Punicalagin and ellagic acid containing Punica granatum L. fruit rind extract prevents vincristine-induced neuropathic pain in rats: an in silico and in vivo evidence of GABAergic action and cytokine inhibition

ABSTRACT

Objectives: We aimed to investigate the protective potential of Punica granatum L. fruit rind extract (PFE) containing punicalagin (10.3% W/W), ellagic acid (EA) (2.7%W/W) in vincristine (75 µg/kg i.p.)- induced neuropathic pain in Wistar rats.

Methods: Docking simulation studies were done on the three-dimensional (3D) structure of the GABA_A and PPAR γ receptor for the binding of EA as well as punicalagin docking studies on TNF-α, and IL-6. The Present Study conceptualized a test battery to evaluate the behavioral, biochemical and histological changes.

Results: Vincristine -induced significant cold allodynia, mechanical hyperalgesia, and functional deficit on 12th and 21st days. It also increased in the levels of TNF-α (Tumor necrosis factor-α), IL-6 (Interleukin-6), and MPO (Myeloperoxidase). Administration of PFE (100 and 300 mg/kg, p.o.), EA (50 mg/kg), and gabapentin (100 mg/kg) attenuated Vincristine-induced behavioral and biochemical changes significantly (P < .05). PFE showed better antinociceptive activity to EA. The histopathological evaluation also revealed the protective effects of PFE. Pretreatment of bicuculline (selective antagonist of GABAA receptors) reversed antinociceptive action of PFE, but administration of γ aminobutyric acid potentiated the action of PFE. PPAR-γ antagonist BADGE did not modify the effect of PFE. Docking results revealed that EA properly positioned into GABA and PPARγ binding site and acts as a partial agonist. Docking score of Punicalagin found to be − 9.02 kcal/mol and - 8.32 kcal/mol on IL-6 and TNFα respectively.

Discussion: Conclusively, the attenuating effect of PFE may be attributed to the GABAergic system, cytokine inhibition, and anti-inflammatory activities.

KEYWORDS:

• Punicaceae
• peripheral neuropathy
• TNF-α
• IL-6
• gabapentin
• ellagic acid
• γ-aminobutyric acid
• PPAR-γ

Acknowledgements

Authors are thankful to Department of Pharmacy, Banasthali University, for providing technical support. Authors are also thankful to Dr Joohee Pradhan, Assistant Professor Department of Pharmaceutical sciences, Mohanlal Sukhadia University, Udaipur, India, for providing the facility to perform docking studies.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Notes on contributors

Vivek Jain

Vivek Jain is an Assistant Professor in Department of Pharmaceutical Sciences Mohanlal Sukhadia University, Udaipur, Rajasthan, India. He is having more than 12 years of experience in teaching and research. He has published more than 25 research and review articles with total citation 554, h-index 8 and i10 – index 8. He has also written one book. He is also the receiver of Young Teacher Award in 2018 from EET CRS and Young Scientist Award from Innovative Pharmacist Group in 2018.

Ashutosh Pareek

Dr. Ashutosh Pareek is working as Associate Professor at Banasthali Vidyapith, one of the world's leading women's university. He has meritorious academic career; received Gold medal & Merit Appreciation for academic excellence during his Masters and Bachelors in Pharmacy. Currently, he has more than 12 years of research and teaching experience in the field of Pharmaceutical Science. In this short span, he has published more than 25 research papers in journals of high repute with h-index of 9 and authored 5 technical books. He has also received various international travel awards from government funding agencies like ICMR, DST-SERB, and DBTand international body like American Association of Pharmaceutical Scientist. Dr. Pareek also handled various research projects of UGC, DST as PI and Co-PI. His major interest is in the areas of neuropharmacology, neuro and ocular drug delivery system and bioanalytical method development.

Yashumati Ratan Bhardwaj

Dr. Yashumati Ratan Bhardwaj is working in capacity of Assistant Professor in department of Pharmacy, Banasthali Vidyapith, India. She is actively involved in synthetic medicinal chemistry and natural product chemistry field from last 14 years. She has published 18 research & review articles with citation 92, h-index 6 and i10-index 4. She has written 5 books, published various conference proceedings and presentations in many national & international conferences related to the synthetic medicinal chemistry, natural product chemistry, analytical chemistry, neuropathy, pharmacological screening and formulation development of novel compounds. She has supervised 1 Ph. D. student and 10 Post Graduate students. At present she is guiding 3 research scholars.

Saurabh Kumar Sinha

Saurabh Kumar Sinha is an Assistant Professor in Department of Pharmaceutical Sciences Mohanlal Sukhadia University, Udaipur, Rajasthan, India. He is having more than 11 years of experience in teaching and research. He has published one patent, more than 25 research and review articles with total citation 515, h-index 12 and i10 – index 16. He has also written one book.

Madan Mohan Gupta

Dr. Madan Mohan Gupta is an Associate Professor (Senior Lecturer) in School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad & Tobago, WI. He is having more than 18 years' experiences in Teaching, Research and Administration. He has published more than 68 research and review papers. He has written five books and one book chapter. Dr. Gupta has received 6 National and International awards for excellence in Teaching and Research.

Nirmal Singh

Nirmal Singh is a Professor and Head in Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India. He is having more than 21 years of experience in teaching and research. He has published more than 200 research and review articles with total citation 9945, h-index 51 and i10 – index 173. He has also written six books.