ED Sciences de la Vie et de la Santé
Combination Therapy to Reduce the Burden of Neonatal Brain Injury: Exploring the Therapeutic Potential of URB447 in a Preclinical Model of Hypoxia-Ischemia
by Marc CHILLIDA FIBLA (Centre de Résonnance Magnétique des Systèmes Biologiques)
The defense will take place at 10h00 - Conference room Barrio Sarriena z/g, Faculty of Nursing and Medicine, 48940 Leioa, Biscay, Spain
in front of the jury composed of
- Silvia CARLONI - Directrice de recherche - Università degli Studi di Urbino Carlo Bo - Rapporteur
- Juan Carlos ARANGO - Directeur de recherche - Faculty of Nursing and Medicine, Department of Cell Biology and Histology - Examinateur
- Emilie PACARY - Chargée de recherche - Neurocentre Magendie - INSERM U 1215 - Examinateur
- Luc PELLERIN - Professeur des universités - praticien hospitalier - Université de Poitiers - Examinateur
- Walter BALDUINI - Professor - Università degli Studi di Urbino Carlo Bo - Rapporteur
Hypoxic-ischemic encephalopathy is a neurological condition caused by inadequate blood flow and oxygen delivery to the brain before, during or shortly after the delivery that may affect term or near-term newborns. Clinically, therapeutic hypothermia is the only treatment for neonates with hypoxic-ischemic encephalopathy. Despite treatment, this neurological condition remains one of the most common causes of mortality and morbidity in neonates. Therefore, there is a need to discover new and more effective therapies that may complement therapeutic hypothermia. In this context, cannabinoids have emerged as potential candidates due to their neuroprotective properties. The synthetic cannabinoid URB447, with a very interesting pharmacological profile as it acts as a CB1 antagonist and CB2 agonist simultaneously, has demonstrated efficacy as monotherapy in a preclinical model of hypoxic-ischemic encephalopathy under normothermic conditions. The main objective of this thesis was to evaluate the neuroprotective potential of URB447 in combination with therapeutic hypothermia in a preclinical model of hypoxic-ischemic brain injury in neonatal rats. Our results indicate that the combined treatment of URB447 and therapeutic hypothermia ameliorates brain injury and enhances the therapeutic effect of cooling, reducing infarct volume, preserving myelination, decreasing astroglial and microglial reactivity, ameliorating the inflammatory response, and increasing the neuroregenerative capacity of the damaged brain, by preserving neurogenesis. Furthermore, its neuroprotective effects were confirmed in motor and cognitive tests in both the medium and the long term. In conclusion, URB447 could be considered as a possible adjunct therapy to therapeutic hypothermia for the treatment of hypoxic-ischemic encephalopathy in newborns.