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Environmental Enrichment Reverses Tyrosine Kinase Inhibitor-Mediated Impairment Through BDNF-TrkB Pathway

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Abstract

Exposure to an enriched environment (EE) has neuroprotective benefits and improves recovery from brain injury due to, among other, increased neurotrophic factor expression. Through these neurotrophins, important cortical and hippocampal changes occur. Vandetanib acts as a tyrosine kinase inhibitor of cell receptors, among others, the vascular endothelial growth factor receptor (VEGFR). Our aim was to investigate the effectiveness of EE counteracting cognitive and cellular effects after tyrosine kinase receptor blockade. Animals were reared under standard laboratory condition or EE; both groups received vandetanib or vehicle. Visuospatial learning was tested with Morris water maze. Neuronal, interneuronal, and vascular densities were measured by inmunohistochemistry and histochemistry techniques. Quantifications were performed in the hippocampus and in the visual cortex. Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), Akt, and Erk were measured by Western blot technique. Vandetanib produces a significant decrease in vascular and neuronal densities and reduction in the expression of molecules involved in survival and proliferation processes such as phospho-Akt/Akt and phospho-Erk/Erk. These results correlated to a cognitive impairment in visuospatial test. On the other hand, animals reared in an EE are able to reverse the negative effects, activating PI3K-AKT and MAP kinase pathways mediated by BDNF-TrkB binding. Present results provide novel and consistent evidences about the usefulness of living in EE as a strategy to improve deleterious effects of blocking neurotrophic pathways by vandetanib and the notable role of the BDNF-TrkB pathway to balance the neurovascular unit and cognitive effects.

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Acknowledgements

Devote to Enrike Gutierrez Argandoña, a collaborator for ones, a mentor for others, and a friend for all. Wherever you are, wait for us looking for an exciting challenge.

The authors thank Prof. Carmen Martínez-Cue (Department of Physiology and Pharmacology of the University of Cantabria) for his assistance with the statistical analysis.

Funding

This work was supported by Government of the Basque Country (GIC IT 794/13) and University of the Basque Country UPV/EHU (UFI 11/32), (EHU 14/33). A. Murueta-Goyena is supported by a predoctoral fellowship of the University of the Basque Country (UPV/EHU).

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Authors and Affiliations

  1. Laboratory of Clinical and Experimental Neuroscience (LaNCE), Department of Neuroscience, Faculty of Medicine and Surgery, University of the Basque Country (UPV/EHU), 48940, Leioa, Bizkaia, Spain

    Harkaitz Bengoetxea, Naiara Ortuzar, Ane Murueta-Goyena & José V. Lafuente

  2. Department of Neuroscience, Faculty of Medicine and Surgery, University of the Basque Country (UPV/EHU), Barrio Sarriena, E-48940, Leioa, Bizkaia, Spain

    Irantzu Rico-Barrio

  3. Nanoneurosurgery Group, BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain

    José V. Lafuente

  4. Faculty of Health Science, Universidad Autónoma de Chile, Santiago de Chile, Chile

    José V. Lafuente

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  1. Harkaitz Bengoetxea
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  2. Irantzu Rico-Barrio
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  3. Naiara Ortuzar
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  4. Ane Murueta-Goyena
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  5. José V. Lafuente
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Correspondence to Harkaitz Bengoetxea.

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Bengoetxea, H., Rico-Barrio, I., Ortuzar, N. et al. Environmental Enrichment Reverses Tyrosine Kinase Inhibitor-Mediated Impairment Through BDNF-TrkB Pathway. Mol Neurobiol 55, 43–59 (2018). https://doi.org/10.1007/s12035-017-0716-y

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