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. 2022 Dec;29(1):1892-1902.
doi: 10.1080/10717544.2022.2086943.

Enhanced healing efficacy of an optimized gabapentin-melittin nanoconjugate gel-loaded formulation in excised wounds of diabetic rats

Hani Z Asfour  1 , Nabil A Alhakamy  2   3   4 , Osama A A Ahmed  2   3   4 , Usama A Fahmy  2 , Shadab Md  2 , Mohamed A El-Moselhy  5 , Waleed Y Rizg  2 , Adel F Alghaith  6 , Basma G Eid  7 , Ashraf B Abdel-Naim  7
Affiliations

Enhanced healing efficacy of an optimized gabapentin-melittin nanoconjugate gel-loaded formulation in excised wounds of diabetic rats

Hani Z Asfour et al. Drug Deliv. 2022 Dec.

Abstract

The present study aimed to design and optimize, a nanoconjugate of gabapentin (GPN)-melittin (MLT) and to evaluate its healing activity in rat diabetic wounds. To explore the wound healing potency of GPN-MLT nanoconjugate, an in vivo study was carried out. Diabetic rats were subjected to excision wounds and received daily topical treatment with conventional formulations of GPN, MLT, GPN-MLT nanoconjugate and a marketed formula. The outcome of the in vivo study showed an expedited wound contraction in GPN-MLT-treated animals. This was confirmed histologically. The nanoconjugate formula exhibited antioxidant activities as evidenced by preventing malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic exhaustion. Further, the nanoconjugate showed superior anti-inflammatory activity as it inhibited the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This is in addition to enhancement of proliferation as indicated by increased expression of transforming growth factor-β (TGF- β), vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor receptor-β (PDGFRB). Also, nanoconjugate enhanced hydroxyproline concentration and mRNA expression of collagen type 1 alpha 1 (Col 1A1). In conclusion, a GPN-MLT nanoconjugate was optimized with respect to particle size. Analysis of pharmacokinetic attributes showed the mean particle size of optimized nanoconjugate as 156.9 nm. The nanoconjugate exhibited potent wound healing activities in diabetic rats. This, at least partly, involve enhanced antioxidant, anti-inflammatory, proliferative and pro-collagen activities. This may help to develop novel formulae that could accelerate wound healing in diabetes.

Keywords: Diabetes; gabapentin; melittin; nanoconjugation; wound healing.

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Conflict of interest statement

The authors report there are no competing interests to declare.

Figures

Figure 1.
Figure 1.
Graphs yielded from experimental design software for the development of GPN-MLT nanoconjugate (a) standard Pareto chart, (b) main effects plot, (c) contour plot, and (d) response surface plot.
Figure 2.
Figure 2.
Effects of GPN, MLT, GPN-MLT nanoconjugate and marketed formulation on the wound contraction and % wound contraction on day 14. (a) Significantly different from Untreated control at p < .05, (b) Significantly different from Vehicle-treated control at p < .05, (c) Significantly different from GPN at p < .05, (d) Significantly different from MLT at p < .05, (e) Significantly different from GPN-MLT at p < .05.
Figure 3.
Figure 3.
Effects of GPN, MLT, GPN-MLT nanoconjugate and marketed formulation on the histopathological analysis (A) H & E staining and (B) MT staining.
Figure 4.
Figure 4.
Effects of GPN, MLT, GPN-MLT nanocomplex and marketed formulation on the markers of antioxidant enzymes (A) MDA, (B) SOD, and (C) GPx. a: Significantly different from Untreated control at p < .05, b: Significantly different from Vehicle-treated control at p < .05, c: Significantly different from GPN at p < .05, d: Significantly different from MLT at p < .05, e: Significantly different from GPN-MLT at p < .05.
Figure 5.
Figure 5.
Effects of GPN, MLT, GPN-MLT nanocomplex and marketed formulation on the expression level of (A) IL-6, and (B) TNF-α. a: Significantly different from Untreated control at p < .05, b: Significantly different from Vehicle-treated control at p < .05, c: Significantly different from GPN at p < .05, d: Significantly different from MLT at p < .05.
Figure 6.
Figure 6.
Effects of GPN, MLT, GPN-MLT nanoconjugate, and marketed formulation on the expression level of (A) TGF-β (B) VEGFA and (C) PDGFR-β. a: Significantly different from Untreated control at p < .05, b: Significantly different from Vehicle-treated control at p < .05, c: Significantly different from GPN at p < .05, d: Significantly different from MLT at p < .05, e: Significantly different from GPN-MLT at p < .05.
Figure 7.
Figure 7.
Effects of GPN, MLT, GPN-MLT nanoconjugate and marketed formulation on the level of (A) hydroxyproline and (B) Col1A1. a: Significantly different from Untreated control at p < .05, b: Significantly different from Vehicle-treated control at p < .05, c: Significantly different from GPN at p < .05, d: Significantly different from MLT at p < .05, e: Significantly different from GPN-MLT at p < .05.
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References

    1. Abdel-Salam OME, El-Batran S. (2005). Pharmacological investigation of trimetazidine in models of inflammation, pain and gastric injury in rodents. Pharmacology 75:122–32. - PubMed
    1. Al-Ani I, Zimmermann S, Reichling J, Wink M. (2015). Pharmacological synergism of bee venom and melittin with antibiotics and plant secondary metabolites against multi-drug resistant microbial pathogens. Phytomedicine 22:245–55. - PubMed
    1. Alhakamy NA, Ahmed OAA, Fahmy UA, Shadab M. (2021a). Apamin-conjugated alendronate sodium nanocomplex for management of pancreatic cancer. Pharmaceuticals 14:729. - PMC - PubMed
    1. Alhakamy NA, Caruso G, Eid BG, et al. (2021b). Ceftriaxone and melittin synergistically promote wound healing in diabetic rats. Pharmaceutics 13:1622. - PMC - PubMed
    1. Ahmedy OA, Ibrahim SM, Salem HH, Kandil EA. (2020). Antiulcerogenic effect of melittin via mitigating TLR4/TRAF6 mediated NF-ΚB and p38MAPK pathways in acetic acid-induced ulcerative colitis in mice. Chem Biol Interact 331:109276. - PubMed

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