The effect of lithium on intracellular sodium in brain in vivo

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，每年造成超过450亿美元的损失，折磨着超过230万美国人。它的分子起源尚不清楚。过去人们注意到，双相情感障碍患者体液中的钠(Na)水平会随着情绪状态的改变而变化。后来通过同位素稀释技术证实了抑郁症和躁狂症患者的异常钠室分布。这些和其他观察结果导致了一种假设，即细胞Na泵，Na，K-ATPase异常引起的离子失衡与BPD有关。锂(Li)是治疗BPD急性躁狂和预防复发的重要一线药物和广泛使用的处方。其治疗BPD的作用机制尚未厘清。锂对BPD的治疗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。Li在活体内取代脑细胞内Na的证明还没有完成。钠-23磁共振成像是一种先进的成像技术，可以无创地探测脑内钠的局部环境，有可能显示锂对脑钠的影响。由于许多双相患者对LI治疗没有足够的反应，因此迫切需要了解LI发挥治疗效果的机制(S)。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，以便提供更好的治疗效果。本应用的目的是确定锂对正常大鼠在体脑细胞内钠离子的影响。我们的理论基础是，这些效应可能与李在BPD中的作用机制有关，特别是Na，K-ATPase假说。这一应用的中心假设是，LI将细胞内的钠置换到正常大脑的细胞外/脑脊液间隙中。这一假说得到了初步研究的支持，这些研究表明，随着急性Li注射，23Na MRI强度和自旋松弛时间的变化与体内脑组织细胞内钠的减少和脑脊液钠的增加一致。我们将通过完成以下具体目标来实现我们的目标：1)在活体内测定Li对正常大鼠脑内钠区划的影响，作为Li浓度的函数。这项工作具有创新性，因为这是首次尝试在活体内直接测量锂对脑钠的影响。它还采用了一种新的多核体内MR方法，在此之后立即使用23Na MRI和7Li MRS来探测局部Na浓度和脑LI。提出的研究具有重要意义，因为它们将证明BPD的Na，K-ATPase假说的一个关键假设在特定条件下是正确的。如果BPD患者细胞内Na升高，并被Li取代，则 ~(23)Na核磁共振LI可作为BPD治疗的早期指标。在确定长期复发疾病之前，在病程早期确定可靠的治疗反应标志物是至关重要的。确定可靠的治疗反应标记物将显著改善治疗分配，产生更好的应答率，并减少情感发作的数量。

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.