Biological Implications of a Stroke Therapy Based in Neuroglobin Hyaluronate Nanoparticles. Neuroprotective Role and Molecular Bases

• Published in: International journal of molecular sciences 2021-12, Vol.23 (1), p.247
• Main Authors: Peinado, María Ángeles, Ovelleiro, David, Del Moral, María Luisa, Hernández, Raquel, Martínez-Lara, Esther, Siles, Eva, Pedrajas, José Rafael, García-Martín, María Luisa, Caro, Carlos, Peralta, Sebastián, Morales, María Encarnación, Ruiz, María Adolfina, Blanco, Santos
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Axonogenesis; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - pathology; Brain; Brain Infarction - pathology; Cell death; Cytoskeleton; Endocytosis; Endocytosis - drug effects; Gene Ontology; hyaluronate nanoparticles; Hypoxia; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Ischemia; Kinases; Magnetic Resonance Imaging; Male; MCAO; Mitochondria; Nanoparticles; Nanoparticles - chemistry; Neurogenesis; Neuroglobin; Neuroglobin - pharmacology; Neuroglobin - therapeutic use; Neurons - drug effects; Neurons - pathology; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Nitrosative Stress - drug effects; Oxidative Stress - drug effects; Physiology; Principal Component Analysis; Protein metabolism; Protein turnover; Proteins; Proteomics; Rats; Rats, Wistar; Reperfusion; Signal transduction; Stroke; Stroke - diagnostic imaging; Stroke - pathology; Stroke - therapy; Survival Analysis; Thiobarbituric Acid Reactive Substances - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23010247

Exogenous neuroprotective protein neuroglobin (Ngb) cannot cross the blood-brain barrier. To overcome this difficulty, we synthesized hyaluronate nanoparticles (NPs), able to deliver Ngb into the brain in an animal model of stroke (MCAO). These NPs effectively reached neurons, and were microscopically identified after 24 h of reperfusion. Compared to MCAO non-treated animals, those treated with Ngb-NPs showed survival rates up to 50% higher, and better neurological scores. Tissue damage improved with the treatment, but no changes in the infarct volume or in the oxidative/nitrosative values were detected. A proteomics approach ( -value < 0.02; fold change = 0.05) in the infarcted areas showed a total of 219 proteins that significantly changed their expression after stroke and treatment with Ngb-NPs. Of special interest, are proteins such as FBXO7 and NTRK2, which were downexpressed in stroke, but overexpressed after treatment with Ngb-NPs; and ATX2L, which was overexpressed only under the effect of Ngb. Interestingly, the proteins affected by the treatment with Ngb were involved in mitochondrial function and cell death, endocytosis, protein metabolism, cytoskeletal remodeling, or synaptic function, and in regenerative processes, such as dendritogenesis, neuritogenesis, or sinaptogenesis. Consequently, our pharmaceutical preparation may open new therapeutic scopes for stroke and possibly for other neurodegenerative pathologies.