EVALUATION OF THE EFFECT OF TLR4 PHARMACOLOGICAL BLOCKADE ON THE DEVELOPMENT OF PERINEURONAL NETS AND IN THE DISTRIBUTION OF INHIBITORY INTERNEURONS OF MICE SUBMITTED TO TWO-HIT MODEL

• Grant number: 24/14877-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Silvia Honda Takada
• Grantee: Helen Indalencio Gomes
• Host Institution: Centro de Matemática, Computação e Cognição (CMCC). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

Abstract

Maternal immune activation is a major cause of premature births, and preterm newborns are at high risk of complications such as perinatal asphyxia. Combined, these two "inflammatory hits" can cause neurodevelopmental impairment and lead to disorders such as autism spectrum disorder. Perineuronal networks are crucial for the maturation of inhibitory interneurons and appear to be directly influenced by oxidative stress and neuroinflammation resulting from perinatal asphyxia. These sequelae are caused by inflammatory responses activated by receptor signaling pathways such as TLR4. Resatorvid, known as TAK-242, is a specific TLR4 inhibitor, making it a potential therapeutic strategy to prevent inflammation from occurring. The aim of this project is to evaluate the effect of pharmacological blockade of TAK-242 after maternal immune activation and perinatal asphyxia in the hippocampus of mice, to investigate possible changes in perineuronal networks and parvalbumin-positive interneurons. Neonatal mice will be submitted to oxygen deprivation. One of the groups will receive administration of TAK-242 for 7 days. Hippocampal perineuronal networks will be evaluated with Wisteria Floribunda (WFA) immunofluorescence and parvalbumin-positive interneurons will be analyzed by parvalbumin immunofluorescence, both at P45. A better understanding of the changes that can be caused by TLR4 activation in the double-hit model may contribute to the development of future therapeutic strategies aimed at alleviating the sequelae of perinatal asphyxia.