Differential Expression of Striatal ΔFosB MRNA and FosB MRNA After Different Levodopa Treatment Regimens in a Rat Model of Parkinson's Disease

Overview

Journal Neurotox Res

Publisher Springer

Specialty Neurology

Date 2019 Jan 16

PMID 30645726

Citations 4

Authors

Victoria Palafox-Sanchez

Victoria Sosti

Gabriel Ramirez-Garcia

Jaime Kulisevsky

Jose Aguilera

I Daniel Limon

Affiliations

Soon will be listed here.

Abstract

Levodopa-induced dyskinesia (LID) is the main side effect associated with levodopa treatment and represents the biggest challenge for Parkinson's disease therapy. While the overexpression of ΔFosB transcription factor is related to the development of LID, few studies have been undertaken on fosB gene transcriptional regulation induced by levodopa in vivo. The aim of this study is to evaluate the expression of ΔFosB mRNA and FosB mRNA in the striatum after acute, chronic, and subchronic levodopa treatment in rats with unilateral 6-OHDA-lesion in the medial forebrain bundle. qRT-PCR was used to compare the levels of ΔFosB and FosB mRNA expression in the dopamine-denervated striatum following levodopa treatment. While the results obtained after a single levodopa dose indicate a significant increase of ∆FosB mRNA expression in the striatum 1 h post-injection, the levels returned to baseline values after 24 h. After subchronic levodopa treatment, the levels of ∆FosB and FosB mRNA expression were lower 1 h post-administration of levodopa in comparison with acute effect. However, after chronic levodopa treatment, ∆FosB mRNA expression in the striatum persisted in dyskinetic rats only, and positive correlation was found between the levels of ∆FosB mRNA expression 1 h after levodopa administration and the level of dyskinetic severity. In summary, acute levodopa treatment led to highly increased levels of ∆FosB mRNA expression in the striatum. While repeated administration induced a partial desensitization of the fosB gene in the striatum, it did not suppress its activity completely, which could explain why dyskinesia appears after chronic levodopa treatment.

Citing Articles

The Role of ΔFosB in the Pathogenesis of Levodopa-Induced Dyskinesia: Mechanisms and Therapeutic Strategies.

Zamanian M, Kamran Z, Tavakoli M, Oghenemaro E, Abohassan M, Kubaev A Mol Neurobiol. 2025; .

PMID: 39890697 DOI: 10.1007/s12035-025-04720-z.

Targeting serum response factor (SRF) deactivates ΔFosB and mitigates Levodopa-induced dyskinesia in a mouse model of Parkinson's disease.

Kambey P, Wu J, Liu W, Su M, Buberwa W, Tang C Gene Ther. 2024; 31(11-12):614-624.

PMID: 39384937 DOI: 10.1038/s41434-024-00492-8.

Amphiregulin blockade decreases the levodopa-induced dyskinesia in a 6-hydroxydopamine Parkinson's disease mouse model.

Kambey P, Liu W, Wu J, Tang C, Buberwa W, Saro A CNS Neurosci Ther. 2023; 29(10):2925-2939.

PMID: 37101388 PMC: 10493657. DOI: 10.1111/cns.14229.

The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson's disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway.

Kambey P, Chengcheng M, Xiaoxiao G, Abdulrahman A, Kanwore K, Nadeem I Metab Brain Dis. 2021; 36(4):609-625.

PMID: 33507465 DOI: 10.1007/s11011-021-00670-2.

Striatal Nurr1, but not FosB expression links a levodopa-induced dyskinesia phenotype to genotype in Fisher 344 vs. Lewis hemiparkinsonian rats.

Steece-Collier K, Collier T, Lipton J, Stancati J, Winn M, Cole-Strauss A Exp Neurol. 2020; 330:113327.

PMID: 32387398 PMC: 7365252. DOI: 10.1016/j.expneurol.2020.113327.

References

Cenci M, Tranberg A, Andersson M, Hilbertson A . Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-dopa treatment. Neuroscience. 1999; 94(2):515-27. DOI: 10.1016/s0306-4522(99)00294-8. View

Andersson M, Hilbertson A, Cenci M . Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease. Neurobiol Dis. 1999; 6(6):461-74. DOI: 10.1006/nbdi.1999.0259. View

Ahlskog J, Muenter M . Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001; 16(3):448-58. DOI: 10.1002/mds.1090. View

Westin J, Andersson M, Lundblad M, Cenci M . Persistent changes in striatal gene expression induced by long-term L-DOPA treatment in a rat model of Parkinson's disease. Eur J Neurosci. 2001; 14(7):1171-6. DOI: 10.1046/j.0953-816x.2001.01743.x. View

Tekumalla P, Calon F, Rahman Z, Birdi S, Rajput A, Hornykiewicz O . Elevated levels of DeltaFosB and RGS9 in striatum in Parkinson's disease. Biol Psychiatry. 2001; 50(10):813-6. DOI: 10.1016/s0006-3223(01)01234-3. View

Andersson M, Konradi C, Cenci M . cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum. J Neurosci. 2001; 21(24):9930-43. PMC: 4204657. View

Winkler C, Kirik D, Bjorklund A, Cenci M . L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of parkinson's disease: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis. 2002; 10(2):165-86. DOI: 10.1006/nbdi.2002.0499. View

Jenner P . The MPTP-treated primate as a model of motor complications in PD: primate model of motor complications. Neurology. 2003; 61(6 Suppl 3):S4-11. DOI: 10.1212/wnl.61.6_suppl_3.s4. View

Rylski M, Kaczmarek L . Ap-1 targets in the brain. Front Biosci. 2004; 9:8-23. DOI: 10.2741/1207. View

10.

Lundblad M, Picconi B, Lindgren H, Cenci M . A model of L-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis. 2004; 16(1):110-23. DOI: 10.1016/j.nbd.2004.01.007. View

11.

Konradi C, Westin J, Carta M, Eaton M, Kuter K, Dekundy A . Transcriptome analysis in a rat model of L-DOPA-induced dyskinesia. Neurobiol Dis. 2004; 17(2):219-36. PMC: 4208672. DOI: 10.1016/j.nbd.2004.07.005. View

12.

Aubert I, Guigoni C, Hakansson K, Li Q, Dovero S, Barthe N . Increased D1 dopamine receptor signaling in levodopa-induced dyskinesia. Ann Neurol. 2004; 57(1):17-26. DOI: 10.1002/ana.20296. View

13.

Carta A, Tronci E, Pinna A, Morelli M . Different responsiveness of striatonigral and striatopallidal neurons to L-DOPA after a subchronic intermittent L-DOPA treatment. Eur J Neurosci. 2005; 21(5):1196-204. DOI: 10.1111/j.1460-9568.2005.03944.x. View

14.

Pavon N, Martin A, Mendialdua A, Moratalla R . ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice. Biol Psychiatry. 2005; 59(1):64-74. DOI: 10.1016/j.biopsych.2005.05.044. View

15.

Valastro B, Andersson M, Lindgren H, Cenci M . Expression pattern of JunD after acute or chronic L-DOPA treatment: comparison with deltaFosB. Neuroscience. 2006; 144(1):198-207. DOI: 10.1016/j.neuroscience.2006.09.001. View

16.

Ulery P, Nestler E . Regulation of DeltaFosB transcriptional activity by Ser27 phosphorylation. Eur J Neurosci. 2007; 25(1):224-30. DOI: 10.1111/j.1460-9568.2006.05262.x. View

17.

Alibhai I, Green T, Potashkin J, Nestler E . Regulation of fosB and DeltafosB mRNA expression: in vivo and in vitro studies. Brain Res. 2007; 1143:22-33. PMC: 1880876. DOI: 10.1016/j.brainres.2007.01.069. View

18.

Guigoni C, Doudnikoff E, Li Q, Bloch B, Bezard E . Altered D(1) dopamine receptor trafficking in parkinsonian and dyskinetic non-human primates. Neurobiol Dis. 2007; 26(2):452-63. DOI: 10.1016/j.nbd.2007.02.001. View

19.

Carle T, Ohnishi Y, Ohnishi Y, Alibhai I, Wilkinson M, Kumar A . Proteasome-dependent and -independent mechanisms for FosB destabilization: identification of FosB degron domains and implications for DeltaFosB stability. Eur J Neurosci. 2007; 25(10):3009-19. DOI: 10.1111/j.1460-9568.2007.05575.x. View

20.

Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault J . Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci. 2007; 27(26):6995-7005. PMC: 6672217. DOI: 10.1523/JNEUROSCI.0852-07.2007. View