Immunomodulatory drugs alleviate l-dopa-induced dyskinesia in a rat model of Parkinson's disease.
Angiogenesis Inhibitors
/ therapeutic use
Animals
Antiparkinson Agents
/ adverse effects
Cytokines
/ metabolism
Dyskinesia, Drug-Induced
/ psychology
Immunologic Factors
/ therapeutic use
Interleukin-10
/ metabolism
Levodopa
/ adverse effects
Male
Neostriatum
/ metabolism
Oxidopamine
Parkinson Disease
/ complications
Rats
Rats, Sprague-Dawley
Receptors, AMPA
/ metabolism
Substantia Nigra
/ metabolism
Thalidomide
/ analogs & derivatives
Tumor Necrosis Factor-alpha
/ metabolism
l-dopa
3,6′-dithiothalidomide
dyskinesia
immunomodulation
thalidomide
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
18
01
2019
revised:
05
06
2019
accepted:
14
06
2019
pubmed:
25
7
2019
medline:
23
6
2020
entrez:
24
7
2019
Statut:
ppublish
Résumé
Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model. Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control. Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels. These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model.
METHODS
Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control.
RESULTS
Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels.
CONCLUSIONS
These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.
Substances chimiques
3,6'-dithiothalidomide
0
Angiogenesis Inhibitors
0
Antiparkinson Agents
0
Cytokines
0
Immunologic Factors
0
Receptors, AMPA
0
Tumor Necrosis Factor-alpha
0
Interleukin-10
130068-27-8
Levodopa
46627O600J
Thalidomide
4Z8R6ORS6L
Oxidopamine
8HW4YBZ748
glutamate receptor ionotropic, AMPA 1
TFZ3H25BS1
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1818-1830Subventions
Organisme : Intramural research Program of the NIH, National institute on Aging
Pays : International
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2019 International Parkinson and Movement Disorder Society.
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