α-Methyl-prednisolone normalizes the PKC mediated brain angiogenesis in dystrophic mdx mice

Tiziana Annese; Simona Ruggieri; Michela De Giorgis; Domenico Ribatti; Roberto Tamma; Beatrice Nico

doi:10.1016/j.brainresbull.2019.01.023

α-Methyl-prednisolone normalizes the PKC mediated brain angiogenesis in dystrophic mdx mice

Brain Res Bull. 2019 Apr:147:69-77. doi: 10.1016/j.brainresbull.2019.01.023. Epub 2019 Jan 31.

Authors

Tiziana Annese¹, Simona Ruggieri², Michela De Giorgis³, Domenico Ribatti⁴, Roberto Tamma⁵, Beatrice Nico⁶

Affiliations

¹ Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, University of Bari, Italy. Electronic address: tiziana.annese@uniba.it.
² Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, University of Bari, Italy. Electronic address: simona.ruggieri@uniba.it.
³ Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, University of Bari, Italy. Electronic address: michelina.degiorgis@uniba.it.
⁴ Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, University of Bari, Italy. Electronic address: domenico.ribatti@uniba.it.
⁵ Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, University of Bari, Italy. Electronic address: roberto.tamma@uniba.it.
⁶ Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School Bari, University of Bari, Italy. Electronic address: beatrice.nico@uniba.it.

PMID: 30711624
DOI: 10.1016/j.brainresbull.2019.01.023

Abstract

A fraction of patients affected by Duchenne Muscular Dystrophy (DMD) shows mental disability as a consequence of neuronal and metabolic alteration. In this study, we evaluated the effect of α-methyl-prednisolone (PDN) on the expression of the angiogenic marker HIF1α, VEGFA and VEGFR-2 (FLK1) in correlation with PKC expression in the brain of mdx mouse, an experimental model of DMD. We demonstrated that HIF1α, VEGFA and FLK1 are overexpressed in the brain of dystrophic mdx mice in parallel with an increase of PKC expression and reduction of the tight junctions Occludin leading to altered angiogenesis. Moreover, we demonstrated that PDN treatment induces a significant reduction in the HIF1α, VEGF, FLK1, and PKC mRNA and proteins levels and restores Occludin expression reducing its phosphorylation pattern. Our results suggest a new mechanism of action of PDN that through PKC suppression normalizes the angiogenesis in dystrophic mdx brains.

Keywords: Angiogenesis; Duchenne Muscular Dystrophy; PKC; Prednisolone; VEGFA; VEGFR-2 (FLK1).

MeSH terms

Angiogenesis Modulating Agents / metabolism
Animals
Blood-Brain Barrier / metabolism
Brain / metabolism
Disease Models, Animal
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Male
Methylprednisolone / metabolism
Methylprednisolone / pharmacology*
Mice
Mice, Inbred C57BL
Mice, Inbred mdx
Muscle, Skeletal / metabolism
Muscular Dystrophy, Duchenne / metabolism*
Neovascularization, Pathologic
Neurons / metabolism
Occludin / metabolism
Phosphorylation
Protein Kinase C / metabolism*
Protein Kinase C / physiology
Tight Junctions / metabolism
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Angiogenesis Modulating Agents
Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
Occludin
Vascular Endothelial Growth Factor A
vascular endothelial growth factor A, mouse
Vascular Endothelial Growth Factor Receptor-2
Protein Kinase C
Methylprednisolone