Preventive Triple Gene Therapy Reduces the Negative Consequences of Ischemia-Induced Brain Injury after Modelling Stroke in a Rat

Autor: Mikhail Evgenyevich Sokolov, Airat Gibadullin, Andrei Izmailov, Dmitry Trofimov, Evgeny Kim, Filip O. Fadeev, Vage Markosyan, Rustem R. Islamov, Farid V. Bashirov, L. F. Nurullin, Zufar Zufarovich Safiullov, Grayr Kundakchyan, Maksim Kuznetsov, Ilnur I. Salafutdinov
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Vascular Endothelial Growth Factor A
Genetic enhancement
Pharmacology
Monocytes
lcsh:Chemistry
preventive gene therapy
Neurotrophic factors
Glial cell line-derived neurotrophic factor
NCAM
Stroke
lcsh:QH301-705.5
Neural Cell Adhesion Molecules
Spectroscopy
biology
human umbilical cord blood mononuclear cells
Penumbra
General Medicine
stroke
VEGF
GDNF
Neuroprotection
Recombinant Proteins
Computer Science Applications
Astrogliosis
Caspases
Cytokines
Intercellular Signaling Peptides and Proteins
Female
Chemokines
Neuroglia
Genetic Vectors
Ischemia
Catalysis
Article
Adenoviridae
Inorganic Chemistry
medicine
Animals
Glial Cell Line-Derived Neurotrophic Factor
Physical and Theoretical Chemistry
Rats
Wistar
Molecular Biology
business.industry
Organic Chemistry
Genetic Therapy
Recovery of Function
medicine.disease
Rats
Disease Models
Animal
lcsh:Biology (General)
lcsh:QD1-999
adenoviral vector
Astrocytes
Brain Injuries
biology.protein
business
Zdroj: International Journal of Molecular Sciences
Volume 21
Issue 18
International Journal of Molecular Sciences, Vol 21, Iss 6858, p 6858 (2020)
ISSN: 1422-0067
Popis: Currently, the main fundamental and clinical interest for stroke therapy is focused on developing a neuroprotective treatment of a penumbra region within the therapeutic window. The development of treatments for ischemic stroke in at-risk patients is of particular interest. Preventive gene therapy may significantly reduce the negative consequences of ischemia-induced brain injury. In the present study, we suggest the approach of preventive gene therapy for stroke. Adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM) or gene engineered umbilical cord blood mononuclear cells (UCB-MC) overexpressing recombinant VEGF, GDNF, and NCAM were intrathecally injected before distal occlusion of the middle cerebral artery in rats. Post-ischemic brain recovery was investigated 21 days after stroke modelling. Morphometric and immunofluorescent analysis revealed a reduction of infarction volume accompanied with a lower number of apoptotic cells and decreased expression of Hsp70 in the peri-infarct region in gene-treated animals. The lower immunopositive areas for astrocytes and microglial cells markers, higher number of oligodendrocytes and increased expression of synaptic proteins suggest the inhibition of astrogliosis, supporting the corresponding myelination and functional recovery of neurons in animals receiving preventive gene therapy. In this study, for the first time, we provide evidence of the beneficial effects of preventive triple gene therapy by an adenoviral- or UCB-MC-mediated intrathecal simultaneous delivery combination of vegf165, gdnf, and ncam1 on the preservation and recovery of the brain in rats with subsequent modelling of stroke.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje