Download PDF
J Reconstr Microsurg 2023; 39(01): 048-058
DOI: 10.1055/s-0042-1749338
Original Article

Cannabidiol Improves Random-Pattern Skin Flap Survival in Rats: Involvement of Cannabinoid Type-2 Receptors

Armin Aryannejad   †
1   Department of Pharmacology, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
2   Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
,
Faezeh Eslami   †
1   Department of Pharmacology, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
2   Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
,
Maryam Shayan
1   Department of Pharmacology, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
2   Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
,
Nafise Noroozi
1   Department of Pharmacology, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
2   Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
,
Keshvad Hedayatyanfard
3   Department of Physiology and Pharmacology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
4   Department of Cardiology, Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
,
Seyed Mohammad Tavangar
5   Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
,
Razieh Mohammad Jafari
1   Department of Pharmacology, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
,
Ahmad Reza Dehpour
1   Department of Pharmacology, Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
2   Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
› Author Affiliations Funding This study was supported by a grant from the Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran (grant no. 99–3-209–49168).
› Further Information
Also available at
    Permissions and Reprints

Abstract

Background One of the major complications associated with random-pattern skin flaps is distal necrosis. Cannabidiol (CBD) has recently gained much attention as a therapeutic anti-inflammatory agent. We aimed to evaluate the efficacy of CBD on the random-pattern skin flap survival (SFS) in rats and to explore the possible involvement of cannabinoid type-2 (CB2) receptors.

Methods In this controlled experimental study, we randomly divided male Wistar rats into seven study groups (six rats each). We performed a random-pattern skin flap model in each rat following pretreatment with vehicle (control) or multiple doses of CBD (0.3, 1, 5, or 10 mg/kg). In a separate group, we injected SR144528 (2 mg/kg), a high affinity and selective CB2 inverse agonist, before the most effective dose of CBD (1 mg/kg). A sham nontreated and nonoperated group was also included. Seven days after surgeries, the percentage of necrotic area (PNA) was calculated. Histopathological microscopy, CB2 expression level, and interleukin (IL)-1β and tumor necrosis factor (TNF)-α concentrations were also investigated in the flap tissue samples.

Results A PNA of 72.7 ± 7.5 (95% confidence interval [CI]: 64.8–80.6) was captured in the control group. Following treatment with CBD 0.3, 1, 5, and 10 mg/kg, a dose-dependent effect was observed with PNAs of 51.0 ± 10.0 (95% CI: 40.5–61.5; p <0.05), 15.4 ± 5.8 (95% CI: 9.3–21.5; p <0.001), 37.1 ± 10.2 (95% CI: 26.3–47.8; p <0.001), and 46.4 ± 14.0 (95% CI: 31.7–61.1; p <0.001), respectively. Histopathologically, tissues enhanced significantly. Besides, CB2 expression surged remarkably, IL-1β and TNF-α concentrations decreased considerably after treatment with CBD of 1 mg/kg compared with the control (p <0.05 and <0.001, respectively). Administering SR144528 reversed the favorable effects of CBD of 1 mg/kg, both macroscopically and microscopically.

Conclusion Pretreatment with CBD of 1 mg/kg improved SFS considerably in rats and exerted desirable anti-inflammatory effects which were possibly mediated by CB2 receptors.

Keywords

cannabidiol - cannabinoid receptors - skin flap - rat - inflammation

Authorship Confirmation

All the authors have read and approved the final draft.


Ethical Approval

The study protocol was approved by the Ethics in Medical Research Committee of Tehran University of Medical Sciences, Tehran, Iran (ethics approval code: IR.TUMS.MEDICINE.REC.1399.1142).


Data Availability

The datasets generated and analyzed during the current study would be available from the corresponding author on reasonable request.


† Armin Aryannejad and Faezeh Eslami contributed equally to this work as co–first authors.


Supplementary Material



Publication History

Received: 29 November 2021

Accepted: 22 March 2022

Article published online:
11 July 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Luo X, Liu J, Chen H. et al. The feasibility and survival mechanism of a large free flap supported by a novel hybrid perfusion mode. Oral Oncol 2020; 101: 104506
    CrossrefPubMedSearch in Google Scholar
  • 2 Guo K, Ma J, Liang W. Effects of SB202190 on expression levels of IL-6 and NF-κB in flap ischemia-reperfusion injury. Exp Ther Med 2018; 16 (03) 2522-2526
    PubMedSearch in Google Scholar
  • 3 Gürsoy K, Teymur H, Koca G. et al. The effect of astaxanthin on random pattern skin flaps. Ann Plast Surg 2020; 84 (02) 208-215
    CrossrefPubMedSearch in Google Scholar
  • 4 Aryannejad A, Gandominejad A, Tabary M. et al. Protective effect of modafinil on skin flap survival in the experimental random-pattern skin flap model in rats: The role of ATP-sensitive potassium channels and nitric oxide pathway. J Plast Reconstr Aesthet Surg 2021; 74 (06) 1346-1354
    CrossrefPubMedSearch in Google Scholar
  • 5 Chen G, Shen H, Zang L. et al. Protective effect of luteolin on skin ischemia-reperfusion injury through an AKT-dependent mechanism. Int J Mol Med 2018; 42 (06) 3073-3082
    PubMedSearch in Google Scholar
  • 6 Wang L-R, Cai L-Y, Lin D-S, Cao B, Li Z-J. Effect of electroacupuncture at the Zusanli point (Stomach-36) on dorsal random pattern skin flap survival in a rat model. Dermatol Surg 2017; 43 (10) 1213-1220
    CrossrefPubMedSearch in Google Scholar
  • 7 Ma X, Lin Y, Liu Y. et al. Effects of Apigenin treatment on random skin flap survival in rats. Front Pharmacol 2021; 12: 625733
    CrossrefPubMedSearch in Google Scholar
  • 8 Kuo Y-R, Wu W-S, Hsieh Y-L. et al. Extracorporeal shock wave enhanced extended skin flap tissue survival via increase of topical blood perfusion and associated with suppression of tissue pro-inflammation. J Surg Res 2007; 143 (02) 385-392
    CrossrefPubMedSearch in Google Scholar
  • 9 Jiang R, Lin C, Jiang C, Huang Z, Gao W, Lin D. Nobiletin enhances the survival of random pattern skin flaps: Involvement of enhancing angiogenesis and inhibiting oxidative stress. Int Immunopharmacol 2020; 78: 106010
    CrossrefPubMedSearch in Google Scholar
  • 10 de Almeida DL, Devi LA. Diversity of molecular targets and signaling pathways for CBD. Pharmacol Res Perspect 2020; 8 (06) e00682
    CrossrefPubMedSearch in Google Scholar
  • 11 Mechoulam R. Marihuana Chemistry: Recent advances in cannabinoid chemistry open the area to more sophisticated biological research. Science 1970; 168 (3936): 1159-1166
    CrossrefPubMedSearch in Google Scholar
  • 12 Juknat A, Kozela E, Kaushansky N, Mechoulam R, Vogel Z. Anti-inflammatory effects of the cannabidiol derivative dimethylheptyl-cannabidiol - studies in BV-2 microglia and encephalitogenic T cells. J Basic Clin Physiol Pharmacol 2016; 27 (03) 289-296
    CrossrefPubMedSearch in Google Scholar
  • 13 Mori MA, Meyer E, Soares LM, Milani H, Guimarães FS, de Oliveira RMW. Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia. Prog Neuropsychopharmacol Biol Psychiatry 2017; 75: 94-105
    CrossrefPubMedSearch in Google Scholar
  • 14 Lindberg GC, Lim KS, Soliman BG. et al. Biological function following radical photo-polymerization of biomedical polymers and surrounding tissues: Design considerations and cellular risk factors. Appl Phys Rev 2021; 8 (01) 011301
    CrossrefPubMedSearch in Google Scholar
  • 15 Ständer S, Schmelz M, Metze D, Luger T, Rukwied R. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci 2005; 38 (03) 177-188
    CrossrefPubMedSearch in Google Scholar
  • 16 Hajrasouliha AR, Tavakoli S, Ghasemi M. et al. Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur J Pharmacol 2008; 579 (1-3): 246-252
    CrossrefPubMedSearch in Google Scholar
  • 17 Campora L, Miragliotta V, Ricci E. et al. Cannabinoid receptor type 1 and 2 expression in the skin of healthy dogs and dogs with atopic dermatitis. Am J Vet Res 2012; 73 (07) 988-995
    CrossrefPubMedSearch in Google Scholar
  • 18 Benito C, Tolón RM, Pazos MR, Núñez E, Castillo AI, Romero J. Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol 2008; 153 (02) 277-285
    CrossrefPubMedSearch in Google Scholar
  • 19 Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol 2008; 153 (02) 263-270
    CrossrefPubMedSearch in Google Scholar
  • 20 Aryannejad A, Noroozi N, Tavangar SM. et al. Involvement of cannabinoid type 2 (CB2) receptors in the favorable effects of sumatriptan on the random-pattern skin flap survival in rats: a novel potential target. Eur Surg Res 2021
    PubMed
  • 21 Horváth B, Magid L, Mukhopadhyay P. et al. A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury. Br J Pharmacol 2012; 165 (08) 2462-2478
    CrossrefPubMedSearch in Google Scholar
  • 22 Tabary M, Aryannejad A, Noroozi N. et al. Ivermectin increases random-pattern skin flap survival in rats: the novel role of GABAergic system. J Surg Res 2021; 259: 431-441
    CrossrefPubMedSearch in Google Scholar
  • 23 Shokrian Zeini M, Haddadi N-S, Shayan M. et al. Losartan ointment attenuates imiquimod-induced psoriasis-like inflammation. Int Immunopharmacol 2021; 100: 108160
    CrossrefPubMedSearch in Google Scholar
  • 24 Percie du Sert N, Ahluwalia A, Alam S. et al. Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol 2020; 18 (07) e3000411
    CrossrefPubMedSearch in Google Scholar
  • 25 Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol 2004; 143 (02) 247-250
    CrossrefPubMedSearch in Google Scholar
  • 26 Wong H, Cairns BE. Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain. Arch Oral Biol 2019; 104: 33-39
    CrossrefPubMedSearch in Google Scholar
  • 27 Ilyasov AA, Milligan CE, Pharr EP, Howlett AC. The endocannabinoid system and oligodendrocytes in health and disease. Front Neurosci 2018; 12: 733
    CrossrefPubMedSearch in Google Scholar
  • 28 Aryannejad A, Tabary M, Noroozi N. et al. Anti-inflammatory effects of ivermectin in the treatment of acetic acid-induced colitis in rats: involvement of GABAB receptors. Dig Dis Sci 2021
    PubMed
  • 29 Eslami F, Rahimi N, Ostovaneh A. et al. Sumatriptan reduces severity of status epilepticus induced by lithium-pilocarpine through nitrergic transmission and 5-HT1B/D receptors in rats: a pharmacological-based evidence. Fundam Clin Pharmacol 2021; 35 (01) 131-140
    CrossrefPubMedSearch in Google Scholar
  • 30 Dejban P, Eslami F, Rahimi N, Takzare N, Jahansouz M, Dehpour AR. Involvement of nitric oxide pathway in the anti-inflammatory effect of modafinil on indomethacin-, stress-, and ethanol -induced gastric mucosal injury in rat. Eur J Pharmacol 2020; 887: 173579
    CrossrefPubMedSearch in Google Scholar
  • 31 Fujioka M. Surgical reconstruction of radiation injuries. Adv Wound Care (New Rochelle) 2014; 3 (01) 25-37
    CrossrefPubMedSearch in Google Scholar
  • 32 Fichter AM, Ritschl LM, Robitzky LK. et al. Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model. Sci Rep 2016; 6 (01) 35833
    CrossrefPubMedSearch in Google Scholar
  • 33 Zhang Y, Cai X, Shen L. et al. Effects of sanguis draconis on perforator flap survival in rats. Molecules 2016; 21 (10) 1262
    CrossrefPubMedSearch in Google Scholar
  • 34 Myers B. Understanding flap necrosis. Plast Reconstr Surg 1986; 78 (06) 813-814
    CrossrefPubMedSearch in Google Scholar
  • 35 Andrews K, Mowlavi A, Neumeister MW, Russell RC. Ischemia-reperfusion injury: a multicellular phenomenon. Plast Reconstr Surg 2000; 106 (07) 1664-1665
    CrossrefPubMedSearch in Google Scholar
  • 36 McFarlane RM, Deyoung G, Henry RA. The design of a pedicle flap in the rat to study necrosis and its prevention. Plast Reconstr Surg 1965; 35 (02) 177-182
    CrossrefPubMedSearch in Google Scholar
  • 37 Demiröz A, Derebaşınlıoğlu H, Ercan A. et al. Comparison of ischemic preconditioning and systemic piracetam for prevention of ischemia-reperfusion injury in musculocutaneous flaps. J Reconstr Microsurg 2021; 37 (04) 322-335
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Masa I, Casado-Sánchez C, Crespo-Lora V, Ballestín A. Effects of ischemic preconditioning and C1 esterase inhibitor administration following ischemia-reperfusion injury in a rat skin flap model. J Reconstr Microsurg 2021; 37 (03) 242-248
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Cheng L, Chen T, Li H, Feng Z, Li Z, Lin D. Effects of tirofiban on random skin flap survival in rats. J Reconstr Microsurg 2018; 34 (02) 138-144
    Thieme ConnectPubMedSearch in Google Scholar
  • 40 Lin B, Lin Y, Lin D, Cao B. Effects of bezafibrate on the survival of random skin flaps in rats. J Reconstr Microsurg 2016; 32 (05) 395-401
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Kailiang Z, Yihui Z, Dingsheng L, Xianyao T. Effects of muscone on random skin flap survival in rats. J Reconstr Microsurg 2016; 32 (03) 200-207
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Abdelfattah U, Elbanoby T, Kim EN, Park EJ, Suh HP, Hong JPJ. Effect of simvastatin use in free tissue transfer: an experimental study in a rat Epigastric free flap model. J Reconstr Microsurg 2020; 36 (04) 281-288
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Howlett AC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat 2002; 68-69: 619-631
    CrossrefPubMedSearch in Google Scholar
  • 44 Lu H-C, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry 2016; 79 (07) 516-525
    CrossrefPubMedSearch in Google Scholar
  • 45 Zheng J-L, Yu T-S, Li X-N. et al. Cannabinoid receptor type 2 is time-dependently expressed during skin wound healing in mice. Int J Legal Med 2012; 126 (05) 807-814
    CrossrefPubMedSearch in Google Scholar
  • 46 Li SS, Wang LL, Liu M. et al. Cannabinoid CB2 receptors are involved in the regulation of fibrogenesis during skin wound repair in mice. Mol Med Rep 2016; 13 (04) 3441-3450
    CrossrefPubMedSearch in Google Scholar
  • 47 Gao F, Xiang H-C, Li HP. et al. Electroacupuncture inhibits NLRP3 inflammasome activation through CB2 receptors in inflammatory pain. Brain Behav Immun 2018; 67: 91-100
    CrossrefPubMedSearch in Google Scholar
  • 48 Ashton JC, Glass M. The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 2007; 5 (02) 73-80
    CrossrefPubMedSearch in Google Scholar
  • 49 Mukhopadhyay P, Rajesh M, Horváth B. et al. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med 2011; 50 (10) 1368-1381
    CrossrefPubMedSearch in Google Scholar
  • 50 Bayram S, Parlar A, Arslan SO. The curative effect of cannabinoid 2 receptor agonist on functional failure and disruptive inflammation caused by intestinal ischemia and reperfusion. Fundam Clin Pharmacol 2020; 34 (01) 80-90
    CrossrefPubMedSearch in Google Scholar
  • 51 Ignatowska-Jankowska B, Jankowski MM, Swiergiel AH. Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci Lett 2011; 490 (01) 82-84
    CrossrefPubMedSearch in Google Scholar
  • 52 Mammana S, Cavalli E, Gugliandolo A. et al. Could the combination of two non-psychotropic cannabinoids counteract neuroinflammation? Effectiveness of cannabidiol associated with cannabigerol. Medicina (Kaunas) 2019; 55 (11) 747
    CrossrefPubMedSearch in Google Scholar
  • 53 Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants 2019; 9 (01) 21
    CrossrefPubMedSearch in Google Scholar
  • 54 Abbas SY, Nogueira MI, Azmitia EC. Antagonist-induced increase in 5-HT1A-receptor expression in adult rat hippocampus and cortex. Synapse 2007; 61 (07) 531-539
    CrossrefPubMedSearch in Google Scholar
  • 55 Gęgotek A, Atalay S, Wroński A, Markowska A, Skrzydlewska E. Cannabidiol decreases metalloproteinase activity and normalizes angiogenesis factor expression in UVB-irradiated keratinocytes from psoriatic patients. Oxid Med Cell Longev 2021; 2021: 7624389
    CrossrefPubMedSearch in Google Scholar
  • 56 García-Martín A, Garrido-Rodríguez M, Navarrete C. et al. EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis. Biochem Pharmacol 2018; 157: 304-313
    CrossrefPubMedSearch in Google Scholar