{"id":{"repo_id":"cadiz","oai_identifier":"oai:rodin.uca.es:10498/39702"},"canonical_url":"https://search.dev.ndltd.org/etd/cadiz/oai:rodin.uca.es:10498/39702","repository":{"repo_id":"cadiz","name":"Universidad de Cadiz","base_url":"https://rodin.uca.es/oai/request"},"display":{"title":"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","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Atienza Navarro, Isabel"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["García Alloza, Mónica","Lubián López, Simón Pedro"],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026","date_published":"2026","updated_at":"2026-07-24T01:29:44Z","subjects":["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"],"languages":["eng"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10498/39702","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["García Alloza, Mónica","Lubián López, Simón Pedro"]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Biomedicina, Biotecnología y Salud Pública","Materno-Infantil y Radiología"]},{"key":"dc:creator","label":"Author","values":["Atienza Navarro, Isabel"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-06-03T11:53:19Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-06-03T11:53:19Z"]},{"key":"dc:date.issued","label":"Date","values":["2026"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["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"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10498/39702"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.","Los avances en neonatología han reducido significativamente las tasas de mortalidad asociadas a la prematuridad. Sin embargo, la incidencia y el impacto de sus complicaciones han permanecido prácticamente inalterados en las últimas décadas, principalmente debido a la mayor supervivencia de los recién nacidos prematuros (PT) extremos. La hemorragia intraventricular de matriz germinal (GM-IVH) es una de las complicaciones más frecuentes y graves de la prematuridad. Como consecuencia, los PT experimentan con frecuencia secuelas a corto y largo plazo. Estas secuelas incluyen parálisis cerebral, déficits cognitivos y motores o trastornos neuropsiquiátricos. A pesar del gran impacto económico, social y emocional de esta patología, actualmente no existe ningún tratamiento eficaz para la GM-IVH, y los PT siguen teniendo la necesidad urgente de nuevos enfoques terapéuticos para prevenir o reducir las complicaciones cerebrales y conductuales. VP3.15 es una pequeña molécula heterocíclica de la familia de los 5-imino-1,2,4- tiadiazoles con doble acción como inhibidor de la glucógeno sintasa quinasa-3β (GSK3β) y de la fosfodiesterasa 7 (PDE7). Ha demostrado efectos neuroprotectores y antiinflamatorios en otros trastornos neurodegenerativos. Dadas sus prometedoras propiedades, VP3.15 puede proporcionar una estrategia terapéutica para reducir las complicaciones asociadas a la GM-IVH, por lo que hemos estudiado sus efectos a corto y largo plazo en un modelo murino que reproduce las complicaciones de esta patología. Por otro lado, estudios previos han demostrado que los programas de intervención temprana pueden tener efectos beneficiosos en el PT, comparables a los observados con entornos enriquecidos (EE) en modelos animales. Por lo tanto, también hemos estudiado los efectos de la exposición a largo plazo a un EE complejo en un modelo murino de GM-IVH. Paralelamente hemos analizado biomarcadores clínicamente relevantes de GM-IVH en pacientes que seguían un programa de intervención centrado en el vínculo y la estimulación parentales. Hemos utilizado un modelo murino de GM-IVH inducido mediante la administración intraventricular unilateral de colagenasa (Col) a ratones CD1 a P7, que recibieron tratamiento i.p. con VP3.15 durante 7 días. Analizamos los efectos a corto (P14) y largo plazo (P110) de VP3.15 sobre la patología cerebral y cerebelosa, así como las complicaciones conductuales. Nuestros resultados mostraron que el tratamiento con VP3.15 limita la atrofia cerebral reduciendo el ensanchamiento ventricular y el adelgazamiento cortical, mientras que también preserva el volumen del cuerpo calloso y aumenta los niveles de la proteína básica de mielina (MBP). El tratamiento con VP3.15 limita la pérdida neuronal y la simplificación de la arborización de las células de Purkinje. Además, el tratamiento disminuye la hiperfosforilación de tau y aumenta la proliferación y la neurogénesis. VP3.15 también impide la propagación de la hemorragia a la región periventricular, reduce la presencia de hemorragias y el depósito de hemosiderina, y contribuye a preservar la integridad de la barrera hematoencefálica (BBB). Del mismo modo, VP3.15 restablece la circulación del líquido cefalorraquídeo (CSF) en diferentes regiones cerebrales y reduce la presencia de microglía, lo que en última instancia conduce a una mejora de los procesos cognitivos y motores tras la lesión. Además, los niveles plasmáticos de gelsolina (p-GSL), un posible biomarcador de daño neuronal, mejoran tras el tratamiento con VP3.15. En conjunto, nuestros datos apoyan los efectos prometedores de VP3.15 para detener y reducir las complicaciones del sistema nervioso central asociadas con GM-IVH del PT. Paralelamente, evaluamos los efectos a largo plazo (P70) de una exposición temprana a un EE en el mismo modelo de ratón. La exposición a un EE atenuó la atrofia cerebral, preservó la densidad neuronal, limitó el daño axonal y contribuyó a mantener la complejidad neuronal. Además, promovió la neurogénesis y atenuó la respuesta inflamatoria. Es importante destacar que la exposición a EE también produjo mejoras en el rendimiento cognitivo, junto con la normalización de marcadores periféricos de daño cerebral, como la ubiquitina carboxiterminal hidrolasa L1 (UCHL1) y p-GSL, en los animales tratados. Del mismo modo, los niveles plasmáticos de GFAP, NfL y UCHL1, disminuyeron con el tiempo en los pacientes control y en los pacientes con GM-IVH. En particular, los niveles plasmáticos de tau, un marcador de daño neuronal, se redujeron significativamente en aquellos pacientes con GM-IVH que recibieron apoyo parental y un entorno enriquecido, mientras que nos niveles de p-GSL aumentaron. En conjunto, nuestros hallazgos demuestran que la intervención temprana, con un EE o el apoyo parental, mejoran características patológicas clave, biomarcadores periféricos y los procesos cognitivos tras una GM-IVH, destacando su potencial terapéutico tanto en contextos preclínicos como clínicos."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["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"]}]}],"canonical_facts":{"dc:contributor.advisor":["García Alloza, Mónica","Lubián López, Simón Pedro"],"dc:contributor.other":["Biomedicina, Biotecnología y Salud Pública","Materno-Infantil y Radiología"],"dc:creator":["Atienza Navarro, Isabel"],"dc:date.accessioned":["2026-06-03T11:53:19Z"],"dc:date.available":["2026-06-03T11:53:19Z"],"dc:date.issued":["2026"],"dc:description.abstract":["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.","Los avances en neonatología han reducido significativamente las tasas de mortalidad asociadas a la prematuridad. Sin embargo, la incidencia y el impacto de sus complicaciones han permanecido prácticamente inalterados en las últimas décadas, principalmente debido a la mayor supervivencia de los recién nacidos prematuros (PT) extremos. La hemorragia intraventricular de matriz germinal (GM-IVH) es una de las complicaciones más frecuentes y graves de la prematuridad. Como consecuencia, los PT experimentan con frecuencia secuelas a corto y largo plazo. Estas secuelas incluyen parálisis cerebral, déficits cognitivos y motores o trastornos neuropsiquiátricos. A pesar del gran impacto económico, social y emocional de esta patología, actualmente no existe ningún tratamiento eficaz para la GM-IVH, y los PT siguen teniendo la necesidad urgente de nuevos enfoques terapéuticos para prevenir o reducir las complicaciones cerebrales y conductuales. VP3.15 es una pequeña molécula heterocíclica de la familia de los 5-imino-1,2,4- tiadiazoles con doble acción como inhibidor de la glucógeno sintasa quinasa-3β (GSK3β) y de la fosfodiesterasa 7 (PDE7). Ha demostrado efectos neuroprotectores y antiinflamatorios en otros trastornos neurodegenerativos. Dadas sus prometedoras propiedades, VP3.15 puede proporcionar una estrategia terapéutica para reducir las complicaciones asociadas a la GM-IVH, por lo que hemos estudiado sus efectos a corto y largo plazo en un modelo murino que reproduce las complicaciones de esta patología. Por otro lado, estudios previos han demostrado que los programas de intervención temprana pueden tener efectos beneficiosos en el PT, comparables a los observados con entornos enriquecidos (EE) en modelos animales. Por lo tanto, también hemos estudiado los efectos de la exposición a largo plazo a un EE complejo en un modelo murino de GM-IVH. Paralelamente hemos analizado biomarcadores clínicamente relevantes de GM-IVH en pacientes que seguían un programa de intervención centrado en el vínculo y la estimulación parentales. Hemos utilizado un modelo murino de GM-IVH inducido mediante la administración intraventricular unilateral de colagenasa (Col) a ratones CD1 a P7, que recibieron tratamiento i.p. con VP3.15 durante 7 días. Analizamos los efectos a corto (P14) y largo plazo (P110) de VP3.15 sobre la patología cerebral y cerebelosa, así como las complicaciones conductuales. Nuestros resultados mostraron que el tratamiento con VP3.15 limita la atrofia cerebral reduciendo el ensanchamiento ventricular y el adelgazamiento cortical, mientras que también preserva el volumen del cuerpo calloso y aumenta los niveles de la proteína básica de mielina (MBP). El tratamiento con VP3.15 limita la pérdida neuronal y la simplificación de la arborización de las células de Purkinje. Además, el tratamiento disminuye la hiperfosforilación de tau y aumenta la proliferación y la neurogénesis. VP3.15 también impide la propagación de la hemorragia a la región periventricular, reduce la presencia de hemorragias y el depósito de hemosiderina, y contribuye a preservar la integridad de la barrera hematoencefálica (BBB). Del mismo modo, VP3.15 restablece la circulación del líquido cefalorraquídeo (CSF) en diferentes regiones cerebrales y reduce la presencia de microglía, lo que en última instancia conduce a una mejora de los procesos cognitivos y motores tras la lesión. Además, los niveles plasmáticos de gelsolina (p-GSL), un posible biomarcador de daño neuronal, mejoran tras el tratamiento con VP3.15. En conjunto, nuestros datos apoyan los efectos prometedores de VP3.15 para detener y reducir las complicaciones del sistema nervioso central asociadas con GM-IVH del PT. Paralelamente, evaluamos los efectos a largo plazo (P70) de una exposición temprana a un EE en el mismo modelo de ratón. La exposición a un EE atenuó la atrofia cerebral, preservó la densidad neuronal, limitó el daño axonal y contribuyó a mantener la complejidad neuronal. Además, promovió la neurogénesis y atenuó la respuesta inflamatoria. Es importante destacar que la exposición a EE también produjo mejoras en el rendimiento cognitivo, junto con la normalización de marcadores periféricos de daño cerebral, como la ubiquitina carboxiterminal hidrolasa L1 (UCHL1) y p-GSL, en los animales tratados. Del mismo modo, los niveles plasmáticos de GFAP, NfL y UCHL1, disminuyeron con el tiempo en los pacientes control y en los pacientes con GM-IVH. En particular, los niveles plasmáticos de tau, un marcador de daño neuronal, se redujeron significativamente en aquellos pacientes con GM-IVH que recibieron apoyo parental y un entorno enriquecido, mientras que nos niveles de p-GSL aumentaron. En conjunto, nuestros hallazgos demuestran que la intervención temprana, con un EE o el apoyo parental, mejoran características patológicas clave, biomarcadores periféricos y los procesos cognitivos tras una GM-IVH, destacando su potencial terapéutico tanto en contextos preclínicos como clínicos."],"dc:format":["application/pdf"],"dc:identifier.uri":["http://hdl.handle.net/10498/39702"],"dc:language.iso":["eng"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:subject":["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"],"dc:title":["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"],"dc:type":["doctoral thesis"]},"updated_at":"2026-07-24T01:29:44Z"}