Neuroprotective effect of caffeine in a neonatal model of inflammation-sensitized hypoxic ischemic brain injury by modulation of the AMPK/mTOR pathway

• Applicant: Professor Dr. Hemmen Sabir
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558456379

Neonatal hypoxic-ischemic encephalopathy (HIE) is a type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. Currently, therapeutic hypothermia is the only standard treatment available. However, up to 45% of treated neonates do not benefit from this treatment. In particular, hypothermia is not effective in inflammation-sensitive HIE. These cases occur primarily in low- and middle-income countries, so HIE remains a significant global burden. We have shown that peripheral cells such as neutrophils and central nervous system immune cells such as microglia play an important role in resolving inflammation after neonatal HIE. Preventing excessive inflammation by regulating the pro/anti-inflammatory balance of microglia is important in mitigating the progression of brain injury and disease. Among the many factors involved in regulating microglial phenotype, cellular energy status plays an important role, and AMPK/mTOR signaling plays a crucial role in this regard. We found that after experimental neonatal HIE AMPK is strongly activated, whereas mTOR is downregulated. Caffeine, a methylxanthine drug, is widely used in neonatal intensive care units for the treatment of neonatal apnea and has attracted attention for its neuroprotective effects. In our experimental HIE model, we found that treatment with caffeine reduced hypoxic-ischemic brain damage and microgliosis. Interestingly, we found that caffeine plays a key role in regulating the AMPK/mTOR pathway and autophagy mechanism early after HIE. This may explain the observed neuroprotective effect of caffeine by directly regulating molecular signaling pathways involved in the early resolution of inflammation. Our findings on caffeine may allow us to develop alternative treatments to therapeutic hypothermia and also serve as a treatment in cases where therapeutic hypothermia is not effective, such as in inflammation-sensitized HIE. The aim of our project is to describe AMPK/mTOR regulatory mechanisms and their role during microglial priming and autophagy using our in vitro and in vivo models of experimental inflammation-sensitized hypoxic-ischemic brain injury. In addition, we will investigate the role of caffeine as a potential neuroprotective agent in our models and analyze its effect on microglial priming and its influence on AMPK/mTOR signaling and subsequent autophagy. We will also analyze the long-term neuroprotective effects of caffeine treatment. Understanding the mechanisms involved in microglial priming may help to develop new therapeutic treatments for those neonates who do not respond to therapeutic hypothermia.

• DFG Programme: Research Grants