The effect of lithium on intracellular sodium in brain in vivo

体内锂对脑细胞内钠的影响

• 批准号: 8727663
• 负责人: Richard A Komoroski
• 金额: $ 23.27万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727663
• 关键词: Acute; Affect; Affective; American; Behavioral; Biochemical; Biochemical Process; Bipolar Disorder; Brain; Cations; Development; Dilution Techniques; Disease; Environment; Genetic Variation; Goals; Homeostasis; Human; Image; Imaging Techniques; Isotopes; Knowledge; Laboratories; Lead; Link; Liquid substance; Lithium; MRI Scans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manic; Measures; Membrane Potentials; Mental Depression; Mental disorders; Methodology; Modeling; Molecular; Moods; Mutation; Na(+)-K(+)-Exchanging ATPase; Neurons; Outcome; Patients; Peripheral; Pharmacotherapy; Phenotype; Process; Psyche structure; Rattus; Recurrence; Relaxation; Research; Rest; Role; Sodium; Sorting - Cell Movement; Techniques; Therapeutic; Therapeutic Effect; Time; Tissues; Work; biophysical chemistry; bipolar mania; brain cell; cost; disorder later incidence prevention; effective therapy; experience; extracellular; improved; in vivo; innovation; ionic balance; mouse model; novel therapeutic intervention; public health relevance; response; treatment response

DESCRIPTION (provided by applicant): Bipolar disorder (BPD) is a devastating mental illness afflicting over 2.3 million Americans at an annual cost of over $45 billion. Its molecular origins remain unknown. It was noted in the past that sodium (Na) levels in bodily fluids of bipolar patients changed with change in mood state. Abnormal Na compartmental distribution was later confirmed in depression and mania using isotope dilution techniques. These and other observations led to the proposal that ionic imbalances arising from abnormalities in the cellular Na pump, Na,K-ATPase, were associated with BPD. Lithium (Li) is an important first-line and widely prescribed treatment for acute mania and relapse prevention in BPD. Its mechanisms of therapeutic action in BPD have not yet been sorted out. Lithium's mechanism of therapeutic action in BPD may consist of normalization of elevated intracellular Na levels, thus re-establishing normal resting membrane potential and cellular excitability. Demonstration that Li displaces intracellular Na in the brain in vivo has not been accomplished. Sodium-23 MRI, an advanced imaging technique for noninvasively probing the regional environment of Na in the brain, has the potential to demonstrate the effects of Li on brain Na. Because many bipolar patients do not respond adequately to Li treatment, there is a critical need to understand the mechanism(s) by which Li exerts its therapeutic effects. Our long-term goal is to improve our understanding of how Li impacts the brain in patients with BPD in order to provide improved therapeutic benefit. The objective of this application is to identify the effects of Li on intracelular Na in normal rat brain in vivo. Our rationale is that these effects may be relevant to Li's mechanism of action in BPD, in particular the Na,K-ATPase hypothesis. The central hypothesis of this application is that Li displaces intracellular Na into the extracellular/CSF space in norma brain. This hypothesis is supported by Preliminary Studies that show changes in 23Na MRI intensities and spin relaxation times with acute Li administration consistent with reduced intracellular and increased CSF Na in the brain in vivo. We will achieve our objective by completing the following Specific Aim: 1) Determine the effects of Li on Na compartmentation in normal rat brain in vivo as a function of Li concentration. This work is innovative because it is the first attempt to measure directly the effects of Li on brain Na in vivo. It also employs a new multinuclear, in vivo MR methodology to probe localized Na concentration using 23Na MRI and brain Li using 7Li MRS immediately thereafter. The proposed studies are significant because they will demonstrate that a key assumption of the Na,K-ATPase hypothesis of BPD is correct under certain conditions. If intracellular Na is elevated in BPD and displaced by Li, the effect of Li on 23Na MRI may be an early marker of treatment for BPD. It is critical to identify reliable markers of treatment response early in the disease course, before the long-term, recurrent illness is established. Identifying reliable markers of treatment response would dramatically improve treatment assignment, generate better response rates, and decrease the number of affective episodes.

描述（申请人提供）：双相情感障碍（BPD）是一种毁灭性的精神疾病，困扰着230多万美国人，每年花费超过450亿美元。其分子起源仍然未知。过去注意到，双相情感障碍患者体液中的钠（Na）水平随着情绪状态的变化而变化。后来用同位素稀释技术证实了抑郁症和躁狂症的异常钠房室分布。这些和其他观察结果导致了这样的建议，即细胞Na泵，Na，K-ATP酶异常引起的离子失衡与BPD相关。锂（Li）是BPD急性躁狂和复发预防的重要一线和广泛处方治疗。其在BPD中的治疗作用机制尚未整理出来。锂在BPD中的治疗作用机制可能包括使升高的细胞内Na水平正常化，从而重建正常的静息膜电位和细胞兴奋性。证明Li在体内置换脑中的细胞内Na尚未完成。钠-23 MRI是一种先进的成像技术，用于无创探测脑中Na的区域环境，有可能证明Li对脑Na的影响。由于许多双相情感障碍患者对Li治疗反应不充分，因此迫切需要了解Li发挥其治疗作用的机制。我们的长期目标是提高我们对Li如何影响BPD患者大脑的理解，以提供更好的治疗益处。本申请的目的是确定锂对正常大鼠脑细胞内钠的影响。我们的基本原理是，这些影响可能与Li在BPD中的作用机制有关，特别是Na，K-ATP酶假说。该应用的中心假设是Li将细胞内Na置换到正常脑中的细胞外/CSF空间中。该假设得到初步研究的支持，初步研究显示，急性Li给药后23 Na MRI强度和自旋弛豫时间的变化与体内脑中细胞内Na减少和CSF Na增加一致。我们将通过完成以下具体目标来实现我们的目标：1）确定Li对正常大鼠脑内Na区室化的影响，作为Li浓度的函数。这项工作是创新的，因为它是第一次尝试直接测量锂对体内脑钠的影响。它还采用了一种新的多核体内MR方法，使用23 Na MRI探测局部Na浓度，然后立即使用7 Li MRS探测脑Li。所提出的研究是有意义的，因为它们将证明BPD的Na，K-ATP酶假说的关键假设在某些条件下是正确的。如果在BPD中细胞内Na升高并被Li取代， 23 Na MRI上的Li可能是BPD治疗的早期标志物。关键是要在病程早期，在确定长期复发性疾病之前，确定治疗反应的可靠标志物。确定治疗反应的可靠标志物将大大改善治疗分配，产生更好的反应率，并减少情感发作的数量。