Inflammation-Induced CNS Glutamate During Breast Cancer Treatment

乳腺癌治疗期间炎症诱导的中枢神经系统谷氨酸

• 批准号: 8815732
• 负责人: ANDREW H MILLER
• 金额: $ 19.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815732
• 关键词: Affect; Aftercare; Age; Agonist; Anterior; Astrocytes; Attention; Basal Ganglia; Behavior; Behavior Therapy; Behavior assessment; Behavioral; Binding; Biological Markers; Blood specimen; Brain; Brain region; Breast Cancer Patient; Breast Cancer Treatment; Cancer Patient; Chemical Shift Imaging; Chemicals; Chronic; Cognition; Cognitive; Creatine; Data; Diagnosis; Disease; Dorsal; Encephalitis; Excitatory Amino Acid Antagonists; Exhibits; Exposure to; Fatigue; Female Breast Carcinoma; Functional disorder; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Human; Image; Impaired cognition; Inflammation; Inflammatory; Interferon-alpha; Interleukin-1 beta; Interleukin-6; Kynurenine; Laboratories; Lead; Left; Link; Magnetic Resonance Spectroscopy; Measures; Mediating; Mediator of activation protein; Memantine; Memory; Memory impairment; Mental Depression; Mus; Neuraxis; Neurons; Neurotransmitters; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Play; Proteins; Quinolinic Acid; Race; Radiation therapy; Receptors, Tumor Necrosis Factor, Type II; Research; Risk; Role; Secondary to; Stimulus; Symptoms; TNFR-Fc fusion protein; Testing; Time; Toxic effect; Tryptophan; Tumor Necrosis Factor-alpha; Woman; Work; anakinra; brain behavior; chemical addition; chemotherapy; cingulate cortex; cognitive change; cognitive function; cytokine; depressive symptoms; executive function; experience; glutamatergic signaling; inflammatory marker; interest; malignant breast neoplasm; neurotoxicity; new therapeutic target; novel; peripheral blood; prevent; processing speed; public health relevance; receptor; reuptake; therapeutic target

DESCRIPTION (provided by applicant): Up to 70% of women with breast cancer experience significant depression, fatigue or cognitive dysfunction at some point during diagnosis and treatment, and up to 30% of breast cancer patients experience these symptoms long after treatment completion. Data from our group and others have linked these behavioral changes with increases in peripheral blood markers of inflammation. One mechanism that may link peripheral inflammation to behavioral alterations is central nervous system (CNS) glutamate. Excessive glutamate has been shown to lead to neuronal toxicity, and increased CNS glutamate has been demonstrated in a number of disorders that are characterized by disturbances in behavior and cognition. Moreover, inflammatory cytokines are well known to inhibit glutamate reuptake and increase glutamate release from astrocytes and activate the kynurenine pathway which leads to quinolinic acid, a glutamate receptor agonist that can also inhibit glutamate reuptake. Glutamate antagonists have also been shown to block inflammation-induced depressive-like behavior in mice, while reversing depressive symptoms in humans. Preliminary data using single voxel magnetic resonance spectroscopy (MRS) have shown that chronic administration of the inflammatory cytokine interferon (IFN)-alpha leads to significant increases in glutamate in brain regions known to be targets of inflammatory stimuli including the dorsal anterior cingulate cortex (dACC) and the basal ganglia. Of note, IFN- alpha-induced increases in CNS glutamate were correlated with behavioral changes as well as plasma soluble tumor necrosis factor (TNF) receptor 2, an inflammatory marker that has been associated with fatigue in breast cancer patients. Interestingly, a recent study demonstrated that the glutamate receptor antagonist memantine reduced cognitive dysfunction in cancer patients undergoing whole brain radiotherapy, indicating that blocking glutamate may have neuroprotective effects in cancer patients with an increased inflammatory load. Taken together, these data support the hypothesis that increased inflammation may cause increased glutamate in specific brain regions which in turn may contribute to behavioral and cognitive changes. To test this hypothesis, we plan to measure 1) CNS glutamate in the dACC, basal ganglia and hippocampus using single voxel and chemical shift (short TE multivoxel) MRS, 2) peripheral biomarkers of inflammation and the kynurenine pathway, and 3) depression, fatigue and cognitive function in 60 women with breast cancer. Because previous work has shown that inflammatory markers are higher in chemotherapy versus non-chemotherapy-treated breast cancer patients, 30 of these women will be treated with surgery and chemotherapy and 30 with surgery alone. 30 healthy women without breast cancer will serve as controls. These data will be the first to examine whether CNS glutamate is an important mediator of effects of inflammation on the brain and behavior, while providing preliminary indication that glutamate may be a therapeutic target for treatment of behavioral and cognitive changes in women with breast cancer.

描述（由申请人提供）：多达70％的乳腺癌女性在诊断和治疗期间的某个时刻经历了明显的抑郁症，疲劳或认知功能障碍，在治疗完成后很长一段时间后，多达30％的乳腺癌患者经历了这些症状。来自我们小组和其他人的数据将这些行为变化与炎症外周血标记的增加联系起来。一种可能将周围炎症与行为改变联系起来的机制是中枢神经系统（CNS）谷氨酸。已证明过量的谷氨酸会导致神经元毒性，并且在许多以行为和认知障碍为特征的疾病中已证明了CNS谷氨酸的增加。此外，众所周知，炎症细胞因子抑制谷氨酸再摄取并增加星形胶质细胞的谷氨酸释放，并激活Kynurenine途径，这会导致喹啉酸，这是一种甲状酸喹啉酸，这是一种谷氨酸受体激动剂，它也可以抑制谷氨酸酸酯。还显示谷氨酸拮抗剂可以阻止小鼠炎症引起的抑郁样行为，同时逆转人类的抑郁症状。使用单个体素磁共振光谱（MRS）的初步数据表明，炎症性细胞因子干扰素（IFN） - α的慢性施用导致已知的脑区域中谷氨酸的谷氨酸显着增加，已知是炎性刺激的靶标，包括背膜前毛状Cortex（DACC）和底层cotalex（DACC）和底部。值得注意的是，IFN-Alpha诱导的谷氨酸中枢神经系统的增加与行为变化以及血浆可溶性肿瘤坏死因子（TNF）受体2相关，这是一种与乳腺癌患者疲劳有关的炎症标记。有趣的是，最近的一项研究表明，谷氨酸受体拮抗剂美容降低了接受整个脑放射疗法的癌症患者的认知功能障碍，这表明阻断谷氨酸可能对炎症负荷增加的癌症患者具有神经保护作用。综上所述，这些数据支持以下假设：炎症增加可能会导致特定大脑区域的谷氨酸增加，从而导致行为和认知变化。为了检验这一假设，我们计划测量1）使用单个体素和化学移位（短TE多氧化氧化）MRS中的DACC，基底神经节和海马中的谷氨酸MR，2）炎症的外围生物标志物，以及Kynurenine Pathway和Kynurine Pathway和Kynurine pathway和3）抑郁症，抑郁症，疲劳和认知能力，在60名女性中均与60名女性患有乳腺癌。由于先前的工作表明，化学疗法与非化学疗法治疗的乳腺癌患者的炎症标记较高，因此其中30名女性将接受手术和化学疗法治疗，单独进行30例手术。 30名没有乳腺癌的健康女性将用作对照。这些数据将是第一个检查CNS谷氨酸是否是炎症对大脑和行为影响的重要介体，同时提供了初步的指示，即谷氨酸可能是治疗乳腺癌女性行为和认知变化的治疗靶标。