2. Academic Validation
  3. Glycogen Synthase Kinase-3β Inhibitor VP3.15 Ameliorates Neurogenesis, Neuronal Loss and Cognitive Impairment in a Model of Germinal Matrix-intraventricular Hemorrhage of the Preterm Newborn

Glycogen Synthase Kinase-3β Inhibitor VP3.15 Ameliorates Neurogenesis, Neuronal Loss and Cognitive Impairment in a Model of Germinal Matrix-intraventricular Hemorrhage of the Preterm Newborn

  • Transl Stroke Res. 2025 Apr;16(2):467-483. doi: 10.1007/s12975-023-01229-2.
Isabel Atienza-Navarro 1 2,  Angel Del Marco 1 2,  Pilar Alves-Martinez 1 2,  Maria de Los Angeles Garcia-Perez 1,  Alvaro Raya-Marin 2,  Isabel Benavente-Fernandez 3 4,  Carmen Gil 5,  Ana Martinez 5 6,  Simon Lubian-Lopez 7 8,  Monica Garcia-Alloza 9 10
Affiliations

Affiliations

  • 1 Division of Physiology, School of Medicine, University of Cadiz, C/Dr. Marañon 3, 3rd Floor, 11002, Cadiz, Spain.
  • 2 Biomedical Research and Innovation Institute of Cadiz (INiBICA) Research Unit, Puerta del Mar University Hospital, Cadiz, Spain.
  • 3 Area of Pediatrics, Department of Child and Mother Health and Radiology, School of Medicine, University of Cadiz, Cadiz, Spain.
  • 4 Section of Neonatology, Division of Pediatrics, Puerta del Mar University Hospital, Avda. Ana de Viya sn, 11007, Cadiz, Spain.
  • 5 Centro de Investigaciones, Biologicas Margarita Salas-CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain.
  • 6 Centro de Investigaciones Biomedicas en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Avda. Monforte de Lemos 3-5, 28029, Madrid, Spain.
  • 7 Area of Pediatrics, Department of Child and Mother Health and Radiology, School of Medicine, University of Cadiz, Cadiz, Spain. [email protected].
  • 8 Section of Neonatology, Division of Pediatrics, Puerta del Mar University Hospital, Avda. Ana de Viya sn, 11007, Cadiz, Spain. [email protected].
  • 9 Division of Physiology, School of Medicine, University of Cadiz, C/Dr. Marañon 3, 3rd Floor, 11002, Cadiz, Spain. [email protected].
  • 10 Biomedical Research and Innovation Institute of Cadiz (INiBICA) Research Unit, Puerta del Mar University Hospital, Cadiz, Spain. [email protected].
PMID: 38231413 DOI: 10.1007/s12975-023-01229-2
Abstract

Advances in neonatology have significantly reduced mortality rates due to prematurity. However, complications of prematurity have barely changed in recent decades. Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications of prematurity, and these children are prone to suffer short- and long-term sequelae, including cerebral palsy, cognitive and motor impairments, or neuropsychiatric disorders. Nevertheless, GM-IVH has no successful treatment. VP3.15 is a small, heterocyclic molecule of the 5-imino-1,2,4-thiadiazole family with a dual action as a phosphodiesterase 7 and glycogen synthase kinase-3β (GSK-3β) inhibitor. VP3.15 reduces neuroinflammation and neuronal loss in Other neurodegenerative disorders and might ameliorate complications associated with GM-IVH. We administered VP3.15 to a mouse model of GM-IVH. VP3.15 reduces the presence of hemorrhages and microglia in the short (P14) and long (P110) term. It ameliorates brain atrophy and ventricle enlargement while limiting tau hyperphosphorylation and neuronal and myelin basic protein loss. VP3.15 also improves proliferation and neurogenesis as well as cognition after the insult. Interestingly, plasma gelsolin levels, a feasible biomarker of brain damage, improved after VP3.15 treatment. Altogether, our data support the beneficial effects of VP3.15 in GM-IVH by ameliorating brain neuroinflammatory, vascular and white matter damage, ultimately improving cognitive impairment associated with GM-IVH.

Keywords

Cognition; Germinal matrix-intraventricular hemorrhage; Neurodegeneration; Neurogenesis; Preterm newborn; VP3.15.

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