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 administrable 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 (≤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.
Highlights
Perinatal hypoxic-ischemic encephalopathy (HIE; referred to as birth asphyxia) remains the leading cause of neonatal mortality and morbidity, with an incidence in developed nations of 2–6 and 7 in every 1000 live term (>36 weeks gestation) and pre-term (≤36 weeks gestation) births, respectively [1,2]
As highlighted previously [19], based on our findings, we have proposed that the neuroprotective properties of most, if not all, putative neuroprotective peptides fused to cationic cell-penetrating peptides (CPPs) (e.g., TAT, R9 and penetratin), as well as other cationic arginine-rich peptides (CARPs), are determined by the arginine content and positive charge of the peptide, with potency influenced by other amino acid residues [19,29]
There is a large body of data from various sources demonstrating that CARPs comprise a class of peptide with significant neuroprotective potential for development as an adjuvant to hypothermia, or when hypothermia cannot be applied, for the treatment of HIE
Summary
Perinatal hypoxic-ischemic encephalopathy (HIE; referred to as birth asphyxia) remains the leading cause of neonatal mortality and morbidity, with an incidence in developed nations of 2–6 and 7 in every 1000 live term (>36 weeks gestation) and pre-term (≤36 weeks gestation) births, respectively [1,2]. 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. Based on the recent application of cationic CPPs for the delivery of putative neuroprotective peptides in animal models of HIE and the recent discovery of the intrinsic neuroprotective properties of CARPs, the objectives of this review are: (i) catalogue studies that have used peptides as neuroprotective agents in HIE, especially those employing a CPP delivery system; and (ii) to evaluate the potential neuroprotective effects of both CPP and cargo molecules in terms of their arginine content and cationic charge, as well as the content of other potentially neuroprotective amino acids such as tryptophan [29]. We provide a brief overview of the major underlying pathophysiological mechanisms associated with HIE and the application of hypothermia as an acute therapy for the disorder
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