Abstract
Much concern was directed towards the crucial role of recombinant tissue plasminogen activator (rt-PA) in improving neuroplasticity in patients with acute ischemic stroke. The aim of the work to investigate the effect of treating patients with acute ischemic stroke with rt-PA, on the level of brain derived neurotrophic factor (BDNF) as a marker of neuroplasticity. This study was conducted on 47 patients presenting with acute ischemic stroke (during the first 4.5 h from stroke onset); 26 patients of them eligible for receiving rt-PA (patient group) and 21 patients having contraindications for treatment with rt-PA (control group). Neurological, radiological and laboratory assessment (including BDNF serum level) were done for both groups at stroke onset (before receiving rt-PA) and at day 7. There was a statistically significant increase in BDNF serum level from day 1 to day 7 in rt-PA treated patients in comparison to control group (P-value˂ 0.001). Serum level of BDNF is significantly higher at the onset of stroke in female patients and non-smokers than males or smokers (P-value = 0.011, 0.01 respectively). There was no effect of either age, body mass index, hypertension, diabetes, drug abuse, past or family history of stroke, valvular heart diseases, atrial fibrillation, cardiomyopathy, ejection fraction, carotid atherosclerotic changes, lipid profile or uric acid, on BDNF serum level measured at the onset of stroke. Treatment of patients with acute ischemic stroke with rt-PA causes significant improvement in neuroplasticity through increasing BDNF serum level.
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request with permission of Faculty of Medicine, Beni-Suef University, Egypt.
Abbreviations
- AF:
-
Atrial fibrillation
- AHA/ASA:
-
American heart association and American stroke association
- B.P:
-
Blood pressure
- BDNF:
-
Brain derived neurotrophic factor
- CT:
-
Computed tomography
- DM:
-
Diabetes mellitus
- DTN:
-
Door to needle
- FDA:
-
Food and drug administration
- GBD:
-
Global burden of disease
- HDL:
-
High lipodensity protein
- HRP:
-
Horseradish peroxidase
- HTN:
-
Hypertension
- LDL:
-
Low density lipoprotein
- MMP-9:
-
Matrix metalloproteinases-9
- NIHSS:
-
National institute of health stroke scale
- NMDA:
-
N-methyl-D-aspartate
- OD:
-
Optical density
- RBS:
-
Random blood sugar
- rt-PA:
-
Recombinant tissue plasminogen activator
- TG:
-
Triglycerides
- TNF-α:
-
Tumor necrosis factor -α
- TrkB:
-
Tropomyosin receptor kinase B
References
Feigin VL, Norrving B, Mensah GA (2017) Global burden of stroke. Circ Res 120(3):439–448
Sacco RL, Benjamin EJ, Broderick JP, Dyken M, Easton JD, Feinberg WM et al (1997) American heart association prevention conference prevention and rehabilitation of stroke risk factors. Stroke 28(7):1507–1517
Zivin JA (2009) Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. food and drug administration (FDA). Ann Neurol 66(1):6–10
Saver JL, Filip B, Hamilton S, Yanes A, Craig S, Cho M et al (2010) Improving the reliability of stroke disability grading in clinical trials and clinical practice: the Rankin focused assessment (RFA). Stroke 41(5):992–995
Adibhatla RM, Hatcher JF (2008) Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets 7(3):243–253
Liu Z, Li Y, Zhang L, Xin H, Cui Y, Hanson LR et al (2012) Subacute intranasal administration of tissue plasminogen activator increases functional recovery and axonal remodeling after stroke in rats. Neurobiol Dis 45(2):804–809
Ho VM, Lee JA, Martin KC (2011) The cell biology of synaptic plasticity. Science 334(6056):623–628
Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736
Pikula A, Beiser AS, Chen TC, Preis SR, Vorgias D, DeCarli C et al (2013) Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: framingham study. Stroke 44(10):2768–2775
Lasek-Bal A, Jedrzejowska-Szypulka H, Rozycka J, Bal W, Holecki M, Dulawa J et al (2015) Low concentration of BDNF in the acute phase of ischemic stroke as a factor in poor prognosis in terms of functional status of patients. Med Sci Monit 21:3900–3905
Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S et al (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306(5695):487–491
Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Phil Trans R Soc B Biol Sci 361(1473):1545–1564
National Institute of Neurological D., Stroke. NIH stroke scale: Dept. of Health and Human Services, USA; 2011.
Xin H, Li Y, Shen LH, Liu X, Wang X, Zhang J et al (2010) Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse. PLoS ONE 5(2):e9027
Rodier M, Quirié A, Prigent-Tessier A, Béjot Y, Jacquin A, Mossiat C et al (2015) Relevance of post-stroke circulating BDNF levels as a prognostic biomarker of stroke outcome. Impact of rt-PA treatment. PLoS ONE 10(10):e0140668
Meng Y, Chopp M, Zhang Y, Liu Z, An A, Mahmood A et al (2014) Subacute intranasal administration of tissue plasminogen activator promotes neuroplasticity and improves functional recovery following traumatic brain injury in rats. PLoS ONE 9(9):e106238
Rodier M, Prigent-Tessier A, Béjot Y, Jacquin A, Mossiat C, Marie C et al (2014) Exogenous t-PA administration increases hippocampal mature BDNF levels plasmin- or NMDA-dependent mechanism? PLoS ONE 9(3):e92416
Ding Q, Ying Z, Gomez-Pinilla F (2011) Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing. Neuroscience 192:773–780
Shen LH, Xin H, Li Y, Zhang RL, Cui Y, Zhang L et al (2011) Endogenous tissue plasminogen activator mediates bone marrow stromal cell-induced neurite remodeling after stroke in mice. Stroke 42(2):459–464
Benarroch EE (2007) Tissue plasminogen activator: beyond thrombolysis. Neurology 69(8):799–802
Haile WB, Wu J, Echeverry R, Wu F, An J, Yepes M (2012) Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-alpha. J Cereb Blood Flow Metab 32(1):57–69
Echeverry R, Wu J, Haile WB, Guzman J, Yepes M (2010) Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus. J Clin Invest 120(6):2194–2205
Kim YH, Park JH, Hong SH, Koh JY (1999) Nonproteolytic neuroprotection by human recombinant tissue plasminogen activator. Science 284(5414):647–650
Cops EJ, Sashindranath M, Daglas M, Short KM, da Fonseca PC, Pang TY et al (2013) Tissue-type plasminogen activator is an extracellular mediator of Purkinje cell damage and altered gait. Exp Neurol 249:8–19
Yepes M, Sandkvist M, Wong MK, Coleman TA, Smith E, Cohan SL et al (2000) Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 96(2):569–576
Yepes M (2015) Tissue-type plasminogen activator is a neuroprotectant in the central nervous system. Front Cell Neurosci 9:304
Weinstein G, Preis SR, Beiser AS, Kaess B, Chen TC, Satizabal C et al (2017) Clinical and environmental correlates of serum BDNF: a descriptive study with plausible implications for AD research. Curr Alzheimer Res 14(7):722–730
Chan CB, Ye K (2017) Sex differences in brain-derived neurotrophic factor signaling and functions. J Neurosci Res 95(1–2):328–335
Begliuomini S, Casarosa E, Pluchino N, Lenzi E, Centofanti M, Freschi L et al (2007) Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor. Hum Reprod 22(4):995–1002
Segal M, Murphy D (2001) Estradiol induces formation of dendritic spines in hippocampal neurons: functional correlates. Horm Behav 40(2):156–159
Kim TS, Kim DJ, Lee H, Kim YK (2007) Increased plasma brain-derived neurotrophic factor levels in chronic smokers following unaided smoking cessation. Neurosci Lett 423(1):53–57
Yeom M, Shim I, Lee HJ, Hahm DH (2005) Proteomic analysis of nicotine-associated protein expression in the striatum of repeated nicotine-treated rats. Biochem Biophys Res Commun 326(2):321–328
Bhang SY, Choi SW, Ahn JH (2010) Changes in plasma brain-derived neurotrophic factor levels in smokers after smoking cessation. Neurosci Lett 468(1):7–11
Xiaoyu W (2015) The exposure to nicotine affects expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in neonate rats. Neurol Sci 36(2):289–295
Gajewska E, Sobieska M, Lojko D, Wieczorowska-Tobis K, Suwalska A (2014) Obesity itself does not influence BDNF serum levels in adults. Eur Rev Med Pharmacol Sci 18(21):3246–3250
Marchelek-Mysliwiec M, Cichocka E, Dziedziejko V, Dutkiewicz GZ, Stepniewska J, Safranow K et al (2015) Insulin resistance and brain-derived neurotrophic factor levels in chronic kidney disease. Ann Clin Biochem 52(Pt 2):213–219
Jin H, Chen Y, Wang B, Zhu Y, Chen L, Han X et al (2018) Association between brain-derived neurotrophic factor and von Willebrand factor levels in patients with stable coronary artery disease. BMC Cardiovasc Disord 18(1):23
Prigent-Tessier A, Quirié A, Maguin-Gaté K, Szostak J, Mossiat C, Nappey M et al (2013) Physical training and hypertension have opposite effects on endothelial brain-derived neurotrophic factor expression. Cardiovasc Res 100(3):374–382
Jiang H, Liu Y, Zhang Y, Chen ZY (2011) Association of plasma brain-derived neurotrophic factor and cardiovascular risk factors and prognosis in angina pectoris. Biochem Biophys Res Commun 415(1):99–103
Qiu Shichao RJ, Luo Hui, Hu Xuejian, Hou Yuanhua (2014) Correlation between BDNF, VEGF and carotid atherosclerosis in type 2 diabetes mellitus. J Second Mil Med Univ 35(8):920–923.
Zhang J, Zhang X, Su H, Tao J, Xie Y, Han B et al (2014) Increased serum brain-derived neurotrophic factor levels during opiate withdrawal. Neurosci Lett 571:61–65
Angelucci F, Ricci V, Pomponi M, Conte G, Mathé AA, Attilio Tonali P et al (2007) Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor. J Psychopharmacol 21(8):820–825
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RS participated in study design, sequence alignment and helped to draft manuscript. HM participated in study design, collection and analysis of data and helped to draft manuscript. LR participated in study design, performed the laboratory work and helped to draft manuscript. MH participated in study design, sequence alignment and helped to draft manuscript. All authors read and approved the final manuscript with agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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A written informed consent was obtained from each participant in this study or from one of his family members and the study was approved by local ethical committee in Faculty of medicine, Beni-Suef University.
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Soliman, R., Mamdouh, H., Rashed, L. et al. The use of recombinant tissue plasminogen activator in in acute ischemic stroke is associated with increased level of BDNF. J Thromb Thrombolysis 52, 1165–1172 (2021). https://doi.org/10.1007/s11239-021-02443-1
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DOI: https://doi.org/10.1007/s11239-021-02443-1