The majority of the cholinesterase inhibitors used in the clinic are derived from natural products and our current paper describes the use of a small marine pharmacophore to develop potent and selective cholinesterase inhibitors. These compounds can slow down the progression of these diseases and can also be used in the treatment of glaucoma and myasthenia gravis. The management of neurological disorders such as dementia associated with Alzheimer's or Parkinson's disease includes the use of cholinesterase inhibitors. The findings indicate that R18, R18D, TAT-NR2B9c and protamine are unlikely to induce histamine mediated anaphylactoid reactions or RBC hemolysis when administered intravenously to patients. This study addressed the potential safety concern of the application of the cationic neuroprotective peptides, especially, R18D, on anaphylactoid responses and hemolysis. Measurement of hemoglobin absorbance revealed that only R18 induced a modest, but significant degree of hemolysis at the 16 μM concentration, and only in the absence of plasma. To examine hemolytic effects, red blood cells (RBCs), were incubated with the peptides at a concentration range of 1–16 μM in the absence or presence of 2% plasma. Similarly, TAT-NR2B9c and protamine did not induce significant mast cell degranulation. Degranulation assay based on β-hexosaminidase release demonstrated that R18 and R18D did not induce significant mast cell degranulation in both untreated (naïve) and IgE-sensitised HCMCs in a dose-response study to a maximum peptide concentration of 16 μM. We also included as controls, the well-characterised neuroprotective TAT-NR2B9c peptide and the widely used heparin reversal peptide, protamine. To address this, we first utilised primary human cultured mast cells (HCMCs) to examine anaphylactoid effects. In the clinical development of R18/R18D, their cationic property raises potential safety concerns on their non-specific effects to induce mast cell degranulation and hemolysis. Our laboratory focuses on the development of novel neuroprotective cationic peptides, such poly-arginine-18 (R18: 18-mer of l-arginine net charge +18) and its d-enantiomer R18D in stroke and other brain injuries.
Furthermore, CARPs represent a broader class of bioactive peptides with a number of other properties that may contribute to their neuroprotective actions, including the ability to reduce intracellular calcium influx, antagonize cell surface receptor function, target mitochondria, scavenge reactive molecules, induce cell signaling, stabilize proteins, inhibit proteolytic enzymes, and reduce inflammation, and in addition to being neuroprotective also have anti-nociceptive, cardioprotective, anti-microbial and anti-cancer properties. Histidine, the other positively charged amino acid only provides a modest contribution to peptide charge with a net charge of +0.1 at pH 7. Whereas, cationic charge can be imparted by the presence of the positively charged amino acids arginine and lysine ( Figure 1A), which have a net charge of +1 at pH 7, arginine is the amino acid essential for neuroprotection. the name suggests, critical factors for CARP neuroprotection are their positive charge and arginine content as well as, the ability to traverse membrane lipid bilayers.
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