Efficacy assessment of novel methanimine derivatives in chronic constriction injury-induced neuropathic model: An in-vivo, ex-vivo and In-Silico approach

Jawad Khan; Gowhar Ali; Aamer Saeed; Asma Khurshid; Sajjad Ahmad; Hamdy Kashtoh; Farid S Ataya; Gaber El-Saber Bathiha; Aman Ullah; Ajmal Khan

doi:10.1016/j.ejps.2024.106797

Efficacy assessment of novel methanimine derivatives in chronic constriction injury-induced neuropathic model: An in-vivo, ex-vivo and In-Silico approach

Eur J Pharm Sci. 2024 May 11:198:106797. doi: 10.1016/j.ejps.2024.106797. Online ahead of print.

Authors

Jawad Khan¹, Gowhar Ali², Aamer Saeed³, Asma Khurshid⁴, Sajjad Ahmad⁵, Hamdy Kashtoh⁶, Farid S Ataya⁷, Gaber El-Saber Bathiha⁸, Aman Ullah⁹, Ajmal Khan¹⁰

Affiliations

¹ Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan. Electronic address: jawadpharmacist111@gmail.com.
² Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan. Electronic address: Gowhar_ali@uop.edu.pk.
³ Department of Chemistry, Quaid-I-Azam University Islamabad 45320, Pakistan.
⁴ Department of Chemistry, Quaid-I-Azam University Islamabad 45320, Pakistan. Electronic address: asmakhurshid@chem.qau.edu.pk.
⁵ Department of Health and Biological Sciences, Abasyn University Peshawar 25000, Pakistan.
⁶ Department of Biotechnology, Yeungnam University, Gyeongbuk, Korea. Electronic address: hamdy_kashtoh@ynu.ac.kr.
⁷ Department of Biochemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia.
⁸ Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheria, Egypt.
⁹ Department of Pharmacy, Saba Medical Center, Abu Dhabi PO Box 20316, United Arab Emirates.
¹⁰ Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Sultanate of Oman.

PMID: 38735401
DOI: 10.1016/j.ejps.2024.106797

Abstract

The multicomponent etiology, complex clinical implications, dose-based side effect and degree of pain mitigation associated with the current pharmacological therapy is incapable in complete resolution of chronic neuropathic pain patients which necessitates the perpetual requirement of novel medication therapy. Therefore, this study explored the ameliorative aptitude of two novel methanimine imitative like (E)-N-(4-nitrobenzylidene)-4‑chloro-2-iodobenzamine (KB 09) and (E)-N-(4-methylbenzylidene)-4‑chloro-2-iodobenzamine (KB 10) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rat model. Standard behavioral tests like dynamic and static allodynia, cold, thermal and mechanical hyperalgesia along with rotarod activity were performed at various experimental days like 0, 3, 7, 14 and 21. Enzyme linked immunosorbent assay (ELISA) on spinal tissue and antioxidant assays on sciatic nerve were executed accompanied by molecular docking and simulation studies. Prolonged ligation of sciatic nerve expressively induced hyperalgesia as well as allodynia in rats. KB 09 and KB 10 substantially attenuated the CCI elicited hyperalgesia and allodynia. They significantly reduced the biomarkers of pain and inflammation like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ELISA and while enhanced the GSH, SOD and CAT and diminished the MDA levels during antioxidant assays. KB 09 displayed -9.62 kcal/mol with TNF-α and -7.68 kcal/mol binding energy with IL-6 whereas KB 10 exhibited binding energy of -8.20 kcal/mol with IL-6 while -11.68 kcal/mol with TNF-α and hence both trial compounds ensured stable interaction with IL-6 and TNF-α during computational analysis. The results advocated that both methanimine derivatives might be novel candidates for attenuation of CCI-induced neuropathic pain prospects via anti-nociceptive, anti-inflammatory and antioxidant mechanisms.

Keywords: Allodynia; Antioxidant; Chronic constriction injury; ELISA; Hyperalgesia; Methanimine.