RT doctoral thesis
T1 Neuroprotective effects of the dual glycogen synthase kinase-3b and phosphodiesterase 7 inhibitor VP3.15 and of an enriched environment in germinal matrix-intraventricular hemorrhage
A1 Atienza Navarro, Isabel
A2 BiomedicinaBiotecnología y Salud Pública
A2 Materno-Infantil y Radiología
K1 recién nacido prematuro
K1 preterm newborn
K1 hemorragia intraventricular de la matriz germinal
K1 germinal matrix-intraventricular hemorrhage
K1 VP3.15
K1 inhibidor de la glucógeno sintasa quinasa-3β
K1 glycogen synthase kinase-3β inhibitor
K1 inhibidor de la fosfodiesterasa 7
K1 phosphodiesterase 7 inhibitor
K1 enriched environment
K1 entorno enriquecido
K1 programas de intervención precoz
K1 early intervention programs
K1 barrera hematoencefálica
K1 blood-brain barrier
K1 líquido cefalorraquídeo
K1 cerebrospinal fluid
K1 neurodegeneración
K1 neurodegeneration
K1 neurogénesis
K1 cognición
K1 atrophy
K1 neurofilamento ligero
K1 neurofilament light
K1 gelsolina
K1 gelsolin
K1 ubiquitina carboxiterminal hidrolasa L1
K1 ubiquitin carboxyterminal hydrolase L1
K1 tau
AB Advances in neonatology have significantly reduced mortality rates associatedwith prematurity. Nevertheless, the incidence and impact of its complications haveremained largely unchanged in recent decades, mainly due to the increased survival ofextremely preterm newborn (PT). Germinal matrix-intraventricular hemorrhage (GMIVH) is one of the most common and severe complications of prematurity. As a result,PT frequently experience short- and long-term sequelae. These impairments includecerebral palsy, cognitive and motor deficits, or neuropsychiatric disorders. Despite thesignificant economic, social, and emotional impact of this pathology, there is currentlyno effective treatment for GM-IVH. PT continue to face an urgent need for newtherapeutic approaches to prevent or reduce associated brain and behavioralcomplicationsVP3.15 is a small heterocyclic molecule belonging to the 5-imino-1,2,4-thiadiazole family, with a dual action as a glycogen synthase kinase-3β (GSK-3β) andphosphodiesterase 7 (PDE7) inhibitor. It has demonstrated neuroprotective and antiinflammatory effects in other neurodegenerative disorders. Given its promisingproperties, VP3.15 may represent a potential therapeutic strategy to reducecomplications associated with GM-IVH, so we studied the short- and long-term effectsof VP3.15 in a murine model that recapitulates the complications of this prematurityrelated pathology. On the other hand, previous studies have shown that earlyintervention programs may have beneficial effects in PT, comparable to those observedin enriched environments (EE) in animal models. Therefore, we also studied the effectsof long-term exposure to a complex EE in a murine model of GM-IVH, and we alsoanalyzed clinically relevant biomarkers of GM-IVH in patients following an interventionprogram focused on parental bonding and stimulation.We have used a murine model of GM-IVH induced by intraventricular unilateraladministration of collagenase (Col) to P7 CD1 mice, who received 7 consecutive days ofi.p. VP3.15 treatment. We analyzed the short (P14) and long-term (P110) effects ofVP3.15 on brain and cerebellar pathology as well as behavioral complications. Ourresults showed that VP3.15 treatment limited brain atrophy by reducing ventricular enlargement and cortical thinning, while it also preserved corpus callosum volume andincreased myelin basic protein (MBP) levels. VP3.15 ameliorated neuronal loss andmaintained Purkinje cell arborization. In addition, the treatment decreased tauhyperphosphorylation and enhanced proliferation and neurogenesis. VP3.15 alsoprevented the spread of the hemorrhage to the periventricular region, reduced thepresence of hemorrhages and hemosiderin deposition, and contributed to preserveblood brain barrier (BBB) integrity. Moreover, VP3.15 restored cerebrospinal fluid (CSF)circulation across several brain areas and reduced the presence of microglia, ultimatelyleading to improve cognitive and motor outcomes following the insult. Interestingly,plasma gelsolin levels (p-GSL), a feasible biomarker of brain damage, improved afterVP3.15 treatment. Altogether, our data support the promising effects of VP3.15 to haltand reduce central nervous system complications associated with GM-IVH of the PT.In parallel, we assessed the long-term effects (P70) of an early exposure to EE inthe same mouse model. EE exposure attenuated brain atrophy, preserved neuronaldensity, limited axonal damage and increased neuronal complexity. Additionally, itpromoted neurogenesis and attenuated the inflammatory response. Importantly, theexposure to EE led to improvements in cognitive performance, alongside normalizationof peripheral markers of brain damage, such as ubiquitin carboxyterminal hydrolase L1(UCHL1) and p-GSL, in treated animals. In parallel, plasma levels of GFAP, NfL and UCHL1,decreased over time in controls and in patients with GM-IVH. Notably, plasma tau levels,a marker of neuronal damage, were significantly reduced in those patients with GM-IVHwho received parental support and nurturing environment whereas p-GSL levels wereincreased. Altogether, our findings demonstrate that early interventions such as EE orparental support improve key pathological features, peripheral biomarkers, andcognitive outcomes associated with GM-IVH, highlighting their therapeutic potential inboth preclinical and clinical contexts.
YR 2026
FD 2026
LK http://hdl.handle.net/10498/39702
UL http://hdl.handle.net/10498/39702
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 05-nov-2026