Abscisic Acid Regulates Immune-inflammatory Responses to Induce Neuroprotection in Spinal Cord Injury: Insights from Gene Expression and Network Analysis
,
Abstract
Spinal cord injuries (SCI) lead to complex primary and secondary damage that disrupts neural function. Current treatments are often insufficient and unable to fully repair spinal cord injuries, highlighting the urgent need for new medicines and innovative therapies.
This study aimed to evaluate the therapeutic potential of abscisic acid (ABA) in SCI by examining its effects on immune-inflammatory genes’ expression in rats. This phytohormone possesses anti-inflammatory and neuroprotective properties, rendering it a potential agent for reducing secondary damage following spinal cord injury. Additionally, we performed protein-protein interaction (PPI), pathway enrichment, functional annotation, and gene ontology (GO) analyses to gain a comprehensive understanding of the functions of the affected genes.
Based on the results, SCI led to changes in the expression of immune/inflammation-related genes in rats. However, the administration of ABA alleviated the effects. ABA downregulated proinflammatory genes (IL-6, IL-1β, MCP, TLR2, TLR4) and neural signaling components (NMDA, AMPA, NK1R), while upregulating adrenergic receptors (ADRA1A, ADRB1) and a gamma-aminobutyric acid receptor (AGBRA2). PPI analysis identified FOS, IL-1β, IL-6, MMP9, and TLR4 as crucial nodes in the network, exhibiting the highest degree of interaction. Functional analyses revealed potential impacts on cellular responses, metabolic processes, and synapse-associated extracellular matrix components. Notably, these genes were enriched in inflammatory signaling pathways according to KEGG analysis.
These findings suggest that ABA has a significant modulatory effect on gene expression following SCI, particularly in reducing inflammation and immune responses, thereby highlighting its potential as a novel therapeutic agent for SCI.
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2. Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A, et al. Traumatic spinal cord injury. Nat Rev Dis Prim. 2017;3:17018.
3. Anjum A, Yazid MD, Fauzi Daud M, Idris J, Ng AMH, Selvi Naicker A, et al. Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. 2020; 21(20):1–35.
4. Karsy M, Hawryluk G. Modern Medical Management of Spinal Cord Injury. Curr Neurol Neurosci Rep. 2019;19: 1–7.
5. Evaniew N, Noonan VK, Fallah N, Kwon BK, Rivers CS, Ahn H, et al. Methylprednisolone for the Treatment of Patients with Acute Spinal Cord Injuries: A Propensity Score-Matched Cohort Study from a Canadian Multi-Center Spinal Cord Injury Registry. J Neurotrauma 2015;32:1674–83.
6. Geisler FH, Moghaddamjou A, Wilson JRF. Methylprednisolone in acute traumatic spinal cord injury: Case-matched outcomes from the NASCIS2 and Sygen historical spinal cord injury studies with contemporary statistical analysis. J Neurosurg Spine. 2023;38(12):595–606.
7. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013; 9(1):30.
8. Liu Z, Yang Y, He L. High-dose methylprednisolone for acute traumatic spinal cord injury: A meta-analysis. Neurology. 2019;93:E841–E850.
9. Khorrami S, Abdollahi Z, Eshaghi G, Khosravi A, Bidram E, Zarrabi A. An Improved Method for Fabrication of Ag-GO Nanocomposite with Controlled Anti-Cancer and Anti-bacterial Behavior; A Comparative Study. Sci Rep. 2019; 9(1):9167.
10. Fereidooni F, Komeili G, Fanaei H, et al. Protective effects of ginseng on memory and learning and prevention of hippocampal oxidative damage in streptozotocin-induced Alzheimer’s in a rat model. Neurol Psychiatry Brain Res 2020; 37: 116–22.
11. Khorrami S, Dogani M, Mahani SE, Moghaddam MM, Taheri RA. Neuroprotective activity of green synthesized silver nanoparticles against methamphet induced cell death in human neuroblastoma SH ‑ SY5Y cells. Sci Rep. 2023;13(1):1–12.
12. Ashour M, Wink M, Gershenzon J. Biochemistry of Terpenoids: Monoterpenes, Sesquiterpenes and Diterpenes. In: Biochemistry of Plant Secondary Metabolism: Second Edition, pp. 258–303.
13. Finkelstein R. Abscisic Acid Synthesis and Response. Arab B 2013; 11: e0166.
14. Chen K, Li GJ, Bressan RA, Song CP, Zhu JK, Zhao Y. Abscisic acid dynamics, signaling, and functions in plants. J Integr Plant Biol. 2020; 62(2):25–54.
15. Li HH, Hao RL, Wu SS. Occurrence, function and potential medicinal applications of the phytohormone abscisic acid in animals and humans. Biochem Pharmacol. 2011;82:701–2.
16. 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(3):21–7.
17. Maixner DW, Christy D, Kong L. Phytohormone abscisic acid ameliorates neuropathic pain via regulating LANCL2 protein abundance and glial activation at the spinal cord. Mol Pain. 2022;18:17448069221107780.
18. Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. BMJ Open Sci. 2020;4:1769–77.
19. Verma R, Virdi JK, Singh N. Animals models of spinal cord contusion injury. Korean J Pain. 2019;32(5):12–21.
20. 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.
21. Szklarczyk D, Franceschini A, Wyder S. STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–D452.
22. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016;44(W1):W90–W97.
23. Rauf A, Badoni H, Abu-Izneid T, et al. Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases. Molecules; 27. Epub ahead of print 2022. DOI: 10.3390/molecules27103194.
24. Rauf A, Badoni H, Abu-Izneid T, Olatunde A, Rahman MM, Painuli S, et al. Strategies for Biomaterial-Based Spinal Cord Injury Repair via the TLR4-NF-κB Signaling Pathway. Front Bioeng Biotechnol. 2022;9:813169.
25. Sanchez-Petidier M, Guerri C, Moreno-Manzano V. Toll-like receptors 2 and 4 differentially regulate the self-renewal and differentiation of spinal cord neural precursor cells. Stem Cell Res Ther. 2022;13:117.
26. Zhang K, Wang H, Xu M, Frank JA, Luo J. Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain. J Neuroinflammation. 2018;15(1):197.
27. Hellenbrand DJ, Quinn CM, Piper ZJ, et al. Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration. J Neuroinflammation. 2021;18:284.
28. Kummer KK, Zeidler M, Kalpachidou T. Role of IL-6 in the regulation of neuronal development, survival and function. Cytokine 2021;144(5):155582.
29. Dong B, Yue Y, Dong H, Wang Y. N-methyl-D-aspartate receptor hypofunction as a potential contributor to the progression and manifestation of many neurological disorders. Front Mol Neurosci. 2023;16:1174738.
30. Ma T, Cheng Q, Chen C, et al. Excessive Activation of NMDA Receptors in the Pathogenesis of Multiple Peripheral Organs via Mitochondrial Dysfunction, Oxidative Stress, and Inflammation. SN Compr Clin Med 2020; 2: 551–69.
31. Ismail V, Zachariassen LG, Godwin A, Sahakian M, Ellard S, Stals KL, et al. Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome. Am J Hum Genet. 2022;109:1217–41.
32. Leem YJ, Cho K, Oh KH, Han SH, Nam KM, Chang J. Central Pain from Excitotoxic Spinal Cord Injury Induced by Intraspinal NMDA Injection: A Pilot Study. Korean J Pain. 2010;23(8):109–5.
33. Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle and Nerve. 2002;26:438–58.
34. Zhang Y, Chu JMT, Wong GTC. Cerebral Glutamate Regulation and Receptor Changes in Perioperative Neuroinflammation and Cognitive Dysfunction. Biomolecules; 12. Epub ahead of print April 2022.
35. Demirsoy IH, Ferrari G. The NK-1 Receptor Signaling: Distribution and Functional Relevance in the Eye. Receptors 2022;1:98–111.
36. Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, Dana R. Neuropeptide substance P and the immune response. Cell Mol Life Sci. 2016;73(8):4249–64.
37. Hamity MV, Walder RY, Hammond DL. Increased neuronal expression of neurokinin-1 receptor and stimulus-evoked internalization of the receptor in the rostral ventromedial medulla of the rat after peripheral inflammatory injury. J Comp Neurol. 2014;522(12):3037–51.
38. Chen W, Marvizon JC. Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain. Neuropharmacology. 2020;177(1):108253.
39. Rezaeezadeh_Roukerd M, Motaghi S, Sadeghi B. Protective effect of abscisic Acid in a spinal cord injury model mediated by suppressed neuroinflammation. Iran J Vet Sci Technol. 2022;14:42–51.
40. Rank MM, Murray KC, Stephens MJ, D'Amico J, Gorassini MA, Bennett DJ. Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury. J Neurophysiol. 2011;105(5):410–22.
41. Johnston S, Staines D, Klein A, Marshall-Gradisnik S. A targeted genome association study examining transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. BMC Med Genet. 2016;17:1–7.
42. Gonzalez-Nunez V. Role of gabra2, GABAA receptor alpha-2 subunit, in CNS development. Biochem Biophys Reports. 2015;3:190–201.
43. Aguilar-Delgadillo A, Cruz-Mendoza F, Luquin-de Andais Teh S, Ruvalcaba-Delgadillo Y, Jáuregui-Huerta F. Immediate Early Gene c-fos in the Brain: Focus on Glial Cells. Brain Sci. 2022;12(10):687.
44. Herdegen T, Kovary K, Leah J, Bravo R. Specific temporal and spatial distribution of JUN, FOS, and KROX‐24 proteins in spinal neurons following noxious transsynaptic stimulation. J Comp Neurol. 1991;313:178–91.
45. Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T, et al. NF-κB and AP-1 connection: mechanism of NF-κB-dependent regulation of AP-1 activity. Mol Cell Biol. 2004;24:7806–19.
46. Ding Y, Chen Q. The NF-κB Pathway: a Focus on Inflammatory Responses in Spinal Cord Injury. Mol Neurobiol. 2023;60(8):5292–5308.
47. Shih RH, Wang CY, Yang CM. NF-kappaB signaling pathways in neurological inflammation: A mini review. Front Mol Neurosci. 2015;8:77.
48. Ageeva T, Rizvanov A, Mukhamedshina Y. NF-κB and JAK/STAT Signaling Pathways as Crucial Regulators of Neuroinflammation and Astrocyte Modulation in Spinal Cord Injury. Cells. 2024;13(2):581.
49. Hsu JY, Bourguignon LY, Adams CM, Peyrollier K, Zhang H, Fandel T, et al. Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord. J Neurosci. 2008;28:13467–77.
50. Xu Y, Jia B, Li J, Li Q, Luo C. The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders. Antioxidants (Basel). 2024;13(4):395.
51. Song H, Park J, Bui PTC, Choi K, Gye MC, Hong YC, et al. Bisphenol A induces COX-2 through the mitogen-activated protein kinase pathway and is associated with levels of inflammation-related markers in elderly populations. Environ Res. 2017;158:490–8.
52. Toi M, Toshiya T, Noguchi K. COX2 expression plays a role in spinal cord injury-induced neuropathic pain. Neurosci Lett. 2024;823:137663.
2. Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A, et al. Traumatic spinal cord injury. Nat Rev Dis Prim. 2017;3:17018.
3. Anjum A, Yazid MD, Fauzi Daud M, Idris J, Ng AMH, Selvi Naicker A, et al. Spinal cord injury: Pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. 2020; 21(20):1–35.
4. Karsy M, Hawryluk G. Modern Medical Management of Spinal Cord Injury. Curr Neurol Neurosci Rep. 2019;19: 1–7.
5. Evaniew N, Noonan VK, Fallah N, Kwon BK, Rivers CS, Ahn H, et al. Methylprednisolone for the Treatment of Patients with Acute Spinal Cord Injuries: A Propensity Score-Matched Cohort Study from a Canadian Multi-Center Spinal Cord Injury Registry. J Neurotrauma 2015;32:1674–83.
6. Geisler FH, Moghaddamjou A, Wilson JRF. Methylprednisolone in acute traumatic spinal cord injury: Case-matched outcomes from the NASCIS2 and Sygen historical spinal cord injury studies with contemporary statistical analysis. J Neurosurg Spine. 2023;38(12):595–606.
7. Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013; 9(1):30.
8. Liu Z, Yang Y, He L. High-dose methylprednisolone for acute traumatic spinal cord injury: A meta-analysis. Neurology. 2019;93:E841–E850.
9. Khorrami S, Abdollahi Z, Eshaghi G, Khosravi A, Bidram E, Zarrabi A. An Improved Method for Fabrication of Ag-GO Nanocomposite with Controlled Anti-Cancer and Anti-bacterial Behavior; A Comparative Study. Sci Rep. 2019; 9(1):9167.
10. Fereidooni F, Komeili G, Fanaei H, et al. Protective effects of ginseng on memory and learning and prevention of hippocampal oxidative damage in streptozotocin-induced Alzheimer’s in a rat model. Neurol Psychiatry Brain Res 2020; 37: 116–22.
11. Khorrami S, Dogani M, Mahani SE, Moghaddam MM, Taheri RA. Neuroprotective activity of green synthesized silver nanoparticles against methamphet induced cell death in human neuroblastoma SH ‑ SY5Y cells. Sci Rep. 2023;13(1):1–12.
12. Ashour M, Wink M, Gershenzon J. Biochemistry of Terpenoids: Monoterpenes, Sesquiterpenes and Diterpenes. In: Biochemistry of Plant Secondary Metabolism: Second Edition, pp. 258–303.
13. Finkelstein R. Abscisic Acid Synthesis and Response. Arab B 2013; 11: e0166.
14. Chen K, Li GJ, Bressan RA, Song CP, Zhu JK, Zhao Y. Abscisic acid dynamics, signaling, and functions in plants. J Integr Plant Biol. 2020; 62(2):25–54.
15. Li HH, Hao RL, Wu SS. Occurrence, function and potential medicinal applications of the phytohormone abscisic acid in animals and humans. Biochem Pharmacol. 2011;82:701–2.
16. 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(3):21–7.
17. Maixner DW, Christy D, Kong L. Phytohormone abscisic acid ameliorates neuropathic pain via regulating LANCL2 protein abundance and glial activation at the spinal cord. Mol Pain. 2022;18:17448069221107780.
18. Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. BMJ Open Sci. 2020;4:1769–77.
19. Verma R, Virdi JK, Singh N. Animals models of spinal cord contusion injury. Korean J Pain. 2019;32(5):12–21.
20. 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.
21. Szklarczyk D, Franceschini A, Wyder S. STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–D452.
22. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016;44(W1):W90–W97.
23. Rauf A, Badoni H, Abu-Izneid T, et al. Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases. Molecules; 27. Epub ahead of print 2022. DOI: 10.3390/molecules27103194.
24. Rauf A, Badoni H, Abu-Izneid T, Olatunde A, Rahman MM, Painuli S, et al. Strategies for Biomaterial-Based Spinal Cord Injury Repair via the TLR4-NF-κB Signaling Pathway. Front Bioeng Biotechnol. 2022;9:813169.
25. Sanchez-Petidier M, Guerri C, Moreno-Manzano V. Toll-like receptors 2 and 4 differentially regulate the self-renewal and differentiation of spinal cord neural precursor cells. Stem Cell Res Ther. 2022;13:117.
26. Zhang K, Wang H, Xu M, Frank JA, Luo J. Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain. J Neuroinflammation. 2018;15(1):197.
27. Hellenbrand DJ, Quinn CM, Piper ZJ, et al. Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration. J Neuroinflammation. 2021;18:284.
28. Kummer KK, Zeidler M, Kalpachidou T. Role of IL-6 in the regulation of neuronal development, survival and function. Cytokine 2021;144(5):155582.
29. Dong B, Yue Y, Dong H, Wang Y. N-methyl-D-aspartate receptor hypofunction as a potential contributor to the progression and manifestation of many neurological disorders. Front Mol Neurosci. 2023;16:1174738.
30. Ma T, Cheng Q, Chen C, et al. Excessive Activation of NMDA Receptors in the Pathogenesis of Multiple Peripheral Organs via Mitochondrial Dysfunction, Oxidative Stress, and Inflammation. SN Compr Clin Med 2020; 2: 551–69.
31. Ismail V, Zachariassen LG, Godwin A, Sahakian M, Ellard S, Stals KL, et al. Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome. Am J Hum Genet. 2022;109:1217–41.
32. Leem YJ, Cho K, Oh KH, Han SH, Nam KM, Chang J. Central Pain from Excitotoxic Spinal Cord Injury Induced by Intraspinal NMDA Injection: A Pilot Study. Korean J Pain. 2010;23(8):109–5.
33. Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle and Nerve. 2002;26:438–58.
34. Zhang Y, Chu JMT, Wong GTC. Cerebral Glutamate Regulation and Receptor Changes in Perioperative Neuroinflammation and Cognitive Dysfunction. Biomolecules; 12. Epub ahead of print April 2022.
35. Demirsoy IH, Ferrari G. The NK-1 Receptor Signaling: Distribution and Functional Relevance in the Eye. Receptors 2022;1:98–111.
36. Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, Dana R. Neuropeptide substance P and the immune response. Cell Mol Life Sci. 2016;73(8):4249–64.
37. Hamity MV, Walder RY, Hammond DL. Increased neuronal expression of neurokinin-1 receptor and stimulus-evoked internalization of the receptor in the rostral ventromedial medulla of the rat after peripheral inflammatory injury. J Comp Neurol. 2014;522(12):3037–51.
38. Chen W, Marvizon JC. Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain. Neuropharmacology. 2020;177(1):108253.
39. Rezaeezadeh_Roukerd M, Motaghi S, Sadeghi B. Protective effect of abscisic Acid in a spinal cord injury model mediated by suppressed neuroinflammation. Iran J Vet Sci Technol. 2022;14:42–51.
40. Rank MM, Murray KC, Stephens MJ, D'Amico J, Gorassini MA, Bennett DJ. Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury. J Neurophysiol. 2011;105(5):410–22.
41. Johnston S, Staines D, Klein A, Marshall-Gradisnik S. A targeted genome association study examining transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. BMC Med Genet. 2016;17:1–7.
42. Gonzalez-Nunez V. Role of gabra2, GABAA receptor alpha-2 subunit, in CNS development. Biochem Biophys Reports. 2015;3:190–201.
43. Aguilar-Delgadillo A, Cruz-Mendoza F, Luquin-de Andais Teh S, Ruvalcaba-Delgadillo Y, Jáuregui-Huerta F. Immediate Early Gene c-fos in the Brain: Focus on Glial Cells. Brain Sci. 2022;12(10):687.
44. Herdegen T, Kovary K, Leah J, Bravo R. Specific temporal and spatial distribution of JUN, FOS, and KROX‐24 proteins in spinal neurons following noxious transsynaptic stimulation. J Comp Neurol. 1991;313:178–91.
45. Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T, et al. NF-κB and AP-1 connection: mechanism of NF-κB-dependent regulation of AP-1 activity. Mol Cell Biol. 2004;24:7806–19.
46. Ding Y, Chen Q. The NF-κB Pathway: a Focus on Inflammatory Responses in Spinal Cord Injury. Mol Neurobiol. 2023;60(8):5292–5308.
47. Shih RH, Wang CY, Yang CM. NF-kappaB signaling pathways in neurological inflammation: A mini review. Front Mol Neurosci. 2015;8:77.
48. Ageeva T, Rizvanov A, Mukhamedshina Y. NF-κB and JAK/STAT Signaling Pathways as Crucial Regulators of Neuroinflammation and Astrocyte Modulation in Spinal Cord Injury. Cells. 2024;13(2):581.
49. Hsu JY, Bourguignon LY, Adams CM, Peyrollier K, Zhang H, Fandel T, et al. Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord. J Neurosci. 2008;28:13467–77.
50. Xu Y, Jia B, Li J, Li Q, Luo C. The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders. Antioxidants (Basel). 2024;13(4):395.
51. Song H, Park J, Bui PTC, Choi K, Gye MC, Hong YC, et al. Bisphenol A induces COX-2 through the mitogen-activated protein kinase pathway and is associated with levels of inflammation-related markers in elderly populations. Environ Res. 2017;158:490–8.
52. Toi M, Toshiya T, Noguchi K. COX2 expression plays a role in spinal cord injury-induced neuropathic pain. Neurosci Lett. 2024;823:137663.
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| Inflammatory response Plant hormones Regulation of gene expression Spinal cord injuries | ||
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How to Cite
1.
Rezaeezade_Roukerd M, Dogani M, Motaghi S, Abbasnejad M. Abscisic Acid Regulates Immune-inflammatory Responses to Induce Neuroprotection in Spinal Cord Injury: Insights from Gene Expression and Network Analysis. Iran J Allergy Asthma Immunol. 2025;:1-16.
