Inhibition of N-Methyl-d-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential

Abstract

Background: NMDA receptor hyperactivity results in mitochondrial dysfunction in neurons promoting neurodegenerative disorders. Results: Short polyarginine peptides target mitochondria to promote neuronal survival. Conclusion: Short polyarginine peptides reduce mitochondrial respiration, membrane hyperpolarization, and generation of reactive oxygen species. Significance: Treatment with polyarginine has the potential to minimize neuronal damage resulting from stroke or traumatic brain injury and may be therapeutic to ameliorate multiple sclerosis and Parkinson disease.

Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs)

“…containing 2–6 arginine residues; net charge +3–+7; e.g., RRRRRR-NH 2 ) were neuroprotective in an in vitro hippocampal neuronal NMDA excitotoxic model. These findings were in line with subsequent studies in our and other laboratories, demonstrating that the CPP TAT (YGRKKRRQRRR; net charge +8) possesses intrinsic neuroprotective properties following in vitro glutamic acid excitotoxicity and oxygen glucose deprivation (OGD), as well as in vivo following excitotoxicity and cerebral ischemia in rats [13,14,15,16,64,65]. We subsequently demonstrated that in an in vitro cortical neuronal excitotoxic model, the CPPs poly-arginine-9 (RRRRRRRRR-NH 2 ; net charge +10) and penetratin (RQIKIWFQNRRMKWKK-NH 2 ; net charge +8) were even more potent than TAT [12].…”

Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

“…tryptophan), as well as providing structural stability. Importantly, studies in our laboratory [219,221,257] and by Marshall et al (2015), and more recently McQueen et al (2017), support a CARP-mediated neuroprotective mechanism for "putative" neuroprotective peptides fused to CCPPs (e.g.…”

“…Furthermore, in HEK cells R7 and C-s-s-C-R7 reduced mitochondrial respiration, m, and ROS generation, and it was proposed that these effects on mitochondria would be neuroprotective for neurons during metabolic stress (e.g. excitotoxicity and ischaemia) [264].…”

“…TAT-NR2B9c and TAT-NR2Bct) [264,277] (for more detail on this subject, see Meloni et al 2015b). Therefore, based on the findings from our and other laboratories, we believe that past neuroprotective studies that have utilized CCPPs need to be critically re-evaluated.…”

Efficient synthesis of CN2097 using in situ activation of sulfhydryl group

“…In preclinical animal studies, CN2097 was found to be effective in the treatment of Angelman syndrome, 10 TBI 18 , and neuroprotective in an excitotoxicity animal model that mimics a stroke. 19 One of the major drawbacks in proceeding to preclinical trial studies is that the reported methodology for the synthesis of CN2097, based on solid phase and microwave chemistry, provides a low yield (~5%) 20 during conjugation of polyarginine and cyclic PDZ peptide to form a disulfide bond. The synthesis consists of an activated cysteine on solid-phase that requires a large amount of cyclic-peptide for disulfide coupling on the resin.…”