Intranasal Administration of Mesenchymal Stem Cells in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy

• Autor(a) principal: Carvalho, Alexandre Martins
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/13895
• topic: Administração Intranasal; Células Estaminais Mesenquimais; Encefalopatia Hipóxico-Isquémica; Terapia Celular; Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas

Neonatal Hypoxic-Ischemic Encephalopathy (HIE) is a specific form of encephalopathy that arises due to a period of diminished oxygen delivery and blood flow to the brain of the neonate. This neurological disorder affects approximately 1.5 and 2 – 9 neonates per 1000 live births in developed and developing countries, respectively. In addition, it is associated with a mortality rate from 15% to 25%. Furthermore, reports indicate that the surviving neonates face additional risks, with approximately 20% to 25% experiencing long-term neurological complications such as cerebral palsy, epilepsy, convulsions, muscular hypotonia, as well as behavioral deficits. At the clinical level, it has been observed that this disease can be caused by various factors, including placental abruption or previa, maternal hypotension, shoulder dystonia, uterine rupture, and umbilical cord prolapse. Currently, the only approved treatment for neonatal HIE is therapeutic hypothermia. This approach entails the controlled reduction of the infant's internal body or head temperature to 33.5ºC during 72 hours. Despite the advantages of this therapy, which have been established in various neurological disorders, it remains a strategy with multiple limitations. Thus, there is an urgent need to devise novel therapeutic modalities, such as cell therapy. This intervention has displayed promising outcomes in pre-clinical studies for diverse neurological disorders, resulting in the amelioration of both motor and cognitive functions, reduction of the brain lesion volume, increased levels of antiapoptotic and trophic factors, and modulation of inflammatory activities. In recent years, there has been a notable interest in the use of mesenchymal stem cells (MSCs) for therapeutic purposes, owing to their remarkable potential for differentiation and self-renewal. Empirical evidence has also established the efficacy of MSCs in promoting functional recuperation and demonstrating neuroprotective properties. The optimal delivery, migration, and integration of MSCs in the lesioned brain tissue are crucial in ensuring the effectiveness of the treatment. Consequently, it is imperative to establish the most suitable route of administration. Among the various delivery routes, the intranasal (IN) route has emerged as a promising technique for the administration of MSCs due to its non-invasive nature and low associated risks, rendering it a feasible option for clinical implementation. This study aims to assess the therapeutic potential of MSCs administered intranasally in improving animal motor and cognitive function, compared to intravenous administration (results obtained in previous studies from our research group) and, additionally, perform an initial study on the impact of hypoxic pre-conditioning of MSCs, intranasally delivered on the treatment efficacy. In this study, IN administration of MSCs at a cell dose of 50x103 cells per animal was conducted to assess the therapeutic efficacy of the administration of reduced cell dosage through IN administration vs intravenous administration. The Rice-Vannucci model was used as a neonatal hypoxic ischemic encephalopathy lesion model in 10-day-0ld Wistar rats, followed by MSCs IN administration. Behavioral tests were performed to evaluate motor and cognitive function of animals to assess treatment effectiveness. Our results show that IN delivery of MSC lead to increased motor and memory recovery than intravenous administration, supporting the potential of IN administration of MSCs for this condition. Preliminary results show that hypoxic pre-conditioning had no significant impact on MSCs-induced functional recovery.