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Project 3: Normalization of Neuronal Excitability

项目 3：神经元兴奋性正常化

基本信息

批准号：
10684091
负责人：
Gene Gabriel Gurkoff
金额：
$ 48.35万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684091
关键词：
Acetylcholinesterase Acute Amygdaloid structure Anticonvulsants Atropine Attention Behavior Behavioral Benzodiazepines Biological Assay Biological Markers Cell Death Chronic Clinical Data Clinical Trials Cognition Cognition Disorders Cognitive Combined Modality Therapy Data Deep Brain Stimulation Development Dorsal Electrodes Epilepsy Evaluation Event Exposure to FDA approved Female Frequencies Functional disorder Glutamine Goals Hippocampus Hour Human Impaired cognition Impairment Implant Individual Injury Interruption Intervention Intoxication Isoflurophate Learning Link Longitudinal Studies Measures Medial Septal Nucleus Memory Modeling Molecular Morbidity - disease rate Motor Muscarinic Acetylcholine Receptor Natural History Nerve Degeneration Neurologic Neurologic Deficit Neurological outcome Organophosphates Outcome Oximes Patients Performance Peripheral Phenotype Pralidoxime chloride Pre-Clinical Model Prefrontal Cortex Rattus Recurrence Riluzole Risk Seizures Severities Short-Term Memory Sodium Channel Status Epilepticus Survivors System Telemetry Testing Therapeutic Time Toxic effect Visuospatial acute care antagonist awake behavioral outcome behavioral study brain tissue calcium-activated potassium channel small-conductance chemical threat cholinergic cognitive function cognitive testing combinatorial comparative efficacy conditioned fear effectiveness evaluation entorhinal cortex executive function falls high risk improved insight long term memory male mass casualty neural neurobehavior neuroinflammation neuronal excitability neuropathology new therapeutic target novel object recognition pre-clinical predictive marker prevent sex standard of care therapeutic candidate touchscreen voltage

项目摘要

Project Summary – Project 3 Both clinical and preclinical data clearly demonstrate that survivors of OP-induced status epilepticus (SE) can develop persistent neuropathology, spontaneous recurring seizures (SRS) and cognitive dysfunction. Current standard-of-care (SOC) for acute OP intoxication includes the muscarinic receptor antagonist, atropine, combined with an oxime, such as pralidoxime chloride (2-PAM) to reactivate acetylcholinesterase and finally a benzodiazepine to increase inhibitory tone. However, it is now clear that the potential for SOC to prevent SE or to counteract the downstream consequences of the OP-induced cholinergic storm rapidly diminishes with time. Specifically, immediate treatment with atropine and 2-PAM can increase viability, but does not prevent a transition into SE. Once in SE, the potential for benzodiazepines to interrupt seizures and protect against ongoing cell death quickly declines. It is also clear that as the interval between acute intoxication and treatment increases, the severity of the corresponding chronic neurological deficits increases as well. It is likely that following a mass casualty event, treatment of civilians exposed to chemical threat agents is going to fall outside of the optimal therapeutic window, increasing the likelihood that they will develop persistent SRS and cognitive disorders. Therefore, there is a clear need to identify biological markers to identify those individuals with the highest risk of developing long-term morbidity and also to move beyond the management of acute OP intoxication in the field, and to investigate therapeutic strategies for managing chronic neurological sequelae, including SRS and cognitive dysfunction. In Project 3, we will first evaluate the natural history of acute DFP intoxication. This will include a rigorous assessment of neural oscillations recorded from depth and cortical electrodes over the course of four months following injury, the quantification of SRS and also evaluation of both a standard battery of cognitive outcomes (Y-maze, novel object recognition and contextual fear conditioning) and also translationally relevant touchscreen behaviors (that evaluate memory, executive function, and attention). We will then evaluate four therapeutic candidates for their potential to modulate excitability, restore oscillations, reduce seizures and improve cognition. These candidates include: (i) FDA-approved lacosamide, which enhances the slow inactivation of voltage-gated sodium channels (Nav); (ii) FDA-approved riluzole, which blocks Nav, but also enhances the activity of small-conductance calcium-activated potassium channels (KCa) and also glutamine transport; (iii) SKA-19, a mixed Nav blocker and KCa activator; and (iv) NS13001, a relatively selective KCa activator. Finally, we will determine the potential of combinatorial therapy including one of the above therapeutic candidates with theta frequency deep brain stimulation to further manage the chronic neurological outcomes associated with acute OP intoxication. Ultimately, Project 3 will uncover molecular mechanisms of toxicity and potentially identify novel therapeutic targets to prevent (with acute delivery of identified therapies) or treat (with chronic delivery) the devastating long-term neurological sequelae, including SRS and cognitive dysfunction.

项目摘要-项目3