[Frontiers in Bioscience S2, 47-72, January 1, 2010] 47 Biochemical markers of perinatal brain damage Pasquale Florio 1 , Raul Abella 2 , Emanuela Marinoni 3 , Romolo Di Iorio 3 , Giovanni Li Volti 4 , Fabio Galvano 4 , Giacomo Pongiglione 5 , Alessandro Frigiola 2 , Serena Pinzauti 1 , Felice Petraglia 1 , Diego Gazzolo 5,6 1 Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Siena, Italy, 2 Department of Cardiac Surgery S. Donato Milanese University Hospital, S. Donato Milanese, Italy, 3 Laboratory of Perinatal Medicine and Molecular Biology, and Department of Internal Medicine University “La Sapienza” Rome, Italy, 4 Department of Biological Chemistry, Medicinal Chemistry and Molecular Biology, University of Catania, Italy, 5 Department of Pediatrics, Neuroscience and Cardiovascular Surgery, G. Gaslini Children’s Hospital University of Genoa, Genoa – Italy, 6 Department of Fetal, Maternal and Neonatal Health, G. Garibaldi Hospital Catania , Italy TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Epidemiology of perinatal asphyxia 4. Pathophysiology of brain damage following H-I insult 4.1. Pathogenesis of hypoxic-ischemic cerebral injury 4.2. Delayed (secondary) brain damage 4.3. Excitatory neurotransmitter release 4.4. Formation of free radicals 4.5. Inflammatory mediators 5. Role of Near-Infrared Spectrometry (NIRS) to evaluate the cerebral oxygenation 6. Experimental reports supporting brain damage markers usefulness 6.1. Activin A: in vitro evidence for a H-I-related regulation 6.2. S100B:in vitro evidences for a H-I-related regulation 6.3. Adrenomedullin: in vitro evidences for a H-I-related regulation 6.4. NSE: evidences for a H-I-related regulation 6.5. GFAP: evidences for a H-I-related regulation 7. Clinical data on usefulness of biochemical screening of brain damage 7.1. Activin A as a brain damage marker in infants complicated by H-I reperfusion injury 7.2. S100B as a brain damage marker in infants complicated by I-R injury 7.3. AM as a brain damage marker in infants complicated by H-I reperfusion injury 7.4. NSE as a brain damage marker in infants complicated by H-I reperfusion injury 8. Brain derived protein and the human milk: an evolutionary strategy? 9. Conclusions 10. Acknowledgement 11. References 1. ABSTRACT Hypoxia-ischemia constitutes a risk in infants by altering cerebral blood flow regulatory mechanisms and causing loss of cerebral vascular auto-regulation. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation leading to cell death and tissue damage. These dramatic phenomena represent a common repertoire in infants complicated by perinatal acute or chronic hypoxia. To date, despite accurate perinatal and intra-operative monitoring, the post-insult period is crucial, since clinical symptoms and monitoring parameters may be of no avail and therapeutic window for pharmacological intervention (6-12 hours) may be limited, at a time when brain damage is already occurring. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk infants. The present review is aimed at investigating the role as circulating biochemical markers such as adrenomedullin, S100B, activin A, neuronal specific enolase (NSE), glial fibrillary acid protein (GFAP), in the cascade of events leading to ischemia reperfusion injury in infants complicated by perinatal asphyxia.