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, andwe 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 neuroprotectionafter 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conditions: cardiopulmonary resuscitation (CPR)after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished).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) wasconducted at a highly clinically relevant timepoint for these conditions (30 min after CPR); (ii) was effective inconjunction with current standard of care (therapeutic hypothermia); and (iii) protected not only from neuronalcell 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 Iproposal, we will first complete the final therapeutically relevant piece of biochemical characterization of theinhibitor. Then, we will initiate the PK studies that are required for an IND application (which first requires avalidation of a method for detection of our inhibitor in serum of the tested species).
Public Health Relevance Statement: 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.
Project Terms: American ; experience ; success ; nerve cell death ; nerve cell loss ; neuron cell death ; neuron cell loss ; neuron death ; neuronal cell death ; neuronal cell loss ; neuronal death ; neuronal loss ; neuron loss ; neuroprotection ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Structure ; Pharmacology and Toxicology ; Modeling ; Sampling ; Property ; Functional impairment ; functional disability ; Adverse Experience ; Adverse event ; Cerebral Ischemia ; Molecular Interaction ; Binding ; kinase inhibitor ; Brain region ; Mediator ; Mediator of Activation ; Mediator of activation protein ; Address ; Dose ; Affinity ; Detection ; in vivo ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Validation ; Pathologic ; Preparation ; Characteristics ; Cardiac ; Behavioral ; safety study ; Instruction ; excitotoxicity ; Synaptic plasticity ; Impairment ; clinically relevant ; clinical relevance ; comparative ; commercialization ; standard of care ; biophysical techniques ; biophysical approaches ; biophysical methodology ; biophysical methods ; Injections ; therapeutic lead compound ; detection method ; detection procedure ; detection technique ; inhibitor/antagonist ; inhibitor ; Asphyxia ; Suffocation ; asphyxiation ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Cardiopulmonary Resuscitation ; cardiac resuscitation ; heart resuscitation ; Cells ; Cell Body ; Colorado ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Cessation of life ; Death ; Mental Depression ; depression ; Drowning ; Freeze Drying ; Freeze Dryings ; Lyophilization ; Heart Arrest ; Asystole ; Cardiac Arrest ; Hospitalization ; Hospital Admission ; Human ; Modern Man ; natural hypothermia ; Hypothermia ; Investments ; Kinetics ; Learning ; Memory ; Methods ; Mutant Strains Mice ; mouse mutant ; Mus ; Mice ; Mice Mammals ; Murine ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Legal patent ; Patents ; Patients ; Peptides ; Drug Kinetics ; Pharmacokinetics ; Pharmacology ; Phosphotransferases ; Kinases ; Phosphotransferase Gene ; Transphosphorylases ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Powder dose form ; Powders ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Rodent ; Rodentia ; Rodents Mammals ; Safety ; Saline ; Saline Solution ; Family suidae ; Pigs ; Suidae ; Swine ; porcine ; suid ; Testing ; Time ; Toxicology ; Universities ; Ventricular Fibrillation ; Water ; Hydrogen Oxide ; N-Methyl-D-Aspartate Receptors ; N-Methylaspartate Receptors ; NMDA Receptor-Ionophore Complex ; NMDA Receptors ; Dissociation ; Injectable ; Mediating ; base ; Site ; Acute ; Clinical ; Residual state ; Residual ; Phase ; Biological ; Biochemical ; Series ; Long-Term Potentiation ; Longterm Potentiation ; Serum ; Blood Serum ; Neuroprotective Agents ; Neuroprotectants ; Neuroprotective Drugs ; calmodulin-dependent protein kinase II ; CaM KII ; CaM PK II ; CaM kinase II ; CaMKII ; calcium-dependent CaM kinase II ; Intellectual Property ; Therapeutic ; tool ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; Hour ; Retrograde amnesia ; Anatomy ; Anatomic ; Anatomic Sites ; Anatomic structures ; Anatomical Sciences ;
