Abstract
Enteric neuropathy underlies long-term gastrointestinal (GI) dysfunction associated with several pathological conditions. Our previous studies have demonstrated that structural and functional changes in the enteric nervous system (ENS) result in persistent alterations of intestinal functions long after the acute insult. These changes lead to aberrant immune response and chronic dysregulation of the epithelial barrier. Damage to the ENS is prognostic of disease progression and plays an important role in the recurrence of clinical manifestations. This suggests that the ENS is a viable therapeutic target to alleviate chronic intestinal dysfunction. Our recent studies in preclinical animal models have progressed into the development of novel therapeutic strategies for the treatment of enteric neuropathy in various chronic GI disorders. We have tested the anti-inflammatory and neuroprotective efficacy of novel compounds targeting specific molecular pathways. Ex vivo studies in human tissues freshly collected after resection surgeries provide an understanding of the molecular mechanisms involved in enteric neuropathy. In vivo treatments in animal models provide data on the efficacy and the mechanisms of actions of the novel compounds and their combinations with clinically used therapies. These novel findings provide avenues for the development of safe, cost-effective, and highly efficacious treatments of GI disorders.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Axelrad JE, Lichtiger S, Yajnik V (2016) Inflammatory bowel disease and cancer: the role of inflammation, immunosuppression, and cancer treatment. World J Gastroenterol 22:4794–4801
Brenna Ø, Furnes MW, Drozdov I, van Beelen Granlund A, Flatberg A, Sandvik AK, Zwiggelaar RTM, Mårvik R, Nordrum IS, Kidd M, Gustafsson BI (2013) Relevance of TNBS-colitis in rats: a methodological study with endoscopic, histologic and Transcriptomic [corrected] characterization and correlation to IBD. PLoS One 8:e54543
Carbone SE, Jovanovska V, Brookes SJ, Nurgali K (2016) Electrophysiological and morphological changes in colonic myenteric neurons from chemotherapy-treated patients: a pilot study. Neurogastroenterol Motil 28:975–984
Eri RD, Adams RJ, Tran TV, Tong H, Das I, Roche DK, Oancea I, Png CW, Jeffery PL, Radford-Smith GL, Cook MC, Florin TH, McGuckin MA (2011) An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity. Mucosal Immunol 4:354–364
Escalante J, McQuade RM, Stojanovska V, Nurgali K (2017) Impact of chemotherapy on gastrointestinal functions and the enteric nervous system. Maturitas 105:23–29
Fang K, Bruce M, Pattillo CB, Zhang S, Stone R 2nd, Clifford J, Kevil CG (2011) Temporal genomewide expression profiling of DSS colitis reveals novel inflammatory and angiogenesis genes similar to ulcerative colitis. Physiol Genomics 43:43–56
Fehrenbacher JC, Guo C, Kelley MR, Vasko MR (2017) DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1. Neuroscience 366:23–35
Heazlewood CK, Cook MC, Eri R, Price GR, Tauro SB, Taupin D, Thornton DJ, Png CW, Crockford TL, Cornall RJ, Adams R, Kato M, Nelms KA, Hong NA, Florin TH, Goodnow CC, McGuckin MA (2008) Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 5:e54
Holgersen K, Kutlu B, Fox B, Serikawa K, Lord J, Hansen AK, Holm TL (2015) High-resolution gene expression profiling using RNA sequencing in patients with inflammatory bowel disease and in mouse models of colitis. J Crohns Colitis 9:492–506
Kelley MR, Wikel JH, Guo C, Pollok KE, Bailey BJ, Wireman R, Fishel ML, Vasko MR (2016) Identification and characterization of new chemical entities targeting apurinic/apyrimidinic endonuclease 1 for the prevention of chemotherapy-induced peripheral neuropathy. J Pharmacol Exp Ther 359:300–309
Lam G, Apostolopoulos V, Zulli A, Nurgali K (2015) NADPH oxidases and inflammatory bowel disease. Curr Med Chem 22:2100–2109
Li G, Liu W, Frenz D (2006) Cisplatin ototoxicity to the rat inner ear: a role for HMG1 and iNOS. Neurotoxicology 27:22–30
Luo P, Liu D, Li J (2020) Pharmacological perspective: glycyrrhizin may be an efficacious therapeutic agent for COVID-19. Int J Antimicrob Agents 55:105995
McQuade RM, Carbone SE, Stojanovska V, Rahman A, Gwynne RM, Robinson AM, Goodman CA, Bornstein JC, Nurgali K (2016) Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice. Br J Pharmacol 173:3502–3521
McQuade RM, Stojanovska V, Abalo R, Bornstein JC, Nurgali K (2016) Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments. Front Pharmacol 7:414
McQuade RM, Stojanovska V, Donald E, Abalo R, Bornstein JC, Nurgali K (2016) Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil. Neurogastroenterol Motil 28:1861–1875
McQuade RM, Stojanovska V, Bornstein JC, Nurgali K (2017) Colorectal cancer chemotherapy: the evolution of treatment and new approaches. Curr Med Chem 24:1537–1557
McQuade RM, Stojanovska V, Donald EL, Rahman AA, Campelj DG, Abalo R, Rybalka E, Bornstein JC, Nurgali K (2017) Irinotecan-induced gastrointestinal dysfunction is associated with enteric neuropathy, but increased numbers of cholinergic myenteric neurons. Front Physiol 8:391
Murck H (2020) Symptomatic protective action of glycyrrhizin (licorice) in COVID-19 infection? Front Immunol 11:1239
Paudel YN, Shaikh MF, Chakraborti A, Kumari Y, Aledo-Serrano Á, Aleksovska K, Alvim MKM, Othman I (2018) HMGB1: a common biomarker and potential target for TBI, neuroinflammation, epilepsy, and cognitive dysfunction. Front Neurosci 12:628
Rahman AA, Robinson AM, Jovanovska V, Eri R, Nurgali K (2015) Alterations in the distal colon innervation in Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res 362:497–512
Rahman AA, Robinson AM, Brookes SJH, Eri R, Nurgali K (2016) Rectal prolapse in Winnie mice with spontaneous chronic colitis: changes in intrinsic and extrinsic innervation of the rectum. Cell Tissue Res 366:285–299
Robinson AM, Gondalia SV, Karpe AV, Eri R, Beale DJ, Morrison PD, Palombo EA, Nurgali K (2016) Fecal microbiota and metabolome in a mouse model of spontaneous chronic colitis: relevance to human inflammatory bowel disease. Inflamm Bowel Dis 22:2767–2787
Robinson AM, Rahman AA, Carbone SE, Randall-Demllo S, Filippone R, Bornstein JC, Eri R, Nurgali K (2017) Alterations of colonic function in the Winnie mouse model of spontaneous chronic colitis. Am J Physiol Gastrointest Liver Physiol 312:G85–g102
Sahakian L, Filippone RT, Stavely R, Robinson AM, Yan XS, Abalo R, Eri R, Bornstein JC, Kelley MR, Nurgali K (2021) Inhibition of APE1/Ref-1 redox signaling alleviates intestinal dysfunction and damage to myenteric neurons in a mouse model of spontaneous chronic colitis. Inflamm Bowel Dis 27:388–406
Shah F, Logsdon D, Messmann RA, Fehrenbacher JC, Fishel ML, Kelley MR (2017) Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol 1:19
Shahda S, Lakhani NJ, O’Neil B, Rasco DW, Wan J, Mosley AL, Liu H, Kelley MR, Messmann RA (2019) A phase I study of the APE1 protein inhibitor APX3330 in patients with advanced solid tumors. J Clin Oncol 37:3097–3097
Stojanovska V, McQuade RM, Fraser S, Prakash M, Gondalia S, Stavely R, Palombo E, Apostolopoulos V, Sakkal S, Nurgali K (2018) Oxaliplatin-induced changes in microbiota, TLR4+ cells and enhanced HMGB1 expression in the murine colon. PLoS One 13:e0198359
Su D, Delaplane S, Luo M, Rempel DL, Vu B, Kelley MR, Gross ML, Georgiadis MM (2011) Interactions of apurinic/apyrimidinic endonuclease with a redox inhibitor: evidence for an alternate conformation of the enzyme. Biochemistry 50:82–92
Sylvester CL, Anderson PH, Stringer AM (2020) New therapeutic strategies for combatting gastrointestinal toxicity. Curr Opin Support Palliat Care 14:142–152
Ugrinova I, Pasheva E (2017) HMGB1 protein: a therapeutic target inside and outside the cell. Adv Protein Chem Struct Biol 107:37–76
Vasko MR, Guo C, Thompson EL, Kelley MR (2011) The repair function of the multifunctional DNA repair/redox protein APE1 is neuroprotective after ionizing radiation. DNA Repair (Amst) 10:942–952
Wafai L, Taher M, Jovanovska V, Bornstein JC, Dass CR, Nurgali K (2013) Effects of oxaliplatin on mouse myenteric neurons and colonic motility. Front Neurosci 7:30
Acknowledgements
This work was supported by the Institute for Health and Sport, Victoria University. R.T.F. is supported by the Australian NHMRC Project grant GNT1158952 to JCB, and KN. M.R.K. was supported by grants from the National Institute of Health CA167291, CA205166, CA231267, HL140961 and DOD grant W81XWH1910217. He is also supported by the Riley Children’s Foundation and the Tom Wood Lexus Foundation.
Conflict of Interest Statement
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this paper
Cite this paper
Sahakian, L. et al. (2022). Molecular Targets to Alleviate Enteric Neuropathy and Gastrointestinal Dysfunction. In: Spencer, N.J., Costa, M., Brierley, S.M. (eds) The Enteric Nervous System II. Advances in Experimental Medicine and Biology, vol 1383. Springer, Cham. https://doi.org/10.1007/978-3-031-05843-1_21
Download citation
DOI: https://doi.org/10.1007/978-3-031-05843-1_21
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-05842-4
Online ISBN: 978-3-031-05843-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)