Chronic Lithium Therapy for Traumatic Brain Injury

慢性锂盐治疗创伤性脑损伤

• 批准号: 9260706
• 负责人: C EDWARD DIXON
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260706
• 关键词: Accounting; Acetylcholine; Afghanistan; Attenuated; Blast Cell; Brain; Brain-Derived Neurotrophic Factor; Cell membrane; Chronic; Clinic; Cognitive deficits; Communication; Complex; Conflict (Psychology); Corpus striatum structure; Craniocerebral Trauma; Dopamine; Dose; Early Intervention; Event; Explosion; Exposure to; Freedom; Goals; Hippocampus (Brain); Histopathology; Impaired cognition; Impairment; Individual; Injury; Intervention; Iraq; Lithium; Long-Term Effects; Mental disorders; Military Personnel; Molecular Chaperones; Motor; Neurons; Pathology; Performance; Persons; Pharmacotherapy; Physiological; Play; Process; Proteins; Recovery; Residual state; Role; SNAP receptor; Scaffolding Protein; Severities; Symptoms; Synapses; Synaptic Vesicles; Therapeutic; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; VAMP-2; Veterans; War; Wild Type Mouse; cognitive function; combat; cysteine string protein; disabling symptom; functional outcomes; high risk; improved; neurotransmission; neurotransmitter release; novel; operation; presynaptic; public health relevance; receptor; restoration; service member; spatial memory; synaptosomal-associated protein 25; syntaxin 1

DESCRIPTION (provided by applicant): Military personnel deployed to the wars in Afghanistan (Operation Enduring Freedom; OEF) and Iraq (Operation Iraqi Freedom; OIF) are at high risk of sustaining a traumatic brain injury (TBI) from exposures to a blast (i.e., blast waves from explosions) and other types of head injuries (12,52). While early interventions are important to blunt secondary injury and maximize functional outcome, chronic interventions are also needed by veterans to aid recovery of persistent debilitating symptoms resulting from TBI. While motor functions tend to improve significantly, residual cognitive disturbance remains the most significant concern of persons with all severities of TBI. Normal brain cognitive function depends on synaptic communication via neurotransmitter release. We have previously shown that experimental TBI can produce persistent deficits in evoked neurotransmitter release, but the mechanisms are unknown. Neurotransmitter release at the synapse requires fusion of synaptic vesicles with the presynaptic plasma membrane. A crucial step in this process involves the assembly of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, a highly stable, parallel four-helix bundle formed between the synaptic vesicle SNARE synaptobrevin 2 (SYB2) and the plasma membrane SNAREs syntaxin 1 and synaptosome-associated protein of 25 kDa (SNAP-25). The pathology of SNARE proteins may play an important role in TBI, especially concerning neurotransmission and subsequent cognitive disturbances. Cysteine string protein alpha (CSP¿) promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. It has recently been discovered that lithium, at therapeutically relevant concentrations, can enhance the expression of CSP¿. This represents a novel mechanism by which lithium may restore neurotransmitter release deficits after TBI. We have preliminary evidence showing a decrease in both CSP¿ expression and SNARE-complex assembly after TBI that is attenuated by lithium treatment. It is well known that lithium has multiple actions. We will also contrast the chronic effects of lithium treatment on SNARE proteins to GSK3b and BDNF levels which represent traditional mechanisms of action of lithium. The goal of this proposal is to determine the effects of chronic TBI on key SNARE-complex mechanisms of neurotransmission. The overall hypothesis is that chronic cognitive deficits following TBI may be, at least partially, attributable to impairment in synaptic SNARE-complex formation and subsequent neurotransmitter release deficits. Specific Aim 1 will examine the effects of TBI on individual SNARE proteins, SNARE-complex assembly, and CSP¿, a key regulator of SNARE-complex assembly. Specific Aim 2 will determine if increasing the expression of CSP¿ by lithium is associated with a restoration of SNARE-complex assembly, cognitive function, and histopathology. Specific Aim 3 will determine if lithium, at doses that attenuate SNARE complex loss, can attenuate evoked neurotransmitter release deficits after TBI. Lithium treatment is initiated at chronic intervals that are relevant to Veteran's exposed to TBI-inducing physical forces. Successful completion of this project may provide evidence that SNARE-complexes and cognitive function are chronically diminished after TBI and can be restored, at least partially, by lithium therapy.

描述（由申请人提供）：