## 4 Neuoprotective Peptides and Their Therapeutic Application in HIE
### Cationic Arginine-Rich Cell-Penetrating Peptide Neuroprotective Mechanisms of Actions  
While the exact mechanisms of the neuroprotective effects are still being explored, we and others have demonstrated that CARPs have multiple, potentially simultaneous mechanisms of action. CARPs and putative neuroprotective peptides fused to cationic arginine-rich CPPs (i.e., TAT or R9; e.g., JNKI-1-TATD, TAT-NR2B9c/NA-1, TAT-CBD3/R9-CBD3-A6K and TAT-3.2-III-IV) can mitigate excitotoxic or potassium evoked neuronal intracellular calcium influx [19; 27; 67; 68; 69]. One mechanism whereby CARPs have the capacity to reduce intracellular calcium influx is the reduction of neuronal cell surface ion channels and receptors; thereby reducing excitotoxic calcium influx. To this end, CARPs have been demonstrated to reduce the cell surface expression or function of neuronal NMDA receptors [23; 63; 70; 71; 72; 73], voltage gated calcium channels (CaV2.2 and CaV3.3) [68; 70; 74; 75], a voltage gated sodium channel (NaV1.7) [76] and the sodium calcium exchanger 3 (NCX3) [70]. Given their effects on different receptors, and the positive charge of CARPs, they may also be antagonizing ion channel receptor function directly and/or by affecting calcium or sodium ion influx via an electrostatic mechanism.  
In addition to neuronal cell surface receptor interactions, CARPs may also exert pleiotropic neuroprotective effects by targeting mitochondria and maintaining mitochondrial integrity by reducing calcium influx into the organelle [65; 77; 78; 79; 80; 81; 82; 83]. CARPs have the capacity to inhibit proteolytic enzymes including the proteasome [84; 85], as well as pro-protein convertases [86; 87; 88] that activate MMPs [89]. Inhibition of the proteasome is known to be beneficial following cerebral ischemia [90; 91; 92]; a mechanism that could be mediated by increased activity of hypoxia-inducible factor 1-\(\alpha\) (HIF1\(\alpha\)) and decreased activity of nuclear factor \(\kappa\)-light-chain-enhancer of B cells (NF\(\kappa\)B). Similarly, MMP activation in the brain is known to be detrimental following cerebral ischemia and inhibiting MMP activation is neuroprotective (see review [PERSON] et al. [93]).  
Furthermore, there is also evidence that CARPs activate pro-survival signaling pathways [67; 94], modulate immune responses [95; 96; 97] and act as anti-oxidant molecules in their own right due to their guanidine group in arginine residues [65; 83; 98; 99; 100; 65; 63; 99; 101].  
Interestingly, the neuroprotective potency of CARPs appears to correlate with the same characteristic that improve the ability of cationic CPPs to target and transverse cellular membranes [19; 29].  
This suggests that CARP-mediated neuroprotection is associated with cellular membrane interactions (e.g., plasma and mitochondrial), anionic structures (phospholipids/cardiolipin, heparan sulfate proteoglycans, chondro sulfate proteoglycans, sialic acid resides, anionic regions of surface receptors) and/or increased levels of cellular uptake, which enable the peptides to interact with membrane (e.g., ion channel receptors) and intracellular targets (e.g., proteins, ROS and mitochondria).