The Possible Protective Effects of Ondansetron and Tropisetron on Optic Nerve Crush Injury in Rats

Abstract

Background This study aimed to evaluate the potential neuroprotective effect of cyclosporine – a calcineurin inhibitor–, ondansetron, and tropisetron-5-hydroxytryptamine (serotonin) 3 receptor (5-HT3R) antagonists–, on optic nerve crush (ONC) injury in rats. Moreover, underlying signaling activities of their beneficial neuroprotective effects were studied.

Methods Adult male rats were treated with the intravitreal administration of cyclosporine (1.6 mM), ondansetron (100 nM), and tropisetron (100 nM) immediately after the induction of ONC. Subsequently, on 7th day after surgery, the rats’ retinas were extracted, and the expression of apoptotic regulators (Bax and Bcl-2) and calcineurin were studied by western blot analysis.

Results The induction of ONC injury was associated to higher expression of Bax and calcineurin, while Bcl-2 expression was considerably decreased in these animals. Intravitreal treatment with cyclosporine (1.6 mM), ondansetron (100 nM), and tropisetron (100 nM) significantly attenuated the increased expression of Bax and calcineurin. Moreover, the treatment with these agents resulted in an elevated expression of Bcl-2 in the retina.

Conclusion Our findings indicate that cyclosporine, ondansetron, and tropisetron protect against ONC injury in rats, possibly via the suppression of apoptosis and modulation of calcineurin activity directly and via 5-HT3 receptors. Moreover, immunoblotting showed that tropisetron was more effective as opposed to ondansetron. Further studies are needed to evaluate the precise mechanism behind cyclosporine, ondansetron, and tropisetron activities.

Key words

cyclosporine - ondansetron - tropisetron - optic nerve crush (ONC) - calcineurin - 5-HT3 receptor - apoptosis - rat

Publication History

Received: 22 August 2022

Accepted: 24 October 2022

Article published online:
24 November 2022

• References

• 1 Almasieh M, Wilson AM, Morquette B. et al. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 2012; 31: 152-181 DOI: 10.1016/j.preteyeres.2011.11.002.
• 2 Hayreh SS, Jonas JB. Optic disk and retinal nerve fiber layer damage after transient central retinal artery occlusion: an experimental study in rhesus monkeys. Am J Ophthalmol 2000; 129: 786-795 DOI: 10.1016/s0002-9394(00)00384-6.
• 3 Dieterich DC, Böckers TM, Gundelfinger ED. et al. Screening for differentially expressed genes in the rat inner retina and optic nerve after optic nerve crush. Neuroscience Letters 2002; 317: 29-32 DOI: 10.1016/S0304-3940(01)02418-1.
• 4 Schuettauf F, Rejdak R, Thaler S. et al. Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. Exp Eye Res 2006; 83: 1128-1134 DOI: 10.1016/j.exer.2006.05.021.
• 5 Donahue RJ, Maes ME, Grosser JA. et al. BAX-Depleted Retinal Ganglion Cells Survive and Become Quiescent Following Optic Nerve Damage. Mol Neurobiol 2020; 57: 1070-1084 DOI: 10.1007/s12035-019-01783-7.
• 6 Jensen K, WuWong DJ, Wong S. et al. Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax. Exp Biol Med (Maywood) 2019; 244: 621-629 DOI: 10.1177/1535370219833624.
• 7 Goldblum D, Mittag T. Prospects for relevant glaucoma models with retinal ganglion cell damage in the rodent eye. Vision Research 2002; 42: 471-478 DOI: 10.1016/S0042-6989(01)00194-8.
• 8 Das A, Guyton MK, Matzelle DD. et al. Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis. J Neurosci Res 2008; 86: 2992-3001 DOI: 10.1002/jnr.21737.
• 9 White BC, Sullivan JM, DeGracia DJ. et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000; 179: 1-33 DOI: 10.1016/s0022-510x(00)00386-5.
• 10 Park YJ, Yoo SA, Kim M. et al. The Role of Calcium-Calcineurin-NFAT Signaling Pathway in Health and Autoimmune Diseases. Front Immunol 2020; 11: 195 DOI: 10.3389/fimmu.2020.00195.
• 11 Wang HG, Pathan N, Ethell IM. et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999; 284: 339-343 DOI: 10.1126/science.284.5412.339.
• 12 Brunken WJ, Jin XT. A role for 5HT3 receptors in visual processing in the mammalian retina. Vis Neurosci 1993; 10: 511-522 DOI: 10.1017/s0952523800004727.
• 13 Masson J. Serotonin in retina. Biochimie 2019; 161: 51-55 DOI: 10.1016/j.biochi.2018.11.006.
• 14 Rahimian R, Fakhfouri G, Ejtemaei Mehr S. et al. Tropisetron attenuates amyloid-beta-induced inflammatory and apoptotic responses in rats. Eur J Clin Invest 2013; 43: 1039-1051 DOI: 10.1111/eci.12141.
• 15 Fakhfouri G, Rahimian R, Dyhrfjeld-Johnsen J. et al. 5-HT(3) Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface. Pharmacol Rev 2019; 71: 383-412 DOI: 10.1124/pr.118.015487.
• 16 Sompol P, Norris CM. Ca2+, Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases. Frontiers in Aging Neuroscience 2018; 10 DOI: 10.3389/fnagi.2018.00199.
• 17 Wilde MI, Markham A. Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications. Drugs 1996; 52: 773-794 DOI: 10.2165/00003495-199652050-00010.
• 18 Lee CR, Plosker GL, McTavish D. Tropisetron. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993; 46: 925-943 DOI: 10.2165/00003495-199346050-00009.
• 19 Vega Lde L, Muñoz E, Calzado MA. et al. The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway. Biochem Pharmacol 2005; 70: 369-380 DOI: 10.1016/j.bcp.2005.04.031.
• 20 Oh-i K, Keino H, Goto H. et al. Intravitreal injection of Tacrolimus (FK506) suppresses ongoing experimental autoimmune uveoretinitis in Rats. Br J Ophthalmol 2007; 91: 237-242 DOI: 10.1136/bjo.2006.103168.
• 21 Swartz MM. Tropisetron as a Neuroprotective Agent Against Glutamate-Induced Excitotoxicity: Potential Mechanisms of Neuroprotection (2012). Masters Theses. 97. available at: https://scholarworks.wmich.edu/masters_theses/97
• 22 Swartz MM, Linn DM, Linn CL. Tropisetron as a neuroprotective agent against glutamate-induced excitotoxicity and mechanisms of action. Neuropharmacology 2013; 73: 111-121 DOI: 10.1016/j.neuropharm.2013.05.020.
• 23 Zahavi A, Weiss S, Vieyra M. et al. Ocular Effects of Sildenafil in Naïve Mice and a Mouse Model of Optic Nerve Crush. Investigative Ophthalmology & Visual Science 2019; 60: 1987-1995 DOI: 10.1167/iovs.18-26333.
• 24 Shayan M, Eslami F, Amanlou A. et al. Neuroprotective effects of Lasmiditan and Sumatriptan in an experimental model of post-stroke seizure in mice: Higher effects with concurrent opioid receptors or KATP channels inhibitors. Toxicology and Applied Pharmacology 2022; 454: 116254 DOI: 10.1016/j.taap.2022.116254.
• 25 Aryannejad A, Eslami F, Shayan M. et al. Cannabidiol Improves Random-Pattern Skin Flap Survival in Rats: Involvement of Cannabinoid Type-2 Receptors. J Reconstr Microsurg. 2022
• 26 Yazdani I, Majdani R, Ghasemnejad-berenji M. et al. Beneficial effects of Cyclosporine A in combination with Nortriptyline on germ cell-specific apoptosis, oxidative stress and epididymal sperm qualities following testicular ischemia/reperfusion in rats: a comparative study. BMC Pharmacology and Toxicology 2022; 23: 59 DOI: 10.1186/s40360-022-00601-6.
• 27 Moheimani HR, Amiriani T, Alizadeh AM. et al. Preconditioning and anti-apoptotic effects of Metformin and Cyclosporine-A in an isolated bile duct-ligated rat heart. European Journal of Pharmacology 2021; 893: 173807 DOI: 10.1016/j.ejphar.2020.173807.
• 28 Rashki A, Mumtaz F, Jazayeri F. et al. Cyclosporin A attenuating morphine tolerance through inhibiting NO/ERK signaling pathway in human glioblastoma cell line: the involvement of calcineurin. Excli j 2018; 17: 1137-1151 DOI: 10.17179/excli2018-1693.
• 29 Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999; 246: 339-346 DOI: 10.1007/s004150050360.
• 30 Kim SY, Shim MS, Kim KY. et al. Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis 2014; 5: e1105 DOI: 10.1038/cddis.2014.80.
• 31 Schultheiss M, Schnichels S, Mlynczak T. et al. Cyclosporine a protects RGC-5 cells from excitotoxic cell death. J Glaucoma 2014; 23: 219-224 DOI: 10.1097/ijg.0000000000000040.
• 32 Haj-Mirzaian A, Kordjazy N, Amiri S. et al. Involvement of nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tropisetron and ondansetron in mice forced swimming test and tail suspension test. European Journal of Pharmacology 2016; 780: 71-81 DOI: 10.1016/j.ejphar.2016.03.034.
• 33 Amini-Khoei H, Momeny M, Abdollahi A. et al. Tropisetron suppresses colitis-associated cancer in a mouse model in the remission stage. International Immunopharmacology 2016; 36: 9-16 DOI: 10.1016/j.intimp.2016.04.014.
• 34 Barzegar-Fallah A, Alimoradi H, Asadi F. et al. Tropisetron ameliorates early diabetic nephropathy in streptozotocin-induced diabetic rats. Clinical and Experimental Pharmacology and Physiology 2015; 42: 361-368 DOI: 10.1111/1440-1681.12373.
• 35 Barzegar-Fallah A, Alimoradi H, Mehrzadi S. et al. The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity. NeuroToxicology 2014; 41: 1-8 DOI: 10.1016/j.neuro.2013.12.002.
• 36 Shiee MR, Kia EB, Zahabiun F. et al. In vitro effects of tropisetron and granisetron against Echinococcus granulosus (s.s.) protoscoleces by involvement of calcineurin and calmodulin. Parasites & Vectors 2021; 14: 197 DOI: 10.1186/s13071-021-04691-9.
• 37 Lee HJ, Ban JY, Seong YH. Blockade of 5-HT(3) receptor with MDL7222 and Y25130 reduces hydrogen peroxide-induced neurotoxicity in cultured rat cortical cells. Life Sci 2005; 78: 294-300 DOI: 10.1016/j.lfs.2005.04.043.
• 38 Papke RL, Schiff HC, Jack BA. et al. Molecular dissection of tropisetron, an alpha7 nicotinic acetylcholine receptor-selective partial agonist. Neurosci Lett 2005; 378: 140-144 DOI: 10.1016/j.neulet.2004.12.025.