###### Abstract  
Perinatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality and morbidity in neonates, with survivors suffering significant neurological sequelae including cerebral palsy, epilepsy, intellectual disability and autism spectrum disorders. While hypothermia is used clinically to reduce neurological injury following HIE, it is only used for term infants (>36 weeks gestation) in tertiary hospitals and improves outcomes in only 30% of patients. For these reasons, a more effective and easily administitable pharmacological therapeutic agent, that can be used in combination with hypothermia or alone when hypothermia cannot be applied, is urgently needed to treat pre-term (\(\leq\)36 weeks gestation) and term infants suffering HIE. Several recent studies have demonstrated that cationic arginine-rich peptides (CARPs), which include many cell-penetrating peptides [CPPs; e.g., transactivator of transcription (TAT) and poly-arginine-9 (R9; 9-mer of arginine)], possess intrinsic neuroprotective properties. For example, we have demonstrated that poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer (R18D) are neuroprotective in vitro following neuronal excitotoxicity, and in vivo following perinatal hypoxia-ischemia (HI). In this paper, we review studies that have used CARPs and other peptides, including putative neuroprotective peptides fused to TAT, in animal models of perinatal HIE. We critically evaluate the evidence that supports our hypothesis that CARP neuroprotection is mediated by peptide arginine content and positive charge and that CARPs represent a novel potential therapeutic for HIE. hypoxic-ischemic encephalopathy; hypoxia-ischemia; birth asphyxia; neuroprotection; cationic arginine-rich peptides; animal models +
Footnote †: journal: J. Neuroc. Neuroc. postnatal period, and an additional 25% will develop severe and permanent neurological sequela. Each year, HIE accounts for up to 1.2 million deaths [5] and some form of central nervous system (CNS) dysfunction in an estimated 1.15 million neonates [6] such as cerebral palsy, epilepsy, global developmental delay, intellectual disability, behavioral disorders and autism spectrum disorders [7; 8; 9; 10; 11]. While hypothermia is used as a therapeutic intervention to minimize brain injury in neonates suffering HIE, it only provides beneficial outcomes in approximately 30% of patients and has several limitations (reviewed below). Therefore, an effective and easily administtable pharmacological therapeutic agent to improve patient outcomes when used as an adjunct to hypothermia, on its own or when hypothermia cannot be applied is urgently needed. In recent years, there has been an increased application of putative neuroprotective peptides designed to target cyto-damaging or cyto-protective pathways to reduce injury in acute brain disorders such as HIE. One reason for this interest is the discovery of cell-penetrating peptides (CPPs), allowing for the delivery of neuroprotective peptides and other molecular cargos (e.g., proteins, nucleic acids and nanoparticles) across the blood brain barrier (BBB) and into cells within the CNS. Most studies assessing neuroprotective peptides in animal models of HIE use the cationic arginine-rich CPP, transactivator of transcription (TAT\({}_{47-57}\) YGRKKRRQRRR), as the 'carrier' molecule. However, several years ago, our and other laboratories demonstrated that the TAT peptide has modest intrinsic neuroprotective properties in its own right [12; 13; 14; 15; 16; 17].