Brain serotonin and angiotensin II systems in migraine

偏头痛中的脑血清素和血管紧张素 II 系统

• 批准号: 6899347
• 负责人: JOSE TERRON
• 金额: $ 5.4万
• 依托单位: CINVESTAV-IPN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899347
• 关键词: ACE inhibitors; angiotensin II; autoradiography; blood chemistry; brain circulation; cerebrovascular imaging /visualization; chemoprevention; high performance liquid chromatography; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; laboratory rat; migraine; neural transmission; neuropharmacology; radioimmunoassay; receptor sensitivity; serotonin; serotonin inhibitor; serotonin receptor; stress; ultrasound blood flow measurement

DESCRIPTION (provided by applicant) Long-term objectives. The brain serotonin (5-HT) system plays an important role in cerebrovascular and neuroendocrine control. These systems have been implicated in migraine. Migraine is a low 5-HT syndrome and attacks may be triggered by a massive release of 5-HT acting on sensitized receptors. This proposal will elucidate the association between the phenomena of decreased 5-HT neurotransmission and altered cerebrovascular and neuroendocrine responsiveness. Focus will be on 5-HT receptors recently implicated in migraine pathogenesis and/or prophylactic treatment (5-HT1A, 5-HTT, 5-HT2s and 5-HT2c). As a key activator of the hypothalamic-pituitary-adrenal (HPA) axis, the role of the brain angiotensin II (Ang II) system will be addressed. The proposal intends to shed light into the pathophysiological mechanisms of migraine, and the mechanism of action of migraine prophylactic 5-HT and Ang II drugs. Specific aims. The following hypotheses will be challenged: 1) A decreased 5-HT transmission in the brain will cause sensitization and/or up-regulation of 5-HT receptor subtypes in the cerebral vasculature and the HPA axis; treatment with a migraine prophylactic compound that target these receptors will restore 5-HT receptor function and/or expression. This may be a useful animal model for drug screening in migraine prophylaxis. 2) The response to stress, which involves sequential activation of the brain Ang II and the HPA systems, will lead to decreased brain 5-HT levels, up-regulation of 5-HT receptors, and/or amplified neuroendocrine and cerebrovascular responses to 5-HT receptor activation; treatment with an inhibitor of Ang II synthesis will restore serotonergic function. Design. 1) Cerebrovascular and neuroendocrine responses to 5-HT agonists, and expression of 5-HT receptors in the cerebral vasculature and the HPA axis, will be determined in control and 5-HT-depleted Wistar rats. It will be determined whether chronic treatment with a migraine prophylactic 5-HT antagonist restore 5-HT receptor function and/or expression. 2) Brain 5-HT content, expression of 5-HT receptors in the HPA axis, and neuroendocrine and cerebrovascular responses will be determined in control and stressed (acute and chronic isolation and restraint) Wistar rats. Reversal of stress-induced changes in these variables will be attempted by chronic treatment with the angiotensin-converting enzyme inhibitor, lisinopril (i.e. a migraine prophylactic agent). In vivo cerebrovascular reactivity will be assessed by laser- Doppler flowmetry (cortical blood flow) and the 4-iodo-[N-methyl-14C]-antipyrine method (regional cerebral blood flow). In vitro cerebrovascular reactivity will be analyzed with an arteriographic chamber system. The hormonal response (ACTH, corticosterone and prolactin) will be measured by radioimmuno assay in blood samples and 5-HT receptor expression will be determined by quantitative receptor autoradiography in tissue sections. 5-HT content will be measured by HPLC in brain homogenates.

描述（由申请人提供） 长期目标。大脑血清素（5-HT）系统在脑血管和神经内分泌控制中发挥着重要作用。这些系统与偏头痛有关。偏头痛是一种低 5-HT 综合征，5-HT 大量释放作用于敏感受体可能引发偏头痛发作。该提案将阐明 5-HT 神经传递减少与脑血管和神经内分泌反应性改变之间的关联。重点将放在最近与偏头痛发病机制和/或预防性治疗有关的 5-HT 受体（5-HT1A、5-HTT、5-HT2s 和 5-HT2c）。作为下丘脑-垂体-肾上腺 (HPA) 轴的关键激活剂，大脑血管紧张素 II (Ang II) 系统的作用将得到讨论。该提案旨在阐明偏头痛的病理生理机制，以及偏头痛预防药物 5-HT 和 Ang II 药物的作用机制。具体目标。以下假设将受到挑战：1）大脑中 5-HT 传输的减少将导致大脑血管系统和 HPA 轴中 5-HT 受体亚型的敏化和/或上调；使用针对这些受体的偏头痛预防性化合物进行治疗将恢复 5-HT 受体功能和/或表达。这可能是用于偏头痛预防药物筛选的有用动物模型。 2）对压力的反应，涉及大脑Ang II和HPA系统的顺序激活，将导致大脑5-HT水平降低，5-HT受体上调，和/或放大神经内分泌和脑血管对5-HT受体激活的反应；用血管紧张素II合成抑制剂治疗将恢复血清素能功能。设计。 1) 将在对照和 5-HT 耗尽的 Wistar 大鼠中测定脑血管和神经内分泌对 5-HT 激动剂的反应，以及脑血管和 HPA 轴中 5-HT 受体的表达。将确定用偏头痛预防性5-HT拮抗剂进行长期治疗是否恢复5-HT受体功能和/或表达。 2)在对照和应激（急性和慢性隔离和约束）Wistar大鼠中测定脑5-HT含量、HP​​A轴中5-HT受体的表达以及神经内分泌和脑血管反应。通过使用血管紧张素转换酶抑制剂赖诺普利（即偏头痛预防剂）进行长期治疗，可以尝试逆转应激引起的这些变量的变化。体内脑血管反应性将通过激光多普勒血流测定法（皮质血流）和4-碘-[N-甲基-14C]-安替比林法（局部脑血流）进行评估。将使用动脉造影室系统分析体外脑血管反应性。将通过血液样本中的放射免疫测定来测量激素反应（ACTH、皮质酮和催乳素），并通过组织切片中的定量受体放射自显影来确定 5-HT 受体表达。将通过 HPLC 测量脑匀浆中的 5-HT 含量。