Cationic
arginine-rich
peptides represent a novel class of
peptides being developed as
neuroprotective agents for
stroke and other acute and chronic
neurological disorders. As a group, cationic
arginine-rich
peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise
ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-
cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds. At present, while many neuroprotective cationic
arginine-rich
peptides have been examined in preclinical animal neuroprotection studies, few have been assessed in human safety studies. Despite this, the safety of the prototypical cationic
arginine-rich
peptide,
protamine, which has been in clinical use for over 70 years to reverse the
anticoagulant effects of
heparin and as an
excipient in certain
insulin preparations, is well established. In addition, the poly-
arginine peptide R9 (ALX40-4C) was developed as an anti-human inmmunodeficiency virus therapeutic in the mid-1990s, and more recently, the neuroprotective cationic
arginine-rich
peptides TAT-NR2B9c (NA-1), CN-105 and RD2 are being evaluated for the treatment of
ischaemic stroke, haemorrhagic
stroke and
Alzheimer's disease, respectively. Based on the available clinical data, cationic
arginine-rich
peptides as a group appear to be safe when administered at therapeutic doses by a slow
intravenous infusion. While
protamine, owing to its isolation from salmon milt and homology with human sperm
protamine, can trigger anaphylactic and
anaphylactoid reactions in a small proportion of patients previously exposed to the
peptide (e.g. diabetic patients), who are allergic to fish or have undergone a
vasectomy, such reactions are unlikely to be triggered in individuals exposed to non-
protamine cationic
arginine-rich
peptides.