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.
Highlights
Despite the enormous global impact of neurological disorders and the extensive research over many decades, there is still a lack of proven clinically effective pharmacological neuroprotective therapies capable of reducing the severity of brain or spinal cord tissue injury in acute or chronic (Alzheimer’scationic arginine-rich peptides (CARPs): Novel Neuroprotective Agents disease, Parkinson’s disease, and amyotrophic lateral sclerosis) neurological disorders
CARPs as a novel class of peptide with great promise for the treatment of acute and chronic neurological disorders, and in so doing summarize their known neuroprotective mechanisms of action, as well as other potential actions whereby they may exert beneficial effects in injured or affected cells. Within this group of compounds are included many putative neuroprotective peptides fused to cationic arginine-rich cell-penetrating peptides (CCPPs) (e.g., TAT, R9, penetratin) that have been developed (Table 2). In this review, such peptides are classified as CARPs, and we propose that in many, if not all instances their putative neuroprotective effects may be mediated by the arginine content and positive charge of the carrier and/or cargo peptide, rather than the cargo peptide itself
There is overwhelming evidence from experimental studies that CARPs represent a novel class of neuroprotective agent with great potential for the treatment of neurological disorders
Summary
Despite the enormous global impact of neurological disorders and the extensive research over many decades, there is still a lack of proven clinically effective pharmacological neuroprotective therapies capable of reducing the severity of brain or spinal cord tissue injury in acute (e.g., stroke, traumatic brain injury and spinal cord injury, and hypoxic-ischemic encephalopathy) or chronic It is intuitive that in order to increase the chances of achieving translational success at the clinical level, it is preferable that any new neuroprotective drug should have a multimodal mechanism of action To this end, cationic arginine-rich peptides (CARPs) represent a relatively novel and expanding class of compounds, which possess an array of intrinsic neuroprotective properties, and are ideal molecules for development as therapies for a broad range of neurological disorders. The aim of this review is to highlight the recognition of CARPs as a novel class of peptide with great promise for the treatment of acute and chronic neurological disorders, and in so doing summarize their known neuroprotective mechanisms of action, as well as other potential actions whereby they may exert beneficial effects in injured or affected cells Within this group of compounds are included many putative neuroprotective peptides fused to CCPPs (e.g., TAT, R9, penetratin) that have been developed (Table 2). Neuroprotective CARPs typically possess the following properties: (i) range in size from 4 to 40 amino acids; (ii) positive net charge ≥ +2 to +20; (iii) one or more positively
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