Brain Fatty Acid Composition and PKC Activity

脑脂肪酸组成和 PKC 活性

基本信息

批准号：
7270126
负责人：
ROBERT K. MCNAMARA
金额：
$ 16.85万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7270126
关键词：
Acute Adverse effects Antipsychotic Agents Bipolar Disorder Brain Brain region Cell Surface Receptors Chromosome Pairing Chronic Classification Clinical Data Development Diabetes Mellitus Diet Docosahexaenoic Acids Dopamine Dopamine D2 Receptor Drug usage Elevation Erythrocytes Event Fatty Acids Foundations Functional disorder Future Haloperidol Hepatic Image In Vitro Inbred Strains Mice Individual Isoenzymes Kidney Knowledge Lead Lithium MARCKS gene Measures Mediating Membrane Molecular Target Mood stabilizers Moods Mouse Strains Mus Neuronal Plasticity Neurons Omega-3 Fatty Acids Patient Noncompliance Patients Pharmaceutical Preparations Phospholipids Phosphorylation Protein Kinase C Rattus Recurrence Relapse Relative (related person)Research Personnel Safety Schizophrenia Solid Synapses Synaptic Membranes Testing Toxic effect Validation Valproic Acid Weight Gain atypical antipsychotic base citrate carrier clinically relevant concept follow-up human subject improved in vivo indexing innovation insight mRNA Expression nervous system disorder neuropsychiatry neurotransmitter release novel novel therapeutics olanzapine pre-clinical programs prophylactic randomized placebo controlled trial receptor binding receptor expression receptor function research study

项目摘要

DESCRIPTION (provided by applicant): Current first-line mood-stabilizer and atypical antipsychotic drugs used in the treatment of bipolar disorder and schizophrenia have limited long-term prophylactic efficacy in 30-40 percent of patients, and several adverse side-effects which frequently lead to additional health-related problems and/or patient noncompliance and relapse. There is therefore an urgent need for the development and validation of new treatments with improved long-term efficacy, safety, and tolerability. Chronic, but not acute, treatment with mood-stabilizer and antipsychotic drugs at therapeutically-relevant concentrations down-regulate protein kinase C (PKC) activity and isozyme expression in rat brain. The principle omega-3 fatty acid found in brain, docosahexaenoic acid (DHA), is derived exclusively from the diet, is specifically enriched in neuronal synaptic membranes, and inhibits PKC in vitro. However, there currently exists a significant knowledge gap in our understanding of the consequences of altering synaptic DHA composition on PKC activity/expression in brain. The primary objective of this proposal is to determine if systematic alterations (increases and decreases) in brain DHA concentrations through dietary manipulations can modulate PKC activity/expression in brain. Our primary HYPOTHESIS is that reductions or elevations in brain DHA concentrations will increase and decrease, respectively, PKC activity/expression. We will also determine if alterations in brain DHA concentrations can modulate the dopamine D2 receptor, a clinically-relevant substrate of PKC. We anticipate that the proposed studies will provide 'proof-of-concept' data demonstrating that dietary-induced reductions/elevations in brain DHA concentrations will increase/decrease PKC activity (SA1) and decrease/increase D2 receptor binding (SA2) in a DHA-concentration-dependent manner. Predicative validity will be evaluated by determining if dietary-induced elevations in PKC activity and reductions in D2 receptor binding can be reversed (normalized) by chronic, but not acute, treatment with haloperidol, olanzapine, lithium, or DHA-rich diets (SA3). The anticipated results will provide a strong scientific foundation and rationale to perform analogous studies in human subjects using in vivo imaging. The proposed experiments are innovative and exploratory in that the effect of altered DHA concentrations on PKC and dopamine D2 receptor expression have not been systematically examined in brain.

描述（由申请人提供）：用于治疗双相情感障碍和精神分裂症的当前一线情绪稳定器和非典型抗精神病药，在30-40％的患者中长期预防性疗效有限，几种不良副作用经常导致其他与健康相关的问题和/或患者的不良问题和/或/或/或与患者的非态度和差异和相关性。因此，迫切需要开发和验证新疗法，并提高了长期疗效，安全性和耐受性。在治疗性相关的浓度下，慢性但不急性治疗在大鼠脑中，在治疗中与抗溶剂浓度下的抗精神病药浓度下调蛋白激酶C（PKC）活性和同工酶表达。在大脑中发现的原理omega-3脂肪酸，二十六烯酸（DHA），专门从饮食中得出，特别富含神经元突触膜，并在体外抑制PKC。但是，目前在我们对改变突触DHA组成对大脑中PKC活性/表达的后果的理解中存在很大的知识差距。该提案的主要目的是确定通过饮食操纵的脑DHA浓度的系统改变（增加和减少）是否可以调节大脑中的PKC活性/表达。我们的主要假设是，脑DHA浓度的降低或升高将分别增加和降低PKC活性/表达。我们还将确定脑DHA浓度的变化是否可以调节多巴胺D2受体，这是PKC的临床上含量与临床相关的底物。我们预计拟议的研究将提供“概念证明”数据，表明饮食诱导的脑DHA浓度的降低/升高将增加/降低PKC活性（SA1），并减少/增加/增加/增加DHA受体结合（SA2）以DHA-浓度依赖性依赖性方式。通过确定饮食诱导的PKC活性升高以及D2受体结合的降低是否可以通过慢性但不急性治疗D2受体结合的升高来评估谓词有效性，并逆转了氟哌啶醇，奥氮平，锂或Dha-rich Diets（SA3）。预期的结果将为使用体内成像在人类受试者中进行类似研究提供强大的科学基础和理由。提出的实验是创新的和探索性的，因为DHA浓度改变对PKC和多巴胺D2受体表达的影响尚未在大脑中系统地检查。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder.

DOI：
10.1016/j.psychres.2007.08.021
发表时间：
2008-09-30
期刊：
PSYCHIATRY RESEARCH
影响因子：
11.3
作者：
McNamara, Robert K.;Jandacek, Ronald;Rider, Therese;Tso, Patrick;Stanford, Kevin E.;Hahn, Chang-Gyu;Richtand, Neil M.
通讯作者：
Richtand, Neil M.

The emerging role of omega-3 fatty acids in psychiatry.