) significantly suppressed all inflammatory mediatorsinduced experiments. As a conclusion, the study strongly confirms the antinociceptive and anti-inflammatory activities of zerumbone and also elucidated the possible mechanism of action through which it exerts its effect. In adition to that,the toxicity studies demonstrated the safety margin of zerumbone in mice, thus scientifically justifying the traditional use of this species of ginger, and setting the path for future studies.

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