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Deleterious effects of VEGFR2 and RET inhibition in a preclinical model of Parkinson’s disease

dc.contributor.authorRequejo C.
dc.contributor.authorRuiz-Ortega J.A.
dc.contributor.authorBengoetxea H.
dc.contributor.authorBulnes S.
dc.contributor.authorUgedo L.
dc.contributor.authorLafuente J.V.
dc.date.accessioned2020-09-02T22:26:54Z
dc.date.available2020-09-02T22:26:54Z
dc.date.issued2018
dc.identifier10.1007/s12035-017-0733-x
dc.identifier.citation55, 1, 201-212
dc.identifier.issn08937648
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5973
dc.descriptionNeurotrophic factors (NTFs) are a promising therapeutic option for Parkinson’s disease (PD). They exert their function through tyrosine kinase receptors. Our goal was to assess the effects of administering a selective tyrosine kinase inhibitor (vandetanib) that blocks VEGFR2 and RET receptors in a preclinical model of PD. Rats underwent intrastriatal injections of 6-hydroxydopamine (6-OHDA). Two weeks later, the rats received 30 mg/kg vandetanib or saline orally. The effects were assessed using the rotational behavioral test, tyrosine hydroxylase (TH) immunohistochemistry, and western blot. In 6-OHDA-lesioned rats, motor symptoms were almost undetectable, but morphological and biochemical changes were significant. Vandetanib treatment, combined with the presence of 6-OHDA lesions, significantly increased behavioral impairment and morphological and biochemical changes. Therefore, after vandetanib treatment, the TH-immunopositive striatal volume, the percentage of TH+ neurons, and the extent of the axodendritic network in the substantia nigra decreased. Glial fibrillary acidic protein-positivity significantly decreased in the striatum and substantia nigra in the vandetanib-treated group. In addition, p-Akt and p-ERK 1/2 levels were significantly lower and caspase-3 expression significantly increased after vandetanib administration. In conclusion, we demonstrate for the first time the deleterious effect of a tyrosine kinase inhibitor on the dopaminergic system, supporting the beneficial and synergistic effect of NTFs reported in previous papers. © Springer Science+Business Media, LLC 2017.
dc.language.isoen
dc.publisherHumana Press Inc.
dc.subject6-OHDA
dc.subjectNeurotrophic factors
dc.subjectParkinson’s disease
dc.subjectPreclinical model
dc.subjectRET
dc.subjectVandetanib
dc.subjectVEGFR2
dc.subjectcaspase 3
dc.subjectglial fibrillary acidic protein
dc.subjectmitogen activated protein kinase 1
dc.subjectmitogen activated protein kinase 3
dc.subjectoxidopamine
dc.subjectprotein kinase B
dc.subjectprotein Ret
dc.subjectsodium chloride
dc.subjecttyrosine 3 monooxygenase
dc.subjectv 9402
dc.subjectvandetanib
dc.subjectvasculotropin receptor 2
dc.subjectKDR protein, human
dc.subjectN-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
dc.subjectpiperidine derivative
dc.subjectprotein Ret
dc.subjectquinazoline derivative
dc.subjectRet protein, rat
dc.subjectvasculotropin receptor 2
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectArticle
dc.subjectbiochemistry
dc.subjectcontrolled study
dc.subjectdrug effect
dc.subjectenzyme inhibition
dc.subjectexperimental behavioral test
dc.subjecthistology
dc.subjectimmunohistochemistry
dc.subjectmale
dc.subjectnerve cell
dc.subjectneuroprotection
dc.subjectnigroneostriatal system
dc.subjectnonhuman
dc.subjectParkinson disease
dc.subjectprotein expression
dc.subjectprotein function
dc.subjectrat
dc.subjectsignal transduction
dc.subjectsubstantia nigra
dc.subjectWestern blotting
dc.subjectanimal
dc.subjectantagonists and inhibitors
dc.subjectchemically induced
dc.subjectmetabolism
dc.subjectparkinsonism
dc.subjectpathology
dc.subjectSprague Dawley rat
dc.subjecttreatment outcome
dc.subjectAnimals
dc.subjectMale
dc.subjectParkinsonian Disorders
dc.subjectPiperidines
dc.subjectProto-Oncogene Proteins c-ret
dc.subjectQuinazolines
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectTreatment Outcome
dc.subjectVascular Endothelial Growth Factor Receptor-2
dc.titleDeleterious effects of VEGFR2 and RET inhibition in a preclinical model of Parkinson’s disease
dc.typeArticle


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