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Front. Pharmacol. | doi: 10.3389/fphar.2018.00140

Antihyperalgesic properties of honokiol in inflammatory pain models through inhibition of NF-κB and Nrf2 signaling

 Sidra Khalid1, Muhammad Zia Ullah1,  Ashrafullah Khan1, Ruqayya Afridi1,  Hina Rasheed1, Adnan Khan1,  Yeong Shik Kim2 and  Salman Khan1*
  • 1Quaid-i-Azam University, Pakistan
  • 2Pharmacy, Seoul National University, South Korea

The present study investigates the possible antinociceptive effect of intraperitoneal (i.p.) honokiol: a phenolic compound originally isolated from Magnolia officinalis, in acute and chronic inflammatory pain models. Doses of 0.1 mg/kg, 5 mg/kg and 10 mg/kg honokiol were administered in carrageenan induced pain and the dose (honokiol 10mg/kg i.p.) with most significant response among behavioral tests was selected for further experiments. The intraperitoneal administration of honokiol inhibits mechanical hyperalgesia, mechanical allodynia and thermal hyperalgesia, without causing any apparent toxicity. To elucidate the effect of honokiol on various cytokines and antioxidant enzymes, quantitative real-time-PCR was performed to determine the expression levels of pro-inflammatory cytokines and antioxidant enzymes. It is demonstrated that honokiol significantly reduced the expression levels of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Similarly, honokiol was also found to potentiate the expression of nuclear factor erythroid 2–related factor 2 (Nrf2), superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) levels. Additionally, honokiol significantly reduced plasma nitrite levels as compared to CFA induced group. X-ray analysis and Hematoxylin and eosin (H&E) staining of inflamed and treated paws showed that honokiol reduced the inflammation with significantly less leukocyte infiltration and soft tissue inflammation. In order to explore the possible mechanism of action of honokiol, agonists (piroxicam (5 mg/kg), tramadol (50 mg/kg) and gabapentin (5mg/kg) i.p) as well as antagonists (naloxone (4 mg/kg), olanzapine (10 mg/kg) and flumazenil (0.2 mg/kg) i.p) were used to study involvement of various receptors on the antinociceptive effect of honokiol. The potential side effects of honokiol on muscle activity were assessed. An adverse effect testing of honokiol by liver and renal functions were also carried out. The effect of oral honokiol was also assessed on GIT mucosa. Our results demonstrate that honokiol has a significant antinociceptive activity through inhibition of anti-inflammatory mediators.

Keywords: honokiol, allodynia, Hyperalgesia, CFA, Carrageenan, cytokines/chemokines

Received: 16 Jan 2018; Accepted: 08 Feb 2018.

Edited by:

Lingling Zhang, Anhui Medical University, China

Reviewed by:

Claudio Ferrante, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy
Giustino Orlando, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy  

Copyright: © 2018 Khalid, Ullah, Khan, Afridi, Rasheed, Khan, Kim and Khan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Salman Khan, Quaid-i-Azam University, Islamabad, Pakistan, skhan@qau.edu.pk