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Principal Investigator: DANIEL KAUFMAN
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $236,250
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
New SARS-CoV-2 variants and novel coronaviruses will constantly arise and affect large proportions of
the worldwide population. Although the current wave of infections with Omicron subvariants is much less lethal
than that caused by previous SARS-CoV-2 variants (e.g., Wuhan-Hu1, Alpha, and Delta), about 10% of Omicron-
infected patients develop prolonged post-acute neurological sequelae involving cognitive impairments (“brain
fog”), difficulty concentrating, anxiety, and depression. Histological studies of brains from COVID-19 patients
have often observed immune cell infiltrates and increased frequencies of glial cells with inflammatory phenotypes
indicative of neuroinflammatory responses. Currently, there are no approved prophylactic or interventive
treatments for SARS-CoV-2-induced neuroinflammation.
There is a growing body of evidence that immune cells, microglia, and astrocytes express γ -aminobutyric
acid receptors (GABAA-Rs). The activation of these GABAA-Rs inhibits their pro-inflammatory activities and shifts
T cells, antigen-presenting cells, microglia, and astrocytes toward anti-inflammatory phenotypes. Taking
advantage of these properties, researchers have used homotaurine, a clinically applicable GABAA-R agonist that
can cross the blood-brain-barrier, to 1) reverse experimental autoimmune encephalomyelitis (EAE) a model of
multiple sclerosis (MS) and 2) reduce the levels inflammatory cytokines in the CNS, decrease neuronal loss, and
ameliorate behavioral deficits in a model of autism spectrum disorder. Furthermore, we have shown that GABAA-
R agonists reduce circulating proinflammatory cytokines/chemokines, viral replication in the lungs, the severity
of illness, and death in mice infected with two different coronaviruses: MHV-1 and SARS-CoV-2. Additionally, in
clinical trials, homotaurine treatment has had some promising beneficial effects in Alzheimer’s disease patients.
We contend that homotaurine is an excellent candidate for preventing and ameliorating SARS-CoV-2-
induced neuroinflammation. We will test this hypothesis in the hamster model of long COVID, arguably the best
rodent model available at this time. We anticipate that we will demonstrate the potential of an entirely new drug
class to help prevent and ameliorate SARS-CoV-2-induced neuroinflammation. Because homotaurine is safe for
human consumption, it could be rapidly tested in clinical trials. Since the mechanism evoked by GABAA-R
activation is unlike that of any other drugs being considered for treating long COVID, GABAA-R agonists are
likely to have enhanced therapeutic effects when combined with other treatments. Finally, the results may have
broader applications to treat other conditions involving CNS inflammation. Therefore, the results of our studies
may provide novel approaches to help improve the health of the global community.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><3-APS><3-amino-1-propanesulfonic acid><3-aminopropanesulfonic acid><3-aminopropylsulfonic acid><4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><A/J Mouse><ACE2><ASD><Acute><Adipose tissue><Affect><Agonist><Alzheimer's disease patient><Alzheimer's patient><Aminalon><Aminalone><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antigen-Presenting Cells><Anxiety><Astrocytes><Astrocytus><Astroglia><Atrophic Arthritis><Autism><Autistic Disorder><BBB crossing><Basal Transcription Factor><Basal transcription factor genes><Behavioral><Biological Markers><Blood - brain barrier anatomy><Blood Serum><Blood-Brain Barrier><Brain><Brain Nervous System><Brain region><Brittle Diabetes Mellitus><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 infection><COVID-19 neural sequela><COVID-19 patient><COVID-19 positive patient><COVID-19 therapy><COVID-19 treatment><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cell Body><Cells><Cessation of life><Chemotactic Cytokines><Clinical Trials><CoV emergence><CoV-2><CoV2><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Community Health><Consumption><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus Infectious Disease 2019><Cricetinae><Death><Dendritic Cells><Development><Diabetic mouse><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disorder><Disseminated Sclerosis><Disturbance in cognition><Dropsy><Drugs><EAE><Early Infantile Autism><Early treatment><Edema><Encephalon><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><Fatty Tissue><Frequencies><GABA><GABA Receptor><GABA-A Receptor><GABA-Benzodiazepine Receptors><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><General Transcription Factor Gene><General Transcription Factors><Glia><Glial Cells><Goals><Golden Hamsters><Golden Syrian Hamsters><Hamsters><Hamsters Mammals><Hemato-Encephalic Barrier><Homologous Chemotactic Cytokines><Hortega cell><Human><Hydrops><IDDM><Immune><Immune infiltrates><Immune response><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Impaired cognition><Infantile Autism><Infection><Inflammation><Inflammatory><Insulin-Dependent Diabetes Mellitus><Intercrines><Investigators><Juvenile-Onset Diabetes Mellitus><K-18><K-18 conjugate><K18><K18 combination><Kanner's Syndrome><Ketosis-Prone Diabetes Mellitus><Kolliker's reticulum><Learning><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lung><Lung Respiratory System><Macrophage><Medical Research><Medication><Mental Depression><Mesocricetus auratus><Metformin><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Multiple Sclerosis><Murine><Mus><Muscimol Receptors><Mφ><N,N-dimethyl-imidodicarbonimidic diamide><Nervous System Diseases><Nervous System Disorder><Neuroglia><Neuroglial Cells><Neurologic><Neurologic Disorders><Neurological><Neurological Disorders><Non-neuronal cell><Nonneuronal cell><Oral><Outcome><Patients><Paxlovid><Pharmaceutical Preparations><Phenotype><Population><Pre-Clinical Model><Preclinical Models><Property><Proteins><Receptor Inhibition><Research Personnel><Researchers><Resistance development><Resistant development><Rheumatoid Arthritis><Risk Reduction><Rodent Model><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 neurological sequelae><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severities><Severity of illness><Steroid Compound><Steroids><Sudden-Onset Diabetes Mellitus><Syrian Hamsters><T cell response><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><Testing><Therapeutic><Therapeutic Effect><Time><Toxic effect><Toxicities><Transcript Expression Analyses><Transcript Expression Analysis><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 diabetic><Type I Diabetes Mellitus><Type II diabetic><Veiled Cells><Viral Burden><Viral Load><Viral Load result><Virus Replication><Wuhan coronavirus><accessory cell><adipose><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><analyze gene expression><angiotensin converting enzyme 2><angiotensin converting enzyme II><astrocytic glia><autism model><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><autoimmune encephalomyelitis><autoreactive T cell><behavior test><behavioral test><bio-markers><biologic marker><biomarker><blood-brain barrier crossing><bloodbrain barrier><bloodbrain barrier crossing><brain fog><chemoattractant cytokine><chemokine><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><clinical applicability><clinical application><cognitive dysfunction><cognitive loss><community-based health><corona virus><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus patient><cytokine><depression><developing resistance><developmental><diabetes mouse model><disease severity><drug/agent><early clinical trial><early phase clinical trial><early therapy><effectiveness testing><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><gamma-Aminobutyric Acid><gamma-Aminobutyric Acid Receptors><gene expression analysis><gene expression assay><gitter cell><global health><hCoV19><histologic studies><histological studies><homotaurine><host response><immune cell infiltrate><immune suppressive agent><immune suppressor><immune system response><immunoresponse><immunosuppressive substance><immunosuppressor><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insular sclerosis><insulin dependent diabetes><insulin dependent type 1><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><mesoglia><microglial cell><microgliocyte><model of autism spectrum disorder><mortality><mouse model><murine model><nCoV><nCoV2><nerve cell death><nerve cell loss><nerve cement><neural inflammation><neural sequela in COVID-19><neuro post-acute sequelae of SARS-CoV-2><neuroPASC><neuroinflammation><neuroinflammatory><neurologic post acute sequelae of SARS-CoV-2><neurologic sequelae of COVID-19><neurological disease><neurological post-acute sequelae of SARS-CoV-2><neurological sequelae associated with SARS-CoV-2><neurological sequelae caused by SARS-CoV-2><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><new CoV><new approaches><new corona virus><new coronavirus><new drug class><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel CoV><novel approaches><novel corona virus><novel coronavirus><novel drug class><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><perivascular glial cell><persistent COVID-19><post COVID syndrome><post COVID-19 syndrome><post SARS-CoV-2 infection><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute CNS symptoms of SARS-CoV-2 infection><post-acute phases of COVID-19><pre-clinical study><preclinical study><prevent><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><prolonged COVID-19 symptoms><prophylactic><pulmonary><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><response><rheumatic arthritis><risk-reducing><self-reactive T cell><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><systemic inflammation><systemic inflammatory response><thymus derived lymphocyte><transcription factor><transcriptional profiling><treat COVID-19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><type I diabetes><type one diabetes><viral multiplication><viral replication><virus multiplication><white adipose tissue><yellow adipose tissue><γ-Aminobutyric Acid>