{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T04:24:51Z","timestamp":1774412691993,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T00:00:00Z","timestamp":1703808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/NEU-BEN\/0156\/2012"],"award-info":[{"award-number":["PTDC\/NEU-BEN\/0156\/2012"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/Multi\/00709\/2019"],"award-info":[{"award-number":["UID\/Multi\/00709\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Overactivation of microglial cells seems to play a crucial role in the degeneration of dopaminergic neurons occurring in Parkinson\u2019s disease. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) present in astrocytes secretome modulates microglial responses induced by an inflammatory insult. Therefore, astrocyte-derived soluble factors may include relevant molecular players of therapeutic interest in the control of excessive neuroinflammatory responses. However, in vivo, the control of neuroinflammation is more complex as it depends on the interaction between different types of cells other than microglia and astrocytes. Whether neurons may interfere in the astrocyte-microglia crosstalk, affecting the control of microglial reactivity exerted by astrocytes, is unclear. Therefore, the present work aimed to disclose if the control of microglial responses mediated by astrocyte-derived factors, including GDNF, could be affected by the crosstalk with neurons, impacting GDNF\u2019s ability to protect dopaminergic neurons exposed to a pro-inflammatory environment. Also, we aimed to disclose if the protection of dopaminergic neurons by GDNF involves the modulation of microglial cells. Our results show that the neuroprotective effect of GDNF was mediated, at least in part, by a direct action on microglial cells through the GDNF family receptor \u03b1-1. However, this protective effect seems to be impaired by other mediators released in response to the neuron-astrocyte crosstalk since neuron-astrocyte secretome, in contrast to astrocytes secretome, was unable to protect dopaminergic neurons from the injury triggered by lipopolysaccharide-activated microglia. Supplementation with exogenous GDNF was needed to afford protection of dopaminergic neurons exposed to the inflammatory environment. In conclusion, our results revealed that dopaminergic protective effects promoted by GDNF involve the control of microglial reactivity. However, endogenous GDNF is insufficient to confer dopaminergic neuron protection against an inflammatory insult. This reinforces the importance of further developing new therapeutic strategies aiming at providing GDNF or enhancing its expression in the brain regions affected by Parkinson\u2019s disease.<\/jats:p>","DOI":"10.3390\/cells13010074","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T06:56:57Z","timestamp":1703833017000},"page":"74","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Endogenous GDNF Is Unable to Halt Dopaminergic Injury Triggered by Microglial Activation"],"prefix":"10.3390","volume":"13","author":[{"given":"Julieta","family":"Mendes-Oliveira","sequence":"first","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"given":"Filipa L.","family":"Campos","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"given":"Susana A.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"given":"Diogo","family":"Tom\u00e9","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"given":"Carla P.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7942-0432","authenticated-orcid":false,"given":"Gra\u00e7a","family":"Baltazar","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1126\/science.8493557","article-title":"GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons","volume":"260","author":"Lin","year":"1993","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3389\/fncel.2020.00209","article-title":"Glia Crosstalk in Neuroinflammatory Diseases","volume":"14","author":"Bernaus","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1007\/s12035-018-1109-6","article-title":"Intranasal Delivery of pGDNF DNA Nanoparticles Provides Neuroprotection in the Rat 6-Hydroxydopamine Model of Parkinson\u2019s Disease","volume":"56","author":"Aly","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pajares, M.A.I.R., Manda, G., Bosca, L., and Cuadrado, A. (2020). Inflammation in Parkinson\u2019s Disease: Mechanisms and Therapeutic Implications. Cells, 9.","DOI":"10.3390\/cells9071687"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jconrel.2020.02.044","article-title":"Ultrasound-responsive neurotrophic factor-loaded microbubble- liposome complex: Preclinical investigation for Parkinson\u2019s disease treatment","volume":"321","author":"Lin","year":"2020","journal-title":"J. Control Release"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Haney, M.J., Fallon, J.K., Rodriguez, M., Swain, C.J., Arzt, C.J., Smith, P.C., Loop, M.S., Harrison, E.B., and El-Hage, N. (2022). Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease. Cells, 11.","DOI":"10.1101\/2022.05.25.493424"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Badanjak, K., Fixemer, S., Smajic, S., Skupin, A., and Grunewald, A. (2021). The Contribution of Microglia to Neuroinflammation in Parkinson\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094676"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Araujo, B., Caridade-Silva, R., Soares-Guedes, C., Martins-Macedo, J., Gomes, E.D., Monteiro, S., and Teixeira, F.G. (2022). Neuroinflammation and Parkinson\u2019s Disease-From Neurodegeneration to Therapeutic Opportunities. Cells, 11.","DOI":"10.3390\/cells11182908"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s11910-022-01207-5","article-title":"Neurodegeneration and Neuroinflammation in Parkinson\u2019s Disease: A Self-Sustained Loop","volume":"22","author":"Arena","year":"2022","journal-title":"Cur. Neurol. Neurosci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1002\/ana.20338","article-title":"Microglial activation and dopamine terminal loss in early Parkinson\u2019s disease","volume":"57","author":"Ouchi","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1007\/s00401-003-0766-2","article-title":"Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson\u2019s disease brains","volume":"106","author":"Imamura","year":"2003","journal-title":"Acta Neuropathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.nbd.2005.08.002","article-title":"In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson\u2019s disease","volume":"21","author":"Gerhard","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nagatsu, T., and Sawada, M. (2007). Biochemistry of Postmortem Brains in Parkinson\u2019s Disease: Historical Overview and Future Prospects, Springer.","DOI":"10.1007\/978-3-211-73574-9_14"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.pbb.2012.12.022","article-title":"Glial cell-line derived neurotrophic factor (GDNF) replacement attenuates motor impairments and nigrostriatal dopamine deficits in 12-month-old mice with a partial deletion of GDNF","volume":"104","author":"Littrell","year":"2013","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8816","DOI":"10.1523\/JNEUROSCI.1067-07.2007","article-title":"Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice","volume":"27","author":"Boger","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jneuroim.2010.04.010","article-title":"Glial cell line-derived neurotrophic factor protects midbrain dopaminergic neurons against lipopolysaccharide neurotoxicity","volume":"225","author":"Xing","year":"2010","journal-title":"J. Neuroimmunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.nbd.2012.04.014","article-title":"Astrocyte-derived GDNF is a potent inhibitor of microglial activation","volume":"47","author":"Rocha","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1016\/j.bbadis.2015.07.004","article-title":"GPER: A new tool to protect dopaminergic neurons?","volume":"1852 Pt A","author":"Bessa","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.bbi.2017.04.016","article-title":"GPER activation is effective in protecting against inflammation-induced nigral dopaminergic loss and motor function impairment","volume":"64","author":"Videira","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrn2038","article-title":"Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms","volume":"8","author":"Block","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1523\/JNEUROSCI.3696-05.2006","article-title":"Astrocytes induce hemeoxygenase-1 expression in microglia: A feasible mechanism for preventing excessive brain inflammation","volume":"26","author":"Min","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.4049\/jimmunol.159.4.1604","article-title":"IL-12 production by central nervous system microglia is inhibited by astrocytes","volume":"159","author":"Aloisi","year":"1997","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1111\/j.1471-4159.2010.07004.x","article-title":"Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses","volume":"115","author":"Kim","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1002\/glia.22573","article-title":"Astrocytes inhibit nitric oxide-dependent Ca2+ dynamics in activated microglia: Involvement of ATP released via pannexin 1 channels","volume":"61","author":"Orellana","year":"2013","journal-title":"Glia"},{"key":"ref_25","first-page":"369468","article-title":"Glial Cell Line-Derived Neurotrophic Factor Family Members Reduce Microglial Activation via Inhibiting p38MAPKs-Mediated Inflammatory Responses","volume":"2014","author":"Rickert","year":"2014","journal-title":"J. Neurodegener. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1742-2094-5-4","article-title":"Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K\/Akt","volume":"5","author":"Xing","year":"2008","journal-title":"J. Neuroinflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1007\/s00702-014-1334-8","article-title":"Inhibition of i-NOS but not n-NOS protects rat primary cell cultures against MPP+-induced neuronal toxicity","volume":"122","author":"Brzozowski","year":"2015","journal-title":"J. Neural Transm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1038\/70978","article-title":"Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease","volume":"5","author":"Liberatore","year":"1999","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1046\/j.1471-4159.2003.01929.x","article-title":"Lipopolysaccharide-induced dopaminergic cell death in rat midbrain slice cultures: Role of inducible nitric oxide synthase and protection by indomethacin","volume":"86","author":"Shibata","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s12031-012-9814-5","article-title":"Neuroprotection by silencing iNOS expression in a 6-OHDA model of Parkinson\u2019s disease","volume":"48","author":"Li","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1046\/j.1471-4159.2000.0742213.x","article-title":"Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo","volume":"74","author":"Dehmer","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1002\/jnr.20583","article-title":"Estrogen provides neuroprotection against activated microglia-induced dopaminergic neuronal injury through both estrogen receptor-alpha and estrogen receptor-beta in microglia","volume":"81","author":"Liu","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jneuroim.2007.09.029","article-title":"Neuroprotection with pioglitazone against LPS insult on dopaminergic neurons may be associated with its inhibition of NF-kappaB and JNK activation and suppression of COX-2 activity","volume":"192","author":"Xing","year":"2007","journal-title":"J. Neuroimmunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.neuropharm.2010.10.002","article-title":"Verapamil protects dopaminergic neuron damage through a novel anti-inflammatory mechanism by inhibition of microglial activation","volume":"60","author":"Liu","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.neuropharm.2008.10.016","article-title":"Nimodipine protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation","volume":"56","author":"Li","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.mad.2005.06.012","article-title":"Involvement of proinflammatory factors, apoptosis, caspase-3 activation and Ca2+ disturbance in microglia activation-mediated dopaminergic cell degeneration","volume":"126","author":"Wang","year":"2005","journal-title":"Mech. Ageing Dev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0891-0618(01)00115-6","article-title":"Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson\u2019s disease brain","volume":"21","author":"Chauhan","year":"2001","journal-title":"J. Chem. Neuroanat."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chu, Y., and Kordower, J.H. (2021). GDNF signaling in subjects with minimal motor deficits and Parkinson\u2019s disease. Neurobiol. Dis., 153.","DOI":"10.1016\/j.nbd.2021.105298"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuroscience.2014.05.019","article-title":"Neurotrophic and neuroprotective efficacy of intranasal GDNF in a rat model of Parkinson\u2019s disease","volume":"274","author":"Migliore","year":"2014","journal-title":"Neuroscience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1016\/j.febslet.2015.11.006","article-title":"GDNF-Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease","volume":"589 Pt A","author":"Kramer","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0304-3940(99)00769-7","article-title":"Rat primary cultured microglia express glial cell line-derived neurotrophic factor receptors","volume":"275","author":"Honda","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.brainres.2008.09.011","article-title":"Differential effects of the dopamine neurotoxin MPTP in animals with a partial deletion of the GDNF receptor, GFR alpha1, gene","volume":"1241","author":"Boger","year":"2008","journal-title":"Brain Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/1\/74\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:43:57Z","timestamp":1760132637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/1\/74"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,29]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["cells13010074"],"URL":"https:\/\/doi.org\/10.3390\/cells13010074","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,29]]}}}