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Dysfunction in the nigrostriatal system: effects of L-DOPA and GDNF
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet , 2013. , s. 88
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1544
Nyckelord [en]
Parkinson’s disease, L-DOPA, dyskinesia, GDNF, dopamine, glutamate, serotonin
Nationell ämneskategori
Farmaceutiska vetenskaper Neurovetenskaper
Forskningsämne
medicinsk utvecklings- och neurobiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-64149ISBN: 9789174595444 (tryckt)OAI: oai:DiVA.org:umu-64149DiVA, id: diva2:589177
Disputation
2013-02-08, BiA201, Biologihuset, Umeå universitet, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-01-18 Skapad: 2013-01-17 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Delarbeten
1. Dopamine release from serotonergic nerve fibers is reduced in L-DOPA-induced dyskinesia
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2011 (Engelska)Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 118, nr 1, s. 12-23Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

L-DOPA is the most commonly used treatment for symptomatic control in patients with Parkinson's disease. Unfortunately, most patients develop severe side-effects, such as dyskinesia, upon chronic l-DOPA treatment. The patophysiology of dyskinesia is unclear; however, involvement of serotonergic nerve fibers in converting l-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of l-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned l-DOPA naïve, and dopamine-denervated chronically l-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local l-DOPA administration into normal and intact hemisphere of dopamine-lesioned l-DOPA naïve animals significantly increased the potassium-evoked dopamine release. l-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted l-DOPA naïve striatum, although these dopamine levels were several-folds lower than in the normal striatum, whereas no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local l-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared with those measured in l-DOPA naïve dopamine-denervated striatum. To conclude, l-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, l-DOPA loading does not increase the dopamine release in dyskinetic animals as found in l-DOPA naïve animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior.

Nyckelord
5-HT, chronoamperometry, L-DOPA-induced dyskinesia, SERT
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-50743 (URN)10.1111/j.1471-4159.2011.07292.x (DOI)21534956 (PubMedID)
Tillgänglig från: 2011-12-20 Skapad: 2011-12-20 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
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4. Glial cell line-derived neurotrophic factor is crucial for long-term maintenance of the nigrostriatal system
Öppna denna publikation i ny flik eller fönster >>Glial cell line-derived neurotrophic factor is crucial for long-term maintenance of the nigrostriatal system
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2010 (Engelska)Ingår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 171, nr 4, s. 1357-1366Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Glial cell line-derived neurotrophic factor (GDNF) is a potent factor for the ventral mesencephalic dopamine neurons. However, studies on the Gdnf gene deleted (Gdnf(-/-)) mouse have been limited to fetal tissue since these mice die prematurely. To evaluate long-term effects of Gdnf gene deletion, this study involves co-grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) derived from different Gdnf genotypes. The VM/LGE co-grafts were evaluated at 3, 6, and 12 months for tyrosine hydroxylase (TH) -positive cell survival and nerve fiber formation in the LGE co-transplant, visualized by dopamine- and cyclic AMP-regulated phosphoprotein relative molecular mass 32,000 (DARPP-32) -immunoreactivity. Cell counts revealed no difference in TH-positive neurons between Gdnf genotypes at 3 months postgrafting. At 6 months, a significant reduction in cell number was observed in the Gdnf(-/-) grafts. In fact, in the majority of the Gdnf(-/-) VM/LGE transplant had degenerated. At 12 months, a reduction in cell number was seen in both Gdnf(-/-) and Gdnf(+/-) compared to wild type transplants. In the Gdnf(-/-) grafts, TH-negative inclusion-like structures were present in the cytoplasm of the TH-positive neurons at 3 months. These structures were also found in the Gdnf(+/-) transplants at 12 months, but not in Gdnf(+/+) controls at any time point. In Gdnf(+/+) grafts, TH-positive nerve fiber innervation of the striatal co-grafts was dense and patchy and overlapped with clusters of DARPP-32-positive neurons. This overlap did mismatch in the Gdnf(+/-) grafts, while the TH-positive innervation was sparse in the Gdnf(-/-) transplants and the DARPP-32-positive neurons were widespread distributed. In conclusion, GDNF is essential for long-term maintenance of both the VM TH-positive neurons and for the striatal tissue, and appears crucial for generation of a proper organization of the striatum.

Ort, förlag, år, upplaga, sidor
Elsevier, 2010
Nyckelord
GDNF, transplant, substantia nigra, striatum, DARPP-32, Gdnf knockout
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:umu:diva-41351 (URN)10.1016/j.neuroscience.2010.10.010 (DOI)000285231000035 ()20933580 (PubMedID)
Tillgänglig från: 2011-03-23 Skapad: 2011-03-23 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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