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

Advances in neonatology have significantly reduced mortality rates associated with prematurity. Nevertheless, the incidence and impact of its complications have remained largely unchanged in recent decades, mainly due to the increased survival of extremely 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 include cerebral palsy, cognitive and motor deficits, or neuropsychiatric disorders. Despite the significant economic, social, and emotional impact of this pathology, there is currently no effective treatment for GM-IVH. PT continue to face an urgent need for new therapeutic approaches to prevent or reduce associated brain and behavioral complications VP3.15 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) and phosphodiesterase 7 (PDE7) inhibitor. It has demonstrated neuroprotective and antiinflammatory effects in other neurodegenerative disorders. Given its promising properties, VP3.15 may represent a potential therapeutic strategy to reduce complications associated with GM-IVH, so we studied the short- and long-term effects of VP3.15 in a murine model that recapitulates the complications of this prematurityrelated pathology. On the other hand, previous studies have shown that early intervention programs may have beneficial effects in PT, comparable to those observed in enriched environments (EE) in animal models. Therefore, we also studied the effects of long-term exposure to a complex EE in a murine model of GM-IVH, and we also analyzed clinically relevant biomarkers of GM-IVH in patients following an intervention program focused on parental bonding and stimulation. We have used a murine model of GM-IVH induced by intraventricular unilateral administration of collagenase (Col) to P7 CD1 mice, who received 7 consecutive days of i.p. VP3.15 treatment. We analyzed the short (P14) and long-term (P110) effects of VP3.15 on brain and cerebellar pathology as well as behavioral complications. Our results showed that VP3.15 treatment limited brain atrophy by reducing ventricular enlargement and cortical thinning, while it also preserved corpus callosum volume and increased myelin basic protein (MBP) levels. VP3.15 ameliorated neuronal loss and maintained Purkinje cell arborization. In addition, the treatment decreased tau hyperphosphorylation and enhanced proliferation and neurogenesis. VP3.15 also prevented the spread of the hemorrhage to the periventricular region, reduced the presence of hemorrhages and hemosiderin deposition, and contributed to preserve blood brain barrier (BBB) integrity. Moreover, VP3.15 restored cerebrospinal fluid (CSF) circulation across several brain areas and reduced the presence of microglia, ultimately leading to improve cognitive and motor outcomes following the insult. Interestingly, plasma gelsolin levels (p-GSL), a feasible biomarker of brain damage, improved after VP3.15 treatment. Altogether, our data support the promising effects of VP3.15 to halt and 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 in the same mouse model. EE exposure attenuated brain atrophy, preserved neuronal density, limited axonal damage and increased neuronal complexity. Additionally, it promoted neurogenesis and attenuated the inflammatory response. Importantly, the exposure to EE led to improvements in cognitive performance, alongside normalization of 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-IVH who received parental support and nurturing environment whereas p-GSL levels were increased. Altogether, our findings demonstrate that early interventions such as EE or parental support improve key pathological features, peripheral biomarkers, and cognitive outcomes associated with GM-IVH, highlighting their therapeutic potential in both preclinical and clinical contexts.

Author dc:creator

• Atienza Navarro, Isabel

Advisors dc:contributor.advisor

• García Alloza, Mónica
• Lubián López, Simón Pedro

• recién nacido prematuro
• preterm newborn
• hemorragia intraventricular de la matriz germinal
• germinal matrix-intraventricular hemorrhage
• VP3.15
• inhibidor de la glucógeno sintasa quinasa-3β
• glycogen synthase kinase-3β inhibitor
• inhibidor de la fosfodiesterasa 7
• phosphodiesterase 7 inhibitor
• enriched environment
• entorno enriquecido
• programas de intervención precoz
• early intervention programs
• barrera hematoencefálica
• blood-brain barrier
• líquido cefalorraquídeo
• cerebrospinal fluid
• neurodegeneración
• neurodegeneration
• neurogénesis
• cognición
• atrophy
• neurofilamento ligero
• neurofilament light
• gelsolina
• gelsolin
• ubiquitina carboxiterminal hidrolasa L1
• ubiquitin carboxyterminal hydrolase L1
• tau

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 Internacional

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10498/39702

OAI identifier oai:identifier

oai:rodin.uca.es:10498/39702