Analgesic and Anti-Inflammatory Effects of the Synthetic Neurosteroid Analogue BNN27 During CFA-Induced Hyperalgesia

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2021 Sep 28

PMID 34572370

Citations 5

Authors

Smaragda Poulaki

Olga Rassouli

George Liapakis

Achille Gravanis

Maria Venihaki

Affiliations

Soon will be listed here.

Abstract

Dehydroepiandrosterone (DHEA), an adrenal and neurosteroid hormone with strong neuroprotective and immunomodulatory properties, and ligand for all high-affinity neurotrophin tyrosine kinase receptors (Trk), also exerts important effects on hyperalgesia. Its synthetic, 17-spiro-epoxy analogue, BNN27, cannot be converted to estrogen or androgen as DHEA; it is a specific agonist of TrkA, the receptor of pain regulator Nerve Growth Factor (NGF), and it conserves the immunomodulatory properties of DHEA. Our study aimed to evaluate the anti-nociceptive and anti-inflammatory properties of BNN27 during Complete Freund's Adjuvant (CFA)-induced inflammatory hyperalgesia in mice. Hyperalgesia was evaluated using the Hargreaves test. Inflammatory markers such as cytokines, NGF and opioids were measured, additionally to corticosterone and the protein kinase B (AKT) signaling pathway. We showed for the first time that treatment with BNN27 reversed hyperalgesia produced by CFA. The effect of BNN27 involved the inhibition of NGF in the dorsal root ganglia (DRG) and the increased synthesis of opioid peptides and their receptors in the inflamed paw. We also found alterations in the cytokine levels as well as in the phosphorylation of AKT2. Our findings strongly support that BNN27 represents a lead molecule for the development of analgesic and anti-inflammatory compounds with potential therapeutic applications in inflammatory hyperalgesia.

Citing Articles

The role of androgens in migraine pathophysiology.

Dourson A, Darken R, Baranski T, Gereau R, Ross W, Nahman-Averbuch H Neurobiol Pain. 2024; 16:100171.

PMID: 39498299 PMC: 11532460. DOI: 10.1016/j.ynpai.2024.100171.

Corticotropin-releasing hormone deficiency results in impaired analgesic response during CFA-induced inflammation.

Karagianni E, Rassouli O, Poulaki S, Dermitzaki E, Liapakis G, Margioris A Hormones (Athens). 2024; 23(3):535-545.

PMID: 38740711 PMC: 11436445. DOI: 10.1007/s42000-024-00565-8.

mRNA expression of CRF family members in urothelial bladder cancer.

Mavridis C, Venihaki M, Dermitzaki E, Deiktakis M, Liapakis G, Mamoulakis C Oncol Lett. 2023; 27(1):13.

PMID: 38034485 PMC: 10688464. DOI: 10.3892/ol.2023.14145.

Bone marrow-derived mesenchymal stem cells attenuate complete Freund's adjuvant-induced inflammatory pain by inhibiting the expression of P2X3.

Deng Y, Yuan D, Deng Z, Liang J, Zhang Z, Hei Z Cell Prolif. 2023; 56(10):e13461.

PMID: 36974350 PMC: 10542618. DOI: 10.1111/cpr.13461.

Optogenetic modulation of electroacupuncture analgesia in a mouse inflammatory pain model.

Hsiao I, Liao H, Lin Y Sci Rep. 2022; 12(1):9067.

PMID: 35641558 PMC: 9156770. DOI: 10.1038/s41598-022-12771-8.

References

Charalampopoulos I, Tsatsanis C, Dermitzaki E, Alexaki V, Castanas E, Margioris A . Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins. Proc Natl Acad Sci U S A. 2004; 101(21):8209-14. PMC: 419582. DOI: 10.1073/pnas.0306631101. View

Cunha F, Poole S, Lorenzetti B, Ferreira S . The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol. 1992; 107(3):660-4. PMC: 1907751. DOI: 10.1111/j.1476-5381.1992.tb14503.x. View

Alves V, Basso P, Nardini V, Silva A, Lazo Chica J, de Barros Cardoso C . Dehydroepiandrosterone (DHEA) restrains intestinal inflammation by rendering leukocytes hyporesponsive and balancing colitogenic inflammatory responses. Immunobiology. 2016; 221(9):934-43. DOI: 10.1016/j.imbio.2016.05.013. View

Hargreaves K, Dubner R, Brown F, Flores C, Joris J . A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988; 32(1):77-88. DOI: 10.1016/0304-3959(88)90026-7. View

Pediaditakis I, Efstathopoulos P, Prousis K, Zervou M, Arevalo J, Alexaki V . Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation. Neuropharmacology. 2016; 111:266-282. DOI: 10.1016/j.neuropharm.2016.09.007. View

Iban-Arias R, Lisa S, Mastrodimou N, Kokona D, Koulakis E, Iordanidou P . The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes. Diabetes. 2017; 67(2):321-333. DOI: 10.2337/db17-0391. View

Lazaridis I, Charalampopoulos I, Alexaki V, Avlonitis N, Pediaditakis I, Efstathopoulos P . Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis. PLoS Biol. 2011; 9(4):e1001051. PMC: 3082517. DOI: 10.1371/journal.pbio.1001051. View

Rittner H, Labuz D, Schaefer M, Mousa S, Schulz S, Schafer M . Pain control by CXCR2 ligands through Ca2+-regulated release of opioid peptides from polymorphonuclear cells. FASEB J. 2006; 20(14):2627-9. DOI: 10.1096/fj.06-6077fje. View

Rueff A, Mendell L . Nerve growth factor NT-5 induce increased thermal sensitivity of cutaneous nociceptors in vitro. J Neurophysiol. 1996; 76(5):3593-6. DOI: 10.1152/jn.1996.76.5.3593. View

10.

Hassan A, Ableitner A, Stein C, Herz A . Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience. 1993; 55(1):185-95. DOI: 10.1016/0306-4522(93)90465-r. View

11.

Machelska H . Functional evidence of pain control by the immune system. Adv Exp Med Biol. 2003; 521:88-97. View

12.

Woolf C . What is this thing called pain?. J Clin Invest. 2010; 120(11):3742-4. PMC: 2965006. DOI: 10.1172/JCI45178. View

13.

Poisbeau P, Patte-Mensah C, Keller A, Barrot M, Breton J, Luis-Delgado O . Inflammatory pain upregulates spinal inhibition via endogenous neurosteroid production. J Neurosci. 2005; 25(50):11768-76. PMC: 6726017. DOI: 10.1523/JNEUROSCI.3841-05.2005. View

14.

Leick M, Azcutia V, Newton G, Luscinskas F . Leukocyte recruitment in inflammation: basic concepts and new mechanistic insights based on new models and microscopic imaging technologies. Cell Tissue Res. 2014; 355(3):647-56. PMC: 3994997. DOI: 10.1007/s00441-014-1809-9. View

15.

Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris A, Charalampopoulos I . Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors. Endocrinology. 2014; 156(1):16-23. DOI: 10.1210/en.2014-1596. View

16.

Contet C, Kieffer B, Befort K . Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol. 2004; 14(3):370-8. DOI: 10.1016/j.conb.2004.05.005. View

17.

Zhang Y, Chen Y, Zhao Z . Resiniferatoxin reversibly blocks adjuvant-induced thermal hyperalgesia in the rat. Eur J Pharmacol. 2003; 481(2-3):301-4. DOI: 10.1016/j.ejphar.2003.09.053. View

18.

Uceyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C . Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum. 2006; 54(8):2656-64. DOI: 10.1002/art.22026. View

19.

Li C, Deng T, Shang Z, Wang D, Xiao Y . Blocking TRPA1 and TNF-α Signal Improves Bortezomib-Induced Neuropathic Pain. Cell Physiol Biochem. 2018; 51(5):2098-2110. DOI: 10.1159/000495828. View

20.

Gregory N, Harris A, Robinson C, Dougherty P, Fuchs P, Sluka K . An overview of animal models of pain: disease models and outcome measures. J Pain. 2013; 14(11):1255-69. PMC: 3818391. DOI: 10.1016/j.jpain.2013.06.008. View