Cationic Arginine-Rich Peptides (CARPs): A Novel Class of Neuroprotective Agents With a Multimodal Mechanism of Action

Abstract

There are virtually no clinically available neuroprotective drugs for the treatment of acute and chronic neurological disorders, hence there is an urgent need for the development of new neuroprotective molecules. Cationic arginine-rich peptides (CARPs) are an expanding and relatively novel class of compounds, which possess intrinsic neuroprotective properties. Intriguingly, CARPs possess a combination of biological properties unprecedented for a neuroprotective agent including the ability to traverse cell membranes and enter the CNS, antagonize calcium influx, target mitochondria, stabilize proteins, inhibit proteolytic enzymes, induce pro-survival signaling, scavenge toxic molecules, and reduce oxidative stress as well as, having a range of anti-inflammatory, analgesic, anti-microbial, and anti-cancer actions. CARPs have also been used as carrier molecules for the delivery of other putative neuroprotective agents across the blood-brain barrier and blood-spinal cord barrier. However, there is increasing evidence that the neuroprotective efficacy of many, if not all these other agents delivered using a cationic arginine-rich cell-penetrating peptide (CCPPs) carrier (e.g., TAT) may actually be mediated largely by the properties of the carrier molecule, with overall efficacy further enhanced according to the amino acid composition of the cargo peptide, in particular its arginine content. Therefore, in reviewing the neuroprotective mechanisms of action of CARPs we also consider studies using CCPPs fused to a putative neuroprotective peptide. We review the history of CARPs in neuroprotection and discuss in detail the intrinsic biological properties that may contribute to their cytoprotective effects and their usefulness as a broad-acting class of neuroprotective drugs.

Emerging cytoprotective peptide therapies for stroke

“…A large number of different CARPs have now demonstrated neuroprotective efficacy in animal models of stroke [3], providing confidence in the potential of this class of peptides with multimodal cytoprotective mechanisms of action to translate to an effective clinical stroke therapeutic. Indeed, the NA-1 and CN-105 peptides have paved the way in demonstrating the translational process from pre-clinical to clinical studies for ischemic and hemorrhagic stroke, respectively.…”

“…Cationic arginine-rich peptides (CARPs) are a new emerging class of neuroprotective agents with multimodal cytoprotective actions. These include the ability to antagonize calcium influx, target and stabilize mitochondria, scavenge toxic molecules and reduce oxidative stress, inhibit proteolytic enzymes, induce prosurvival signaling, as well as having a range of anti-inflammatory properties (reviewed in depth in [3]). Moreover, CARPs have shown consistent efficacy in a variety of in vitro and animal models of ischemic and hemorrhagic stroke [3], and have demonstrated a favorable safety profile [4].…”

“…These include the ability to antagonize calcium influx, target and stabilize mitochondria, scavenge toxic molecules and reduce oxidative stress, inhibit proteolytic enzymes, induce prosurvival signaling, as well as having a range of anti-inflammatory properties (reviewed in depth in [3]). Moreover, CARPs have shown consistent efficacy in a variety of in vitro and animal models of ischemic and hemorrhagic stroke [3], and have demonstrated a favorable safety profile [4]. With respect to CARP neuroprotection, while cationic charge can be imparted by positively charged arginine, lysine and histidine residues, and while other amino acids can influence efficacy (e.g.…”

“…With respect to CARP neuroprotection, while cationic charge can be imparted by positively charged arginine, lysine and histidine residues, and while other amino acids can influence efficacy (e.g. tryptophan), arginine is the amino acid essential for neuroprotection [3,[5][6][7].…”

Poly-arginine-18 (R18) Confers Neuroprotection through Glutamate Receptor Modulation, Intracellular Calcium Reduction, and Preservation of Mitochondrial Function

“…Recent studies in our laboratory have identified cationic arginine-rich peptides (CARPs), which include poly-arginine peptides, have intrinsic neuroprotective and cell-penetrating properties (reviewed in [ 18 ]). In particular, we have demonstrated that poly-arginine-18 (R18, 18-mer of arginine) is neuroprotective in in vitro neuronal excitotoxicity models and in in vivo rodent and non-human primate models of stroke [ 19 , 20 , 21 , 22 , 23 , 24 ], as well as rodent models of HIE [ 25 , 26 ] and TBI [ 27 , 28 ].…”