Mustafa Çağlar BEKER, Ahmet Burak ÇAĞLAYAN, Ülkan KILIÇ, Ertuğrul KILIÇ, Merve BEKER, Busenur BOLAT, Gamze TORUN KÖSE

Striatal dopaminergic neurons as a potential target for GDNF based ischemic stroke therapy

Background/aim: Glial cell-line-derived neurotrophic factor (GDNF) is a well-known regulatory neurotrophic factor on dopaminergic neurons. Several pathologies have been documented so far in case of any impairment in the dopaminergic system. This study aimed to investigate the potential protective role of lentiviral GNDF delivery on the small population of tyrosine hydroxylase (TH) positive dopamine producing striatal neurons after ischemic stroke. Materials and methods: Fourteen C57BL/6J male mice (8–10 weeks) were intracerebrally treated with lentiviral GDNF (Lv-GDNF) or vehicle. Ten days after injections, cerebral ischemia was induced by blockage of the middle cerebral artery. Animals were terminated 72 h after ischemia, and their brains were taken for histological and molecular investigations. Following confirmation of GDNF overexpression, TH immunostaining and immunoblotting were used to evaluate the role of GDNF on dopaminergic neurons. Next, Fluro Jade C staining was implemented to examine the degree of neuronal degeneration at the damaged parenchyma. Results: Neither the amount of TH positive dopaminergic neurons nor the expression of TH changed in the Lv-GDNF treated animals comparing to the vehicle group. On the other hand, GDNF exposure caused a significant increase in the expression of Nurr1, an essential transcription factor for dopaminergic neurons and Gap43, growth and plasticity promoting protein, in the ischemic striatum. Treatment with Lv-GDNF gave rise to a significant reduction in the number of degenerated neurons. Finally, enhanced GDNF expression also induced expression of an important stress-related transcription factor NF-κB as well as the nitric oxide synthase enzymes iNOS and nNOS in the contralesional hemisphere. Conclusion: Considering these results together, GDNF’s impact on the survival of striatal dopaminergic neurons is not outstanding for its neuroprotective role. However, it seems that GDNF conducts several signaling pathways by acting on key transcription factors and shows its protective feature by fine-tuning the degeneration-related processes.

PDF

___

1. Mikulik R, Wahlgren N. Treatment of acute stroke: an update. Journal of Internal Medicine 2015; 278(2):145-165. doi: 10.1111/joim.12387
2. Pena ID, Borlongan C, Shen G, Davis W. Strategies to Extend Thrombolytic Time Window for Ischemic Stroke Treatment: An Unmet Clinical Need. Journal of Stroke 2017; 19(1):50-60. doi: 10.5853/jos.2016.01515
3. Leng T, Xiong ZG. Treatment for ischemic stroke: From thrombolysis to thrombectomy and remaining challenges. Brain Circulation 2019; 5(1):8-11. doi: 10.4103/bc.bc_36_18
4. Hermann DM, Chopp M. Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. The Lancet Neurology 2012; 11(4):369-380. doi: 10.1016/S1474-4422(12)70039-X
5. Dimyan MA, Cohen LG. Neuroplasticity in the context of motor rehabilitation after stroke. Nature Reviews Neurology 2011; 7(2):76-85. doi: 10.1038/nrneurol.2010.200
6. Xiao N, Le QT. Neurotrophic Factors and Their Potential Applications in Tissue Regeneration. Archivum Immunologiae et Therapiae Experimentalis 2016; 64(2):89-99. doi: 10.1007/ s00005-015-0376-4
7. Jin G, Omori N, Li F, Nagano I, Manabe Y et al. Protection against ischemic brain damage by GDNF affecting cell survival and death signals. Neurological Research 2003; 25(3):249-253. doi: 10.1179/016164103101201454
8. Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 1995; 373(6512):335-339. doi: 10.1038/373335a0
9. d’Anglemont de Tassigny X, Pascual A, Lopez-Barneo J. GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson’s disease. Frontiers in Neuroanatomy 2015; 9:10. doi: 10.3389/fnana.2015.00010
10. Beker M, Caglayan AB, Beker MC, Altunay S, Karacay R 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. Experimental Neurology 2020; 331:113364. doi: 10.1016/j. expneurol.2020.113364
11. Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T et al. alpha-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Science Translational Medicine 2012; 4(163):163ra156. doi: 10.1126/ scitranslmed.3004676
12. Su X, Fischer DL, Li X, Bankiewicz K, Sortwell CE et al. AlphaSynuclein mRNA Is Not Increased in Sporadic PD and AlphaSynuclein Accumulation Does Not Block GDNF Signaling in Parkinson’s Disease and Disease Models. Molecular Therapy 2017; 25(10):2231-2235. doi: 10.1016/j.ymthe.2017.04.018
13. Berke JD. What does dopamine mean? Nature Neuroscience 2018; 21(6):787-793. doi: 10.1038/s41593-018-0152-y
14. Tande D, Hoglinger G, Debeir T, Freundlieb N, Hirsch EC et al. New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 2006; 129(Pt 5):1194-1200. doi: 10.1093/brain/awl041
15. Huot P, Levesque M, Parent A. The fate of striatal dopaminergic neurons in Parkinson’s disease and Huntington’s chorea. Brain 2007; 130(Pt 1):222-232. doi: 10.1093/brain/awl332
16. Rangel-Barajas C, Coronel I, Floran B. Dopamine Receptors and Neurodegeneration. Aging and Disease 2015; 6(5):349- 368. doi: 10.14336/AD.2015.0330
17. Chen JY, Wang EA, Cepeda C, Levine MS. Dopamine imbalance in Huntington’s disease: a mechanism for the lack of behavioral flexibility. Frontiers in Neuroscience 2013; 7:114. doi: 10.3389/fnins.2013.00114
18. Ding S, Gu Y, Cai Y, Cai M, Yang T et al. Integrative systems and functional analyses reveal a role of dopaminergic signaling in myelin pathogenesis. Journal of Translational Medicine 2020; 18(1):109. doi: 10.1186/s12967-020-02276-1
19. Huot P, Parent A. Dopaminergic neurons intrinsic to the striatum. Journal of Neurochemistry 2007; 101(6):1441-1447. doi: 10.1111/j.1471-4159.2006.04430.x
20. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends in Neurosciences 1999; 22(9):391-397. doi: 10.1016/s0166-2236(99)01401-0
21. Hermann DM, Kilic E, Kugler S, Isenmann S, Bahr M. Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiology of disease 2001; 8(4):655-666. doi: 10.1006/nbdi.2001.0399
22. Beker MC, Caglayan B, Yalcin E, Caglayan AB, Turkseven S et al. Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT. Molecular Neurobiology 2018; 55(3):2565-2576. doi: 10.1007/s12035-017-0524-4
23. Beker MC, Caglayan AB, Kelestemur T, Caglayan B, Yalcin E et al. Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation. Oncotarget 2015; 6(31):30604-30614. doi: 10.18632/oncotarget.5773
24. Kobayashi T, Ahlenius H, Thored P, Kobayashi R, Kokaia Z et al. Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats. Stroke 2006; 37(9):2361-2367. doi: 10.1161/01. STR.0000236025.44089.e1
25. Daubner SC, Le T, Wang S. Tyrosine hydroxylase and regulation of dopamine synthesis. Archives of Biochemistry and Biophysics 2011; 508(1):1-12. doi: 10.1016/j.abb.2010.12.017
26. Chinta SJ, Andersen JK. Dopaminergic neurons. International Journal of Biochemistry & Cell Biology 2005; 37(5):942-946. doi: 10.1016/j.biocel.2004.09.009
27. Kuriakose D, Xiao Z. Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. International Journal of Molecular Sciences 2020; 21(20). doi: 10.3390/ijms21207609
28. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993; 260(5111):1130-1132. doi: 10.1126/science.8493557
29. Ikenari T, Kurata H, Satoh T, Hata Y, Mori T. Evaluation of Fluoro-Jade C Staining: Specificity and Application to Damaged Immature Neuronal Cells in the Normal and Injured Mouse Brain. Neuroscience 2020; 425:146-156. doi: 10.1016/j. neuroscience.2019.11.029
30. Simoes AP, Silva CG, Marques JM, Pochmann D, Porciuncula LO et al. Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation. Cell Death & Disease 2018; 9(3):297. doi: 10.1038/s41419-018-0351-1
31. Decressac M, Volakakis N, Bjorklund A, Perlmann T. NURR1 in Parkinson disease--from pathogenesis to therapeutic potential. Nature Reviews Neurology 2013; 9(11):629-636. doi: 10.1038/ nrneurol.2013.209
32. Dodd KC, Nair VA, Prabhakaran V. Role of the Contralesional vs. Ipsilesional Hemisphere in Stroke Recovery. Frontiers in Human Neuroscience 2017; 11:469. doi: 10.3389/ fnhum.2017.00469
33. Tonges L, Szego EM, Hause P, Saal KA, Tatenhorst L et al. Alpha-synuclein mutations impair axonal regeneration in models of Parkinson’s disease. Frontiers in Aging Neuroscience 2014; 6:239. doi: 10.3389/fnagi.2014.00239
34. Jeon SG, Yoo A, Chun DW, Hong SB, Chung H et al. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis. Aging and Disease 2020; 11(3):705-724. doi: 10.14336/AD.2019.0718
35. Harari OA, Liao JK. NF-kappaB and innate immunity in ischemic stroke. Annals of the New York Academy of Sciences 2010; 1207:32-40. doi: 10.1111/j.1749-6632.2010.05735.x
36. Suschek CV, Schnorr O, Kolb-Bachofen V. The role of iNOS in chronic inflammatory processes in vivo: is it damagepromoting, protective, or active at all? Current Molecular Medicine 2004; 4(7):763-775. doi: 10.2174/1566524043359908
37. Chen ZQ, Mou RT, Feng DX, Wang Z, Chen G. The role of nitric oxide in stroke. Medical Gas Research 2017; 7(3):194- 203. doi: 10.4103/2045-9912.215750
38. Terpolilli NA, Kim SW, Thal SC, Kataoka H, Zeisig V et al. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circulation Research 2012; 110(5):727-738. doi: 10.1161/CIRCRESAHA.111.253419