Project 3: Normalization of Neuronal Excitability

项目 3：神经元兴奋性正常化

• 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
• 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

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.

项目总结 – 项目 3 临床和临床前数据都清楚地表明，OP 引起的癫痫持续状态 (SE) 的幸存者可以 出现持续性神经病理学、自发性复发性癫痫发作 (SRS) 和认知功能障碍。当前的 急性 OP 中毒的标准护理 (SOC) 包括毒蕈碱受体拮抗剂阿托品、 与肟结合，例如氯化解磷定 (2-PAM)，重新激活乙酰胆碱酯酶，最后 苯二氮卓类药物可增加抑制音调。然而，现在很明显，SOC 有可能防止 SE 或 抵消 OP 引起的胆碱能风暴的下游后果的能力随着时间的推移而迅速减弱。 具体来说，立即使用阿托品和 2-PAM 治疗可以增加活力，但不能阻止 过渡到 SE。一旦进入东南部，苯二氮卓类药物就有可能中断癫痫发作并防止持续发作 细胞死亡迅速减少。同样清楚的是，随着急性中毒和治疗之间的间隔时间的增加， 相应的慢性神经功能缺损的严重程度也会增加。很可能是在一场弥撒之后 伤亡事件中，暴露于化学威胁剂的平民的治疗将超出最佳范围 治疗窗口，增加了他们出现持续性 SRS 和认知障碍的可能性。 因此，显然需要识别生物标记来识别那些具有最高风险的个体。 发展长期发病率，并超越现场急性OP中毒的治疗， 并研究治疗慢性神经系统后遗症的策略，包括立体定向放射外科（SRS）和 认知功能障碍。在项目 3 中，我们将首先评估急性 DFP 中毒的自然史。这将 包括对整个过程中从深度和皮质电极记录的神经振荡进行严格评估 受伤后四个月内，SRS 的量化以及标准电池的评估 认知结果（Y 迷宫、新物体识别和情境恐惧调节）以及转化 相关的触摸屏行为（评估记忆力、执行功能和注意力）。然后我们将评估 四种候选治疗药物具有调节兴奋性、恢复振荡、减少癫痫发作和 提高认知能力。这些候选药物包括： (i) FDA 批准的拉科酰胺，可增强缓慢的 电压门控钠通道 (Nav) 失活； (ii) FDA 批准的利鲁唑，它可以阻断 Nav，但也 增强小电导钙激活钾通道 (KCa) 和谷氨酰胺的活性 运输; (iii) SKA-19，一种混合​​ Nav 阻滞剂和 KCa 激活剂； (iv) NS13001，一种相对选择性的 KCa 激活剂。最后，我们将确定组合疗法的潜力，包括上述治疗之一 使用 theta 频率深部脑刺激的候选人可进一步管理慢性神经系统结果 与急性OP中毒有关。最终，项目 3 将揭示毒性和毒性的分子机制。 潜在地识别新的治疗靶点来预防（通过快速提供已识别的疗法）或治疗（通过 慢性分娩）会造成毁灭性的长期神经系统后遗症，包括 SRS 和认知功能障碍。