Protective effect of abscisic Acid in a spinal cord injury model mediated by suppressed neuroinflammation

Document Type : Research Article

Authors

1 Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran.

2 Food, Hygiene and Public Health Department, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran.

3 Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran.

Abstract

Abscisic acid (ABA) is a phytohormone with modulatory roles. The anti-inflammatory effect of this hormone has been reported on different animal tissues. Immediately after spinal cord injury (SCI), neuroinflammation causes neuropathic pain and locomotor impairments. We investigated the impacts of ABA as an anti-inflammatory substance on an acute SCI model. The weight-drop contusion injury model was applied for inducing SCI in rats. The solvent, ABA (10, 15 μg/rat, IT), and MP (30 mg/kg, IP) were administered after injury. For the evaluation of proinflammatory gene expression, a real-time polymerase chain reaction was applied for the two inflammation markers tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, the tail-flick and Basso, Beattie, Bresnahan (BBB) tests were performed to determine the effects of ABA on the neuropathic pain and locomotor function in the chronic phase of injury, respectively. Our data showed that ABA reduced the gene expression of TNF-α and IL-1β in the spinal cord of injured rats. It also increased the latency response to nociceptive thermal stimuli and improved locomotor function. Our findings showed the anti-inflammatory impacts of ABA in improving neuropathic pain and locomotor functional recovery after SCI.

Keywords


1.     James ND, McMahon SB, Field-Fote EC, Bradbury EJ. Neuromodulation in the restoration of function after spinal cord injury. Lancet Neurol. 2018;17(10):905–17. 
2.     National Spinal Cord Injury Statistical Center. Spinal cord injury facts and figures at a glance. J Spinal Cord Med. 2020;36(1):1–2. 
3.     Profyris C, Cheema SS, Zang D, Azari MF, Boyle K, Petratos S. Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Dis. 2004;15(3):415–36. 
4.     Brommer B, Engel O, Kopp MA, Watzlawick R, Müller S, Prüss H, et al. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain. 2016;139(3):692–707. 
5.     Huebner EA, Strittmatter SM. Axon regeneration in the peripheral and central nervous systems. Cell Biol axon. 2009;305–60. 
6.     Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms. Front Neurol. 2019;10:282-307. 
7.     Kaynar MY, Hanci M, Kafadar A, Gümüştaş K, Belce A, Çiplak N. The effect of duration of compression on lipid peroxidation after experimental spinal cord injury. Neurosurg Rev. 1998;21(2):117–20. 
8.     Zelenka M, Schäfers M, Sommer C. Intraneural injection of interleukin-1β and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain. 2005;116(3):257–63. 
9.     Myers RR, Campana WM, Shubayev VI. The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets. Drug Discov Today. 2006;11(1–2):8–20. 
10.     Schnell L, Fearn S, Klassen H, Schwab ME, Perry VH. Acute inflammatory responses to mechanical lesions in the CNS: differences between brain and spinal cord. Eur J Neurosci. 1999;11(10):3648–58. 
11.     Rust R, Kaiser J. Insights into the dual role of inflammation after spinal cord injury. J Neurosci. 2017;37(18):4658–60. 
12.     Nesic O, Xu G-Y, McAdoo D, Westlund High K, Hulsebosch C, Perez-Polo R. IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J Neurotrauma. 2001;18(9):947–56. 
13.     Genovese T, Mazzon E, Crisafulli C, Di Paola R, Muià C, Esposito E, et al. TNF-α blockage in a mouse model of SCI: evidence for improved outcome. Shock. 2008;29(1):32–41. 
14.     Fehlings MG, Wilson JR, Tetreault LA, Aarabi B, Anderson P, Arnold PM, et al. A clinical practice guideline for the management of patients with acute spinal cord injury: recommendations on the use of methylprednisolone sodium succinate. Glob spine J. 2017;7(3_suppl):203S-211S. 
15.     Sultan I, Lamba N, Liew A, Doung P, Tewarie I, Amamoo JJ, et al. The safety and efficacy of steroid treatment for acute spinal cord injury: A Systematic Review and meta-analysis. Heliyon. 2020;6(2):e03414. 
16.     Daliu P, Annunziata G, Tenore GC, Santini A. Abscisic acid identification in Okra, Abelmoschus esculentus L.(Moench): Perspective nutraceutical use for the treatment of diabetes. Nat Prod Res. 2020;34(1):3–9. 
17.     Rafiepour K, Esmaeili-Mahani S, Salehzadeh A, Sheibani V. Phytohormone abscisic acid protects human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced neurotoxicity through its antioxidant and antiapoptotic properties. Rejuvenation Res. 2019;22(2):99–108. 
18.     Baliño, P., Gómez-Cadenas, A., López-Malo, D., Romero, F. J., & Muriach M. Is there a role for abscisic acid, a proven anti-inflammatory agent, in the treatment of ischemic retinopathies? Antioxidants. 2019;8(4):104-115.
19.     Jones CS. UBIQUITOUS PHYTOHORMONE ABSCISIC ACID IN PHYTOREMEDIATION AND BIOMEDICAL APPLICATIONS: AN OVERVIEW. Bhumi Publishing; 2020. 
20.     Khorasani A, Abbasnejad M, Esmaeili-Mahani S. Phytohormone abscisic acid ameliorates cognitive impairments in streptozotocin-induced rat model of Alzheimer’s disease through PPARβ/δ and PKA signaling. Int J Neurosci. 2019;129(11):1053–65. 
21.     Guri AJ, Evans NP, Hontecillas R, Bassaganya-Riera J. T cell PPARγ is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD. J Nutr Biochem. 2011;22(9):812–9. 
22.     Li HH, Hao RL, Wu SS, Guo PC, Chen CJ, Pan LP, et al. Occurrence, function and potential medicinal applications of the phytohormone abscisic acid in animals and humans. Biochemical Pharmacology. 2011. 
23.     Hellenbrand DJ, Quinn CM, Piper ZJ, Morehouse CN, Fixel JA, Hanna AS. Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration. J Neuroinflammation. 2021;18(1):1–16. 
24.     Pineau I, Lacroix S. Proinflammatory cytokine synthesis in the injured mouse spinal cord: Multiphasic expression pattern and identification of the cell types involved. J Comp Neurol. 2007;500(2):267-85.
25.     Sánchez-Sarasúa S, Moustafa S, García-Avilés Á, López-Climent MF, Gómez-Cadenas A, Olucha-Bordonau FE, et al. The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation. Nutr Metab. 2016;13(1):1-1.
26.     Leber A, Hontecillas R, Tubau-Juni N, Zoccoli-Rodriguez V, Goodpaster B, Bassaganya-Riera J. Abscisic acid enriched fig extract promotes insulin sensitivity by decreasing systemic inflammation and activating LANCL2 in skeletal muscle. Sci Rep. 2020;10(1):1–9. 
27.     Chen X, Ding C, Liu W, Liu X, Zhao Y, Zheng Y, et al. Abscisic acid ameliorates oxidative stress, inflammation, and apoptosis in thioacetamide-induced hepatic fibrosis by regulating the NF-кB signaling pathway in mice. Eur J Pharmacol. 2021;891:173652. 
28.     Calvo M, Dawes JM, Bennett DLH. The role of the immune system in the generation of neuropathic pain. lancet Neurol. 2012;11(7):629–42. 
29.     Mollashahi M, Abbasnejad M, Esmaeili-Mahani S. Phytohormone abscisic acid elicits antinociceptive effects in rats through the activation of opioid and peroxisome proliferator-activated receptors β/δ. Eur J Pharmacol. 2018;832:75–80. 
30.     Guri AJ, Hontecillas R, Si H, Liu D, Bassaganya-Riera J. Dietary abscisic acid ameliorates glucose tolerance and obesity-related inflammation in db/db mice fed high-fat diets. Clin Nutr. 2007;26(1):107-16.
31.     Cullingford TE, Bhakoo K, Peuchen S, Dolphin CT, Patel R, Clark JB. Distribution of mRNAs Encoding the Peroxisome Proliferator‐Activated Receptor α, β, and γ and the Retinoid X Receptor α, β, and γ in Rat Central Nervous System. J Neurochem. 1998;70(4):1366–75. 
32.     Warden A, Truitt J, Merriman M, Ponomareva O, Jameson K, Ferguson LB, et al. Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep. 2016;6:27618. 
33.     Kim Y, Park K-W, Oh J, Kim J, Yoon YW. Alterations in protein expression patterns of spinal peroxisome proliferator-activated receptors after spinal cord injury. Neurol Res. 2019;41(10):883–92. 
34.     Okine BN, Gaspar JC, Finn DP. PPARs and pain. Br J Pharmacol. 2019;176(10):1421–42. 
35.     Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W. The PPARα–leukotriene B 4 pathway to inflammation control. Nature. 1996;384(6604):39–43. 
36.     Park S-W, Yi J-H, Miranpuri G, Satriotomo I, Bowen K, Resnick DK, et al. Thiazolidinedione class of peroxisome proliferator-activated receptor γ agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. J Pharmacol Exp Ther. 2007;320(3):1002–12. 
37.     Li X, Du J, Xu S, Lin X, Ling Z. Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury. J Int Med Res. 2013;41(1):153–61. 
38.     Zhang Q, Hu W, Meng B, Tang T. PPAR γ agonist rosiglitazone is neuroprotective after traumatic spinal cord injury via anti-inflammatory in adult rats. Neurol Res. 2010;32(8):852–9. 
39.     Landreth GE, Heneka MT. Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheimer’s disease. Neurobiol Aging. 2001;22(6):937–44. 
40.     Bernardo A, Minghetti L. PPAR-γ agonists as regulators of microglial activation and brain inflammation. Curr Pharm Des. 2006;12(1):93–109. 
41.     Bassaganya-Riera J, Guri AJ, Lu P, Climent M, Carbo A, Sobral BW, et al. Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor γ. Journal of Biological Chemistry. 2011;286(4):2504-16.
42.     Mollashahi M, Abbasnejad M, Esmaeili-Mahani S. Spinal protein kinase A and phosphorylated extracellular signal-regulated kinase signaling are involved in the antinociceptive effect of phytohormone abscisic acid in rats. Arq Neuropsiquiatr. 2020;78:21-7. 
43.     Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. Animal research: reporting in vivo experiments—the ARRIVE guidelines. Vol. 31, Journal of Cerebral Blood Flow & Metabolism. SAGE Publications Sage UK: London, England; 2011. p. 991–3. 
44.     Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983;16(2):109–10. 
45.     Verma R, Virdi JK, Singh N, Jaggi AS. Animals models of spinal cord contusion injury. Korean J Pain. 2019;32(1):12-21. 
46.     Akbari M, Khaksari M, Rezaeezadeh-Roukerd M, Mirzaee M, Nazari-Robati M. Effect of chondroitinase ABC on inflammatory and oxidative response following spinal cord injury. Iran J Basic Med Sci. 2017;20(7):807–13. 
47.     Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101-8.
48.     Schneider L, Reichert E, Faulkner J, Reichert B, Sonnen J, Hawryluk GWJ. CNS inflammation and neurodegeneration: sequelae of peripheral inoculation with spinal cord tissue in rat. J Neurosurg. 2019;132(3):933–44. 
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Volume 14, Issue 4 - Serial Number 29
This issue XML file is being prepared.
November 2022
Pages 42-51
  • Receive Date: 12 May 2022
  • Revise Date: 27 August 2022
  • Accept Date: 03 September 2022
  • First Publish Date: 10 September 2022