Preparing for IND-enabling safety studies for a potent and efficient neuroprotective drug.

Project Summary/Abstract The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central mediator of two opposing forms of NMDA- receptor (NMDAR)-dependent synaptic plasticity: long-term potentiation (LTP) and depression (LTD). Pathological overstimulation of NMDARs during cerebral ischemia causes excitotoxic neuronal cell death, and we have recently shown that CaMKII also mediates the neuronal damage after global cerebral ischemia (GCI). Importantly, in vivo injection of our optimized CaMKII inhibitor (tatCN19o) provided significant neuroprotection after GCI in models that closely mimic the most relevant human conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished). CaMKII inhibition (i) was conducted at a highly clinically relevant timepoint for these conditions (30 min after CPR); (ii) was effective in conjunction with current standard of care (therapeutic hypothermia); and (iii) protected not only from neuronal cell death, but also from the long-lasting functional impairments in LTP that are seen in the surviving neurons. In order to enable testing in humans, this SBIR project will conduct the studies required for a successful IND- application with the FDA, specifically including complete toxicology and safety pharmacology. In this phase I proposal, we will first complete the final therapeutically relevant piece of biochemical characterization of the inhibitor. Then, we will initiate the PK studies that are required for an IND application (which first requires a validation of a method for detection of our inhibitor in serum of the tested species).Project Narrative Global cerebral ischemia (GCI) occurs not only during drowning and suffocation, but also during cardiac arrest. This results in neuronal cell death, especially in regions of the brain important for learning and memory. Consequently, many GCI patients experience long-lasting impairments in learning and memory. This proposal will help evaluate the pharmacokinetic properties of a compound (tatCN19o) that can protect neurons from cell death even when injected after GCI has already occurred. This will be an important step towards developing a therapy to protect neurons from cell death following GCI in patients.