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The Unconventional Growth Factors Cerebral Dopamine Neurotrophic Factor and Mesencephalic Astrocyte–Derived Neurotrophic Factor Promote Post-ischemic Neurological Recovery, Perilesional Brain Remodeling, and Lesion-Remote Axonal Plasticity

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Abstract

Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3 days post-stroke (1 µg/day for 28 days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1β and TNFα in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019;16:142.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ. 2020;368:l6983.

    Article  PubMed  Google Scholar 

  3. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67:181–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bacigaluppi M, Pluchino S, Peruzzotti-Jametti L, Kilic E, Kilic U, Salani G, et al. Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain. 2009;132:2239–51.

    Article  PubMed  Google Scholar 

  5. Hermann DM, Chopp M. Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol. 2012;11:369–80.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Reitmeir R, Kilic E, Kilic U, Bacigaluppi M, ElAli A, Salani G, et al. Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity. Brain. 2011;134:84–99.

    Article  PubMed  Google Scholar 

  7. Lindau NT, Banninger BJ, Gullo M, Good NA, Bachmann LC, Starkey ML, et al. Rewiring of the corticospinal tract in the adult rat after unilateral stroke and anti-Nogo-A therapy. Brain. 2014;137:739–56.

    Article  PubMed  Google Scholar 

  8. Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci U S A. 2006;103:13198–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rahman AA, Amruta N, Pinteaux E, Bix GJ. Neurogenesis after stroke: a therapeutic perspective. Transl Stroke Res. 2021;12:1–14.

    Article  CAS  PubMed  Google Scholar 

  10. Reitmeir R, Kilic E, Reinboth BS, Guo Z, ElAli A, Zechariah A, et al. Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain. Acta Neuropathol. 2012;123:273–84.

    Article  CAS  PubMed  Google Scholar 

  11. Nygren J, Wieloch T, Pesic J, Brundin P, Deierborg T. Enriched environment attenuates cell genesis in subventricular zone after focal ischemia in mice and decreases migration of newborn cells to the striatum. Stroke. 2006;37:2824–9.

    Article  PubMed  Google Scholar 

  12. Lindholm P, Peranen J, Andressoo JO, Kalkkinen N, Kokaia Z, Lindvall O, et al. MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol Cell Neurosci. 2008;39:356–71.

    Article  CAS  PubMed  Google Scholar 

  13. Petrova P, Raibekas A, Pevsner J, Vigo N, Anafi M, Moore MK, et al. MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci. 2003;20:173–88.

    Article  CAS  PubMed  Google Scholar 

  14. Airavaara M, Chiocco MJ, Howard DB, Zuchowski KL, Peranen J, Liu C, et al. Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury. Exp Neurol. 2010;225:104–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Airavaara M, Shen H, Kuo CC, Peranen J, Saarma M, Hoffer B, et al. Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats. J Comp Neurol. 2009;515:116–24.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang Y, Xiang Y, Wang X, Zhu L, Li H, Wang S, et al. Cerebral dopamine neurotrophic factor protects microglia by combining with AKT and by regulating FoxO1/mTOR signaling during neuroinflammation. Biomed Pharmacother. 2019;109:2278–84.

    Article  CAS  PubMed  Google Scholar 

  17. Sousa-Victor P, Jasper H, Neves J. Trophic factors in inflammation and regeneration: the role of MANF and CDNF. Front Physiol. 2018;9:1629.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang XY, Song MM, Bi SX, Shen YJ, Shen YX, Yu YQ. MRI dynamically evaluates the therapeutic effect of recombinant human MANF on ischemia/reperfusion injury in rats. Int J Mol Sci. 2016;17:1476. https://doi.org/10.3390/ijms17091476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao B, Deng J, Zhang X, Sun H, Jia G, Li J, et al. Effects of mesencephalic astrocyte-derived neurotrophic factor on cerebral angiogenesis in a rat model of cerebral ischemia. Neurosci Lett. 2020;715:134657.

    Article  CAS  PubMed  Google Scholar 

  20. Matlik K, Anttila JE, Kuan-Yin T, Smolander OP, Pakarinen E, Lehtonen L, et al. Poststroke delivery of MANF promotes functional recovery in rats. Sci Adv. 2018;4:eaap8957.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tseng KY, Anttila JE, Khodosevich K, Tuominen RK, Lindahl M, Domanskyi A, et al. MANF promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke. Mol Ther. 2018;26:238–55.

    Article  CAS  PubMed  Google Scholar 

  22. Caglayan AB, Beker MC, Caglayan B, Yalcin E, Caglayan A, Yulug B, et al. Acute and post-acute neuromodulation induces stroke recovery by promoting survival signaling, neurogenesis, and pyramidal tract plasticity. Front Cell Neurosci. 2019;13:144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kilic E, Kilic U, Bacigaluppi M, Guo Z, Abdallah NB, Wolfer DP, et al. Delayed melatonin administration promotes neuronal survival, neurogenesis and motor recovery, and attenuates hyperactivity and anxiety after mild focal cerebral ischemia in mice. J Pineal Res. 2008;45:142–8.

    Article  CAS  PubMed  Google Scholar 

  24. Kilic E, ElAli A, Kilic U, Guo Z, Ugur M, Uslu U, et al. Role of Nogo-A in neuronal survival in the reperfused ischemic brain. J Cereb Blood Flow Metab. 2010;30:969–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoyo-Becerra C, Liu Z, Yao J, Kaltwasser B, Gerken G, Hermann DM, et al. Rapid regulation of depression-associated genes in a new mouse model mimicking interferon-alpha-related depression in hepatitis C virus infection. Mol Neurobiol. 2015;52:318–29.

    Article  CAS  PubMed  Google Scholar 

  26. Kilic E, Reitmeir R, Kilic U, Caglayan AB, Beker MC, Kelestemur T, et al. HMG-CoA reductase inhibition promotes neurological recoverY, peri-lesional tissue remodeling, and contralesional pyramidal tract plasticity after focal cerebral ischemia. Front Cell Neurosci. 2014;8:422.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Beker M, Caglayan AB, Beker MC, Altunay S, Karacay R, Dalay A, et al. Lentivirally administered glial cell line-derived neurotrophic factor promotes post-ischemic neurological recovery, brain remodeling and contralesional pyramidal tract plasticity by regulating axonal growth inhibitors and guidance proteins. Exp Neurol. 2020;331:113364.

    Article  CAS  PubMed  Google Scholar 

  28. Kelestemur T, Beker MC, Caglayan AB, Caglayan B, Altunay S, Kutlu S, et al. Normobaric oxygen treatment improves neuronal survival functional recovery and axonal plasticity after newborn hypoxia-ischemia. Behav Brain Res. 2020;379:112338.

    Article  CAS  PubMed  Google Scholar 

  29. Kilic U, Elibol B, Beker M, Altug-Tasa B, Caglayan AB, Beker MC, et al. Inflammatory cytokines are in action: brain plasticity and recovery after brain ischemia due to delayed melatonin administration. J Stroke Cerebrovasc Dis. 2021;30:106105.

    Article  PubMed  Google Scholar 

  30. Beker MC, Caglayan AB, Kelestemur T, Caglayan B, Yalcin E, Yulug B, et al. Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation. Oncotarget. 2015;6:30604–14.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Caglayan B, Caglayan AB, Beker MC, Yalcin E, Beker M, Kelestemur T, et al. Evidence that activation of P2X7R does not exacerbate neuronal death after optic nerve transection and focal cerebral ischemia in mice. Exp Neurol. 2017;296:23–31.

    Article  CAS  PubMed  Google Scholar 

  32. Anttila JE, Poyhonen S, Airavaara M. Secondary pathology of the thalamus after focal cortical stroke in rats is not associated with thermal or mechanical hypersensitivity and is not alleviated by intra-thalamic post-stroke delivery of recombinant CDNF or MANF. Cell Transplant. 2019;28:425–38.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Li T, Xu W, Gao L, Guan G, Zhang Z, He P, et al. Mesencephalic astrocyte-derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt-dependent prosurvival pathway and defending blood-brain barrier integrity. FASEB J. 2019;33:1727–41.

    Article  CAS  PubMed  Google Scholar 

  34. Malone K, Amu S, Moore AC, Waeber C. The immune system and stroke: from current targets to future therapy. Immunol Cell Biol. 2019;97:5–16.

    Article  PubMed  Google Scholar 

  35. Vidale S, Consoli A, Arnaboldi M, Consoli D. Postischemic inflammation in acute stroke. J Clin Neurol. 2017;13:1–9.

    Article  PubMed  Google Scholar 

  36. Tseng KY, Danilova T, Domanskyi A, Saarma M, Lindahl M, Airavaara M. MANF is essential for neurite extension and neuronal migration in the developing cortex. eNeuro. 2017;4:ENEURO.0214-17.2017. https://doi.org/10.1523/ENEURO.0214-17.2017.

  37. Matlik K, Vihinen H, Bienemann A, Palgi J, Voutilainen MH, Booms S, et al. Intrastriatally infused exogenous CDNF is endocytosed and retrogradely transported to substantia nigra. eNeuro. 2017;4:ENEURO.0128-16.2017. https://doi.org/10.1523/ENEURO.0128-16.2017.

  38. Young CC, Brooks KJ, Buchan AM, Szele FG. Cellular and molecular determinants of stroke-induced changes in subventricular zone cell migration. Antioxid Redox Signal. 2011;14:1877–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xia Y, Pu H, Leak RK, Shi Y, Mu H, Hu X, et al. Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury. Proc Natl Acad Sci U S A. 2018;115:E9230–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Doeppner TR, Kaltwasser B, Sanchez-Mendoza EH, Caglayan AB, Bahr M, Hermann DM. Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3beta inhibition-independent pathways. J Cereb Blood Flow Metab. 2017;37:914–26.

    Article  CAS  PubMed  Google Scholar 

  41. Teppo J, Vaikkinen A, Stratoulias V, Matlik K, Anttila JE, Smolander OP, et al. Molecular profile of the rat peri-infarct region four days after stroke: study with MANF. Exp Neurol. 2020;329:113288.

    Article  CAS  PubMed  Google Scholar 

  42. Neves J, Zhu J, Sousa-Victor P, Konjikusic M, Riley R, Chew S, et al. Immune modulation by MANF promotes tissue repair and regenerative success in the retina. Science. 2016;353:aaf3646.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zhao H, Liu Y, Cheng L, Liu B, Zhang W, Guo YJ, et al. Mesencephalic astrocyte-derived neurotrophic factor inhibits oxygen-glucose deprivation-induced cell damage and inflammation by suppressing endoplasmic reticulum stress in rat primary astrocytes. J Mol Neurosci. 2013;51:671–8.

    Article  CAS  PubMed  Google Scholar 

  44. Zhu W, Li J, Liu Y, Xie K, Wang L, Fang J. Mesencephalic astrocyte-derived neurotrophic factor attenuates inflammatory responses in lipopolysaccharide-induced neural stem cells by regulating NF-kappaB and phosphorylation of p38-MAPKs pathways. Immunopharmacol Immunotoxicol. 2016;38:205–13.

    Article  CAS  PubMed  Google Scholar 

  45. Yagi T, Asada R, Kanekura K, Eesmaa A, Lindahl M, Saarma M, et al. Neuroplastin modulates anti-inflammatory Effects of MANF. iScience. 2020;23:101810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cheng L, Zhao H, Zhang W, Liu B, Liu Y, Guo Y, et al. Overexpression of conserved dopamine neurotrophic factor (CDNF) in astrocytes alleviates endoplasmic reticulum stress-induced cell damage and inflammatory cytokine secretion. Biochem Biophys Res Commun. 2013;435:34–9.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by Turkish Academy of Sciences (TUBA) and the Scientific and Technological Research Council of Turkey (TÜBİTAK), grant no: 114S402.

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Authors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    Ahmet Burak Caglayan

  2. International School of Medicine, Department of Physiology, Istanbul Medipol University, Istanbul, Turkey

    Ahmet Burak Caglayan

  3. Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey

    Ahmet Burak Caglayan, Mustafa Caglar Beker, Elif Sertel Evren, Berrak Caglayan, Nilay Ates, Aysun Caglayan, Muhammed Furkan Dasdelen, Thorsten Roland Doeppner & Ertugrul Kilic

  4. School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey

    Mustafa Caglar Beker, Elif Sertel Evren, Aysun Caglayan, Muhammed Furkan Dasdelen & Ertugrul Kilic

  5. International School of Medicine, Dept. of Medical Biology, Istanbul Medipol University, Istanbul, Turkey

    Berrak Caglayan

  6. Hamidiye School of Medicine, Department of Medical Biology, University of Health Sciences Turkey, Istanbul, Turkey

    Ülkan Kilic

  7. Faculty of Medicine, Department of Pharmacology, Istanbul Medipol University, Istanbul, Turkey

    Nilay Ates

  8. Department of Neurology, University Medical Center Göttingen, Göttingen, Germany

    Thorsten Roland Doeppner

  9. Department of Neurology, University Hospital Giessen, Giessen, Germany

    Thorsten Roland Doeppner

  10. Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland

    Mart Saarma

  11. Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    Dirk Matthias Hermann

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  1. Ahmet Burak Caglayan
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Correspondence to Ertugrul Kilic.

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Caglayan, A.B., Beker, M.C., Sertel Evren, E. et al. The Unconventional Growth Factors Cerebral Dopamine Neurotrophic Factor and Mesencephalic Astrocyte–Derived Neurotrophic Factor Promote Post-ischemic Neurological Recovery, Perilesional Brain Remodeling, and Lesion-Remote Axonal Plasticity. Transl. Stroke Res. 14, 263–277 (2023). https://doi.org/10.1007/s12975-022-01035-2

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