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Meglumine cyclic adenylate improves cardiovascular hemodynamics and motor-function in a rat model of acute T4 thoracic spinal cord injury

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Abstract

Study design

Animal experimental study.

Objectives

Spinal cord injury (SCI) at or above the T6 level causes cardiovascular dysfunction. Maintaining cAMP levels with cAMP analogs can facilitate neurological recovery. In the present study, the effects of meglumine cyclic adenylate (MCA), a cAMP analog and approved cardiovascular drug, on cardiovascular and neurological recovery in acute T4-SCI in rats were investigated.

Setting

Hospital in Kunming, China.

Methods

Eighty rats were randomly allocated to five groups, and groups A-D received SCI: (A) a group administered MCA at 2 mg/kg/d iv qd, (B) a group administered dopamine at 2.5 to 5 μg/kg/min iv to maintain mean arterial pressure above 85 mm Hg, (C) a group administered atropine at 1 mg/kg iv bid, (D) a group receiving an equal volume of saline iv qd for 3 weeks after SCI and (E) a group undergoing laminectomy only. The cardiovascular and behavioral parameters of the rats were examined, and spinal cord tissues were processed for hematoxylin and eosin staining, Nissl staining, electron microscopy, and analysis of cAMP levels.

Results

Compared with dopamine or atropine, MCA significantly reversed the decrease in cAMP levels in both myocardial cells and the injured spinal cord; improved hypotension, bradycardia and behavioral parameters at 6 weeks; and improved spinal cord blood flow and histological structure at 7 days post-SCI. The regression analysis suggested spinal cord motor-function improved as decreased heart rate and mean arterial pressure were stopped post-SCI.

Conclusions

MCA may be an effective treatment for acute SCI by sustaining cAMP-dependent reparative processes and improving post-SCI cardiovascular dysfunction.

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Fig. 1: Recovery of cardiovascular and behavioral assessments after SCI.
Fig. 2: HE staining after SCI.
Fig. 3: Nissl staining after SCI.
Fig. 4: Electron micrographs after SCI.

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Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

References

  1. Harman KA, States G, Wade A, Stepp C, Wainwright G, DeVeau K, et al. Temporal analysis of cardiovascular control and function following incomplete T3 and T10 spinal cord injury in rodents. Physiol Rep. 2018;6:e13634.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sabharwal S. Addressing cardiometabolic risk in adults with spinal cord injury: acting now despite knowledge gaps. Spinal Cord Ser Cases. 2019;5:96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Phillips AA, Krassioukov AV. Contemporary Cardiovascular Concerns after Spinal Cord Injury: Mechanisms, Maladaptations, and Management. J Neurotrauma. 2015;32:1927–42.

    Article  PubMed  Google Scholar 

  4. Popok DW, West CR, Hubli M, Currie KD, Krassioukov AV. Characterizing the Severity of Autonomic Cardiovascular Dysfunction after Spinal Cord Injury Using a Novel 24 h Ambulatory Blood Pressure Analysis Software. J Neurotrauma. 2017;34:559–66.

    Article  PubMed  Google Scholar 

  5. Karim F, Chang P, Garrison C, Steiner M. Role of Theophylline in Management of Bradycardia Secondary to High Cervical Spinal Cord Injury in a Seven-Year-Old Child: Case Report and a Review of Literature. Cureus. 2020;12:e10941.

    PubMed  PubMed Central  Google Scholar 

  6. Soubeyrand M, Dubory A, Laemmel E, Court C, Vicaut E, Duranteau J, et al. Effect of norepinephrine on spinal cord blood flow and parenchymal hemorrhage size in acute-phase experimental spinal cord injury. Eur Spine J. 2014;23:658–65.

    Article  PubMed  Google Scholar 

  7. Sadek MS, Cachorro E, El-Armouche A, Kämmerer S. Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases. Int J Mol Sci. 2020;21:7462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Winslow RL, Walker MA, Greenstein JL. Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte. Wiley Interdiscip Rev Syst Biol Med. 2016;8:37–67.

    Article  CAS  PubMed  Google Scholar 

  9. McCabe KJ, Rangamani P. Computational modeling approaches to cAMP/PKA signaling in cardiomyocytes. J Mol Cell Cardiol. 2021;154:32–40.

    Article  CAS  PubMed  Google Scholar 

  10. Batty NJ, Fenrich KK, Fouad K. The role of cAMP and its downstream targets in neurite growth in the adult nervous system. Neurosci Lett. 2017;652:56–63.

    Article  CAS  PubMed  Google Scholar 

  11. Siddiq MM, Hannila SS. Looking downstream: the role of cyclic AMP-regulated genes in axonal regeneration. Front Mol Neurosci. 2015;8:26.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bavencoffe A, Li Y, Wu Z, Yang Q, Herrera J, Kennedy EJ, et al. Persistent Electrical Activity in Primary Nociceptors after Spinal Cord Injury Is Maintained by Scaffolded Adenylyl Cyclase and Protein Kinase A and Is Associated with Altered Adenylyl Cyclase Regulation. J Neurosci. 2016;36:1660–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Blesch A, Lu P, Tsukada S, Alto LT, Roet K, Coppola G, et al. Conditioning lesions before or after spinal cord injury recruit broad genetic mechanisms that sustain axonal regeneration: superiority to camp-mediated effects. Exp Neurol. 2012;235:162–73.

    Article  PubMed  Google Scholar 

  14. Boomkamp SD, McGrath MA, Houslay MD, Barnett SC. Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model. Br J Pharm. 2014;171:2385–98.

    Article  CAS  Google Scholar 

  15. Xia T, Huang B, Ni S, Gao L, Wang J, Wang J, et al. The combination of db-cAMP and ChABC with poly(propylene carbonate) microfibers promote axonal regenerative sprouting and functional recovery after spinal cord hemisection injury. Biomed Pharmacother. 2017;86:354–62.

    Article  CAS  PubMed  Google Scholar 

  16. Sierksma AS, Van den Hove DL, Pfau F, Philippens M, Bruno O, Fedele E, et al. Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology. 2014;77:120–30.

    Article  CAS  PubMed  Google Scholar 

  17. Wu D, Zhao Y, Yang Y, Wang W, Xu R. A multicenter clinical study on clinical effects of meglumine cyclic adenylate in treating patients with chronic pulmonary heart disease. Zhonghua Nei Ke Za Zhi. 2001;40:467–70.

    CAS  PubMed  Google Scholar 

  18. Feng L, Lai Y, Bu SZ. The efficacy of Meglumine adenosine cyclophosphate vs Amrinone in the treatment of congestive heart failure. Foreing Med Sci Sect Cardiovusc Dis. 2002;29:41–3.

    Google Scholar 

  19. Ding D, Ding J, Jin Z, Qin X, Guan L, Cui X, et al. Evaluation of curative effect of meglumine cyclic adenylate combined with recombinant human brain natriuretic peptide in treatment of coronary artery disease patients with heart failure. J Jilin Univ. 2011;37:723–6.

    CAS  Google Scholar 

  20. LI QF, Huang LJ, Wei S. Therapeutic effect of meglumine cyclic adenosine monophosphate on chronic heart failure in patients with type 2 diabetes mellitus and coronary heart disease. Chin Foreign Med Res. 2014;12:9–11.

    Google Scholar 

  21. Liao J, Xie J, Lin D, Lu N, Guo L, Li W, et al. Meglumine cyclic adenylate improves neurological function following acute spinal cord injury in rats. Mol Med Rep. 2014;10:1225–30.

    Article  CAS  PubMed  Google Scholar 

  22. Arifin WN, Zahiruddin WM. Sample Size Calculation in Animal Studies Using Resource Equation Approach[J]. Malaysian J Med Sci. 2017;24:101–5.

  23. Wrathall JR, Pettegrew RK, Harvey F. Spinal cord contusion in the rat: production of graded, reproducible, injury groups. Exp Neurol. 1985;88:108–22.

    Article  CAS  PubMed  Google Scholar 

  24. Ploumis A, Yadlapalli N, Fehlings MG, Kwon BK, Vaccaro AR. A systematic review of the evidence supporting a role for vasopressor support in acute SCI. Spinal Cord. 2010;48:356–62.

    Article  CAS  PubMed  Google Scholar 

  25. Hawryluk G, Whetstone W, Saigal R, Ferguson A, Talbott J, Bresnahan J, et al. Mean Arterial Blood Pressure Correlates with Neurological Recovery after Human Spinal Cord Injury: Analysis of High Frequency Physiologic Data. J Neurotrauma. 2015;32:1958–67.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Aigbe F, Adeyemi O, Zubaid M, Rathore H, Sofidiya M. Effect of the aqueous root extract of aristolochiaringens and its fractions on haemodynamic parameters in a rodent model of essential hypertension. basic Clin Pharmacol Toxicol. 2014;115:21–21.

    Google Scholar 

  27. Merrick A, Hadley WM, Holcslaw TL. The effect of large doses of atropine sulfate on heart rate and blood pressure in rats. Res Commun Chem Pathol Pharm. 1979;25:13–22.

    CAS  Google Scholar 

  28. Walters BC, Hadley MN, Hurlbert RJ, Aarabi B, Dhall SS, Gelb DE, et al. Guidelines for the management of acute cervical spine and spinal cord injuries: 2013 update. Neurosurgery. 2013;60:82–91.

    Article  PubMed  Google Scholar 

  29. Evans LT, Lollis SS, Ball PA. Management of acute spinal cord injury in the neurocritical care unit. Neurosurg Clin N Am. 2013;24:339–47.

    Article  PubMed  Google Scholar 

  30. Scheff SW, Saucier DA, Cain ME. A statistical method for analyzing rating scale data: the BBB locomotor score. J Neurotrauma. 2002;19:1251–60.

    Article  PubMed  Google Scholar 

  31. Rivlin AS, Tator CH. Objective clinical assessment of motor function after experimental spinal cord injury in the rat. J Neurosurg. 1977;47:577–81.

    Article  CAS  PubMed  Google Scholar 

  32. Buñag RD, Butterfield J. Tail-cuff blood pressure measurement without external preheating in awake rats. Hypertension 1982;4:898–903.

    Article  PubMed  Google Scholar 

  33. Cawthon DF, Senter HJ, Stewart WB. Comparison of hydrogen clearance and 14C-antipyrine autoradiography in the measurement of spinal cord blood flow after severe impact injury. J Neurosurg. 1980;52:801–7.

    Article  CAS  PubMed  Google Scholar 

  34. Augulis V, Sepinwall J. Brazilin-toluidine blue O and hematoxylin-darrow red methods for brain and spinal cord. Stain Technol. 1969;44:131–7.

    Article  CAS  PubMed  Google Scholar 

  35. Schleicher A, Zilles K. A quantitative approach to cytoarchitectonics: analysis of structural inhomogeneities in nervous tissue using an image analyser. J Microsc. 1990;157:367–81.

    Article  CAS  PubMed  Google Scholar 

  36. Dykstra M, Reuss L. Biological Electron Microscopy: Theory, Techniques, and Troubleshooting. Springer Science & Business Med. 2003; 2003: 182–95.

  37. Oh YM, Eun JP. Cardiovascular dysfunction due to sympathetic hypoactivity after complete cervical spinal cord injury: A case report and literature review. Med (Baltim). 2015;94:e686.

    Article  Google Scholar 

  38. Hou S, Saltos TM, Mironets E, Trueblood CT, Connors TM, Tom VJ, et al. Grafting Embryonic Raphe Neurons Reestablishes Serotonergic Regulation of Sympathetic Activity to Improve Cardiovascular Function after Spinal Cord Injury. J Neurosci. 2020;40:1248–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Laird AS, Carrive P, Waite PM. Cardiovascular and temperature changes in spinal cord injured rats at rest and during autonomic dysreflexia. J Physiol. 2006;577:539–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Iorio-Morin C, Noonan VK, White B, Noreau L, Leblond J, Dumont FS, et al. Quality of Life and Health Utility Scores Among Canadians Living With Traumatic Spinal Cord Injury - A National Cross-Sectional Study. Spine (Philos Pa 1976). 2018;43:999–1006.

    Article  Google Scholar 

  41. Inskip JA, Ramer LM, Ramer MS, Krassioukov AV, Claydon VE. Spectral analyses of cardiovascular control in rodents with spinal cord injury. J Neurotrauma. 2012;29:1638–49.

    Article  PubMed  Google Scholar 

  42. Ventura AM, Shieh HH, Bousso A, Góes PF, de Cássia FOFI, de Souza DC, et al. Double-Blind Prospective Randomized Controlled Trial of Dopamine Versus Epinephrine as First-Line Vasoactive Drugs in Pediatric Septic Shock. Crit Care Med. 2015;43:2292–302.

    Article  CAS  PubMed  Google Scholar 

  43. Bobin P, Belacel-Ouari M, Bedioune I, Zhang L, Leroy J, Leblais V, et al. Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective. Arch Cardiovasc Dis. 2016;109:431–43.

    Article  PubMed  Google Scholar 

  44. Motiejunaite J, Amar L, Vidal-Petiot E. Adrenergic receptors and cardiovascular effects of catecholamines. Ann Endocrinol (Paris). 2021;82:193–7.

    Article  PubMed  Google Scholar 

  45. Nait Taleb Ali H, Morel MP, Doulazmi M, Scotto-Lomassese S, Gaspar P, Dusart I, et al. Lack of adenylate cyclase 1 (AC1): consequences on corticospinal tract development and on locomotor recovery after spinal cord injury. Brain Res. 2014;1549:1–10.

    Article  CAS  PubMed  Google Scholar 

  46. Omura T, Omura K, Tedeschi A, Riva P, Painter MW, Rojas L, et al. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron. 2015;86:1215–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nikulina E, Tidwell JL, Dai HN, Bregman BS, Filbin MT. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci USA. 2004;101:8786–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pearse DD, Pereira FC, Marcillo AE, Bates ML, Berrocal YA, Filbin MT, et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat Med. 2004;10:610–6.

    Article  CAS  PubMed  Google Scholar 

  49. Wilson JR, Cadotte DW, Fehlings MG. Clinical predictors of neurological outcome, functional status, and survival after traumatic spinal cord injury: a systematic review[J]. J Neurosurg: Spine. 2012;17:11–26.

    PubMed  Google Scholar 

  50. Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Traumatic spinal cord injury: an overview of pathophysiology, models and acute injury mechanisms[J]. Front Neurol. 2019;10:282.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mputu PM, Beauséjour M, Richard-Denis A, Mac-Thiong JM. Early predictors of neurological outcomes after traumatic spinal cord injury: a systematic review and proposal of a conceptual framework[J]. Am J Phys Med Rehab. 2021;100:700–11.

    Article  Google Scholar 

  52. Mccawley LJ, Li S, Benavidez M, Halbleib J, Wattenberg EV, Hudson LG. Elevation of intracellular cAMP inhibits growth factor-mediated matrix metalloproteinase-9 induction and keratinocyte migration.[J]. Mol Pharmacol. 2000;58:145–51.

    Article  CAS  PubMed  Google Scholar 

  53. Szabo-Fresnais N, Blondeau JP, Pomérance M. Activation of the cAMP pathway synergistically increases IL-1-induced IL-6 gene expression in FRTL-5 thyroid cells: involvement of AP-1 transcription factors[J]. Mol Cell Endocrinol. 2008;284:28–37.

    Article  CAS  PubMed  Google Scholar 

  54. Garcia-Gil M, Camici M, Allegrini S, Pesi R, Tozzi MG. Metabolic aspects of adenosine functions in the brain[J]. Front Pharmacol. 2021;12:672182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tate DG, Wheeler T, Lane GI, Forchheimer M, Anderson KD, Biering-Sorensen F, et al. Recommendations for evaluation of neurogenic bladder and bowel dysfunction after spinal cord injury and/or disease[J]. J Spinal Cord Med. 2020;43:141–64.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bhattacharyya S, Dinda A, Vishnubhatla S, Anwar MF, Jain S. A combinatorial approach to modulate microenvironment toward regeneration and repair after spinal cord injury in rats[J]. Neurosci Lett. 2021;741:135500.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Wang Bang Biochemical Pharmaceutical Co., Ltd for their generous gift of MCA. We are also grateful to Xuexu Liu and Qiongying Li for their technical assistance. We would also like to thank Yinghua Zhong, Wu Li, Malin Li, Meiqiong Li, and Yu Wei for their constructive criticism of the research, critical review of the manuscript and sincere help.

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Author notes

  1. These authors contributed equally: Yueming Song, Limin Guo.

Authors and Affiliations

  1. Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Yueming Song

  2. Orthopedic-Traumatology Department, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China

    Limin Guo, Xingxiong Jiang, Minglin Dong, Dong Xiang, Ming Wen, Shaoxuan He, Yong Yuan, Feng Lin, Gang Zhao & Jingwu Liao

  3. Department of Orthopedic Surgery, The 2nd Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China

    Luping Liu

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  1. Yueming Song
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Contributions

YS and JL conceived and designed research. JL and LG conducted experiments. JL wrote the manuscript. The other authors contributed new reagents, analytical tools, or analyzed data. All authors have read and approved the manuscript, and all data were generated in-house and that no paper mill was used. YS and LG contributed equally to this work.

Corresponding author

Correspondence to Jingwu Liao.

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Ethical approval

All experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Sichuan University (approved animal protocol number 20096029 A) and met the ''Guide for the Regulations on the administration of laboratory animals'' and ''Guiding opinions on treating experimental animals well'' of China.

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The authors declare no competing interests.

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Song, Y., Guo, L., Jiang, X. et al. Meglumine cyclic adenylate improves cardiovascular hemodynamics and motor-function in a rat model of acute T4 thoracic spinal cord injury. Spinal Cord 61, 422–429 (2023). https://doi.org/10.1038/s41393-023-00909-y

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