Improved carnosic acid congener compounds for Alzheimer's disease Five million Americans currently suffer the devastating consequences of Alzheimer's disease (AD), and unfortunately, the numbers are increasing due to our aging population. While some treatments can lower disease burden, there is no cure and all patients inevitably succumb. Cost of care for treatment of AD is expected to reach $1.1 trillion without an effective treatment or a change in the trajectory of AD. Loss of synaptic function is associated with cognitive decline in AD and is a better predictor of cognitive loss in AD than plaques or tangles. Damage to neurons occurs at least partially through generation of oxidative and nitrosative stress, due to excessive generation of reactive oxygen/nitrogen species (ROS/RNS) triggered by oligomeric amyloid beta (Aβ)peptide and downstream hyperphosphorylation and aggregation of tau protein (pTau). Carnosic acid (CA), aphenolic diterpene particularly abundant in the herb rosemary (Rosmarinus officinal is), protects neurons and synapses from damage caused by oxidative stress. In addition to direct antioxidant activity, CA belongs to a class of "pro-electrophiles" that activate the Keap1/Nrf2 pathway, up regulating transcription of a broad range of phase II antioxidant and anti-inflammatory proteins through the antioxidant responsive element (ARE). In vitro, CA protects neurons from Aβ toxicity. CA treatment ameliorates various behavioral and histological deficits in transgenic AD model mice, while showing no significant side effects. During this Phase 1 project, we will develop a novel, proprietary CA-derived therapeutic with improved bioavailability to achieve therapeutic levels with once daily dosing. We will then evaluate this novel compound as a therapeutic small molecule for the treatment of AD.
Public Health Relevance Statement: Narrative Alzheimer's disease (AD) is a devastating form of dementia with an increasing incidence due to our aging population. We have identified a potent activator of the master antioxidant switch and have demonstrated its effectiveness in vitro and in animal models of AD. Development of this novel drug will result in a potentially disease-modifying treatment for AD.
Project Terms: Enzymes, Enzyme Gene, Esters, Family, Genes, Glutamates, L-Glutamate, glutamatergic, glutathione peroxidase, Glutathione S-Transferase, EC 2.5.1.18, Glutathione Organic Nitrate Ester Reductase, Glutathione S-Alkyltransferase, Glutathione S-Aralkyltransferase, Glutathione S-Aryltransferase, Glutathione S-Epoxidetransferase, Glutathione Transferase, Heme Transfer Protein, Ligandins, S-Hydroxyalkyl Glutathione Lyase, glutathione aralkyltransferase, glutathione aryltransferase, Goals, Half-Life, Herb, Human, Modern Man, In Vitro, Incidence, Lead, Pb element, heavy metal Pb, heavy metal lead, Ligase, Ligase Gene, Synthetases, Transgenic Mice, Coenzyme II, NAD phosphate, NAD(H) phosphate, NADH phosphate, NADPH, Nicotinamide-Adenine Dinucleotide Phosphate, Triphosphopyridine Nucleotide, NADP, Nerve Cells, Nerve Unit, Neural Cell, Neurocyte, neuronal, Neurons, Nitrogen, Dehydrogenases, Oxidoreductase Gene, Reductases, Oxidoreductase, O element, O2 element, Oxygen, Patients, Peptides, Pharmacokinetics, Drug Kinetics, Carbol, Carbolic Acid, Hydroxybenzene, Phenols, Drug Precursors, Pro-Drugs, Prodrugs, Promotor Regions, genetic promoter element, genetic promoter sequence, promoter sequence, Promoter Regions, Proteins, Public Health, Quinone Compound, Quinones, Mercaptans, Mercapto Compounds, Thiols, sulfhydryl group, Sulfhydryl Compounds, Synaptic, synapse, Synapses, transcription factor, Basal Transcription Factor, Basal transcription factor genes, General Transcription Factor Gene, General Transcription Factors, Transcription Factor Proto-Oncogene, Transcription factor genes, Genetic Transcription, Gene Transcription, RNA Expression, Transcription, Work, Glutathione Disulfide, GSSG, Oxidized Glutathione, salvin, carnosic acid, Amyloid beta-Protein, Alzheimer beta-Protein, Alzheimer's Amyloid beta-Protein, Alzheimer's amyloid, Amyloid Alzheimer's Dementia Amyloid Protein, Amyloid Beta-Peptide, Amyloid Protein A4, Amyloid β, Amyloid β-Peptide, Amyloid β-Protein, Aβ, a beta peptide, abeta, amyloid beta, amyloid-b protein, beta amyloid fibril, soluble amyloid precursor protein, Generations, Neurofibrillary Tangles, neurofibrillary degeneration, neurofibrillary lesion, neurofibrillary pathology, tangle, tau Proteins, MT-bound tau, microtubule bound tau, microtubule-bound tau, tau, tau factor, Ï Proteins, improved, Phase, Histologic, Histologically, Failure, Oxidative Stress, Letters, Therapeutic, Amyloid Plaques, Neuritic Plaques, amyloid beta plaque, amyloid-b plaque, aβ plaques, cored plaque, diffuse plaque, Senile Plaques, Cognitive Disturbance, Cognitive Impairment, Cognitive decline, Cognitive function abnormal, Disturbance in cognition, cognitive dysfunction, cognitive loss, Impaired cognition, Side, Oral, Reaction, Amentia, Dementia, Degenerative Neurologic Diseases, Degenerative Neurologic Disorders, Nervous System Degenerative Diseases, Neural Degenerative Diseases, Neural degenerative Disorders, Neurodegenerative Diseases, Neurologic Degenerative Conditions, degenerative diseases of motor and sensory neurons, degenerative neurological diseases, neurodegenerative illness, Neurodegenerative Disorders, American, mutant, 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, Animal Models and Related Studies, model of animal, model organism, Animal Model, Catalytic Core, Catalytic Region, Catalytic Site, Catalytic Subunit, Catalytic Domain, Toxicities, Toxic effect, novel, hydroxyl group, Drug Exposure, Modeling, assay development, thioredoxin reductase, ABCC1 gene, ABC29, ABCC, ABCC1, GS-X, MRP1, peroxiredoxin II, peroxiredoxin 2, Molecular Interaction, Binding, Rosmarinus officinalis, Rosemary, Effectiveness, Cytoplasmic Protein, TRX gene, TRX protein, TRX1, Thioredoxin, TXN gene, GCLC, GLCLC, Gamma-Glutamylcysteine Synthetase Catalytic Subunit, Glutamate-Cysteine Ligase, Catalytic Subunit, GCLC gene, GCLM, GLCLR, Gamma-Glutamylcysteine Synthetase, Regulatory Subunit, Glutamate-Cysteine Ligase, Modifier Subunit, Glutamate-Cysteine Ligase, Regulatory, GCLM gene, Dose, Data, in vitro Assay, Monitor, Development, developmental, Behavioral, Pathway interactions, pathway, pre-clinical, preclinical, burden of illness, burden of disease, disease burden, years of life lost to disability, years of life lost to disease, tau aggregation, abnormally aggregated tau protein, filamentous tau inclusion, microtubule associated protein tau aggregation, microtubule associated protein tau deposit, paired helical filament of tau, self-aggregate tau, tau PHF, tau accumulation, tau aggregate, tau fibrillization, tau filament, tau neurofibrillary tangle, tau oligomer, tau paired helical filament, tau polymerization, tau-tau interaction, Ï aggregation, synaptic function, synapse function, novel therapeutics, new drug treatments, new drugs, new therapeutics, new therapy, next generation therapeutics, novel drug treatments, novel drugs, novel therapy, abeta toxicity, Amyloid β toxicity, amyloid beta toxicity, aβ toxicity, mouse model, murine model, Alzheimer's disease model, AD model, alzheimer model, transgenic model of alzheimer disease, transgenic AD model, transgenic Alzheimer's model, aging population, aged population, population aging, effective therapy, effective treatment, nitrosative stress, oAβ, oligomeric amyloid beta, oligomeric amyloid-β, small molecule therapeutics, care costs, side effect, Alzheimer's disease patient, Alzheimer's patient, Alzheimer's Disease, AD dementia, Alzheimer, Alzheimer Type Dementia, Alzheimer disease, Alzheimer sclerosis, Alzheimer syndrome, Alzheimer's, Alzheimer's disease dementia, Alzheimers Dementia, Alzheimers disease, Primary Senile Degenerative Dementia, dementia of the Alzheimer type, primary degenerative dementia, senile dementia of the Alzheimer type, Animals, Anti-Inflammatory Agents, Anti-Inflammatories, Anti-inflammatory, Antiinflammatories, Antiinflammatory Agents, antiinflammatory, Antioxidants, anti-oxidant, Biological Availability, Bioavailability, Biologic Availability, Physiologic Availability, Brain, Brain Nervous System, Encephalon, Carbamates, Catechols, 1,2-benzenediol, 1,2-dihydroxybenzene, 2-hydroxyphenol, Pyrocatechols, o-Dihydroxybenzenes, ortho-Dihydroxybenzenes, Cell Nucleus, Nucleus, Clinical Trials, Cysteine, Half-Cystine, L-Cysteine, Cystine, L-Cystine, Disease, Disorder, Diterpenes, Diterpenoids, Pharmaceutical Preparations, Drugs, Medication, Pharmaceutic Preparations, drug/agent, Elements
