Antinociceptive and anti inflammatory activities of 3-(2,5 dimethoxyphenyl)-1-(5 methylfuran-2-YL) prop-2-en-1 in mice

Chalcone is being extensively explored due to its pharmacological properties. The search on chalcone derivatives as an analgesic agent increased as the current pain treatment caused severe side effects. This study aimed to determine the analgesic activity of new chalcone derivative, 3-(2,5-dimethoxy phenyl)-1-(5-methyl furan-2-yl) prop-2-en-1 (DMPF-1) and to identify its possible mechanism of actions. Analysis of acute and sub-acute toxicity of DMPF-1 supplementation was performed. A single oral dose (1000 mg/kg) and 28-days repeated treatment of DMPF-1 (0.1-10 mg/kg) showed no significant changes in body weight, haematological, serum biochemical, macroscopic and microscopic analysis proved the absence of changes in the treated subjects. Antinociceptive study of DMPF-1 was started using the acetic acid-induced abdominal writhing test, formalin-induced paw licking test and hot plate test. The results showed DMPF-1 significantly reduce pain in a dose-dependent manner and suggests central and peripheral antinociceptive effect. Accordingly, the study on the possible involvement of opioid receptors was done. The challenge of DMPF-1 with naloxone showed no reversion of its antinociceptive effect, suggesting no contribution to the opioid system. Further examination using capsaicin, glutamate and phorbol 12-myristate 13-acetate (PMA)-induced paw licking test showed that the systemic administration of DMPF-1 at various doses significantly reduced the nociceptive response of the mice in a dose-dependent manner. This result proposed that DMPF-1 was acted through the vanilloid, glutamatergic and protein kinase C system in mediating analgesic action. In addition, the pre-treatment of DMPF-1 with L-arginine and ODQ had reversed the DMPF-1 antinociceptive effect indicating the involvement of nitric oxide and cyclic GMP synthesis. In sequence, pre-treatment of the animals with various potassium channels blockers such as charybdotoxin, glibenclamide and tetraethylammonium significantly abolished its antinociceptive activity, which suggests the facilitation of NO-cGMP pathway, large Ca2+ activated, ATP sensitive, and voltage-dependent potassium channels in its mechanism of action implied. At present, the possible involvement of various inhibitory neuroreceptors was performed. Pre-treatment with bicuculine appears to block its antinociceptive profile in which the event was not seen in pre-treatment with phaclofen, thus suggesting the involvement of the GABAA receptor. Meanwhile, pre-treatment of the subject with haloperidol and metoclopramide was carried out to investigate the involvement of dopaminergic receptors. Marked inhibition of DMFP-1 activity by only metoclopramide was observed, which indicated the contribution of the D2 dopaminergic receptor. Further investigation using atropine, yohimbine, and caffeine attenuated its antinociceptive action, thus suggesting those receptors' participation in pain modulation. Moreover, pre-treatment of the mice with various serotonergic receptor antagonists, including WAY 100635, pindolol and kentanserin but not ondansetron, however, fail to affect the antinociceptive activity of DMPF-1. This concludes that DMPF-1 could stimulate the 5HT3 receptor in order to produce antinociception. A paw oedema test was carried out to determine its peripheral antinociceptive capability. DMPF-1 at various dosages can reduce the volume of paw oedema induced by carrageenan, bradykinin, substance P, prostaglandin E, histamine, arachidonic acid and serotonin. Results indicate that DMPF-1 exerts peripheral activity by attenuating the action of the inflammatory mediators. In conclusion, this study confirms the antinociceptive activities of DMPF-1 and elucidates the possible mechanism of action through which it exerts its antinociceptive effects.

Text NOOR AZLINA ABU BAKAR - IR.pdf Download (1MB)

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