Targeting TRPM2 channels to improve synaptic and cognitive function after cerebral ischemia

靶向TRPM2通道改善脑缺血后的突触和认知功能

• 批准号: 9203070
• 负责人: Paco S Herson
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203070
• 关键词: Acute; Calcineurin; Cause of Death; Cell model; Cerebral Ischemia; Chronic Phase; Clinical Trials; Cognitive; Data; Disease; Electrophysiology (science); Exhibits; Functional disorder; Heart Arrest; Hippocampus (Brain); Human; Hypoxia; Impaired cognition; Impairment; Induced Heart Arrest; Injury; Intervention; Ion Channel; Ischemia; Learning; Long-Term Potentiation; Mediating; Memory; Memory Disorders; Memory impairment; Modeling; Molecular; Myocardial Infarction; Neuronal Dysfunction; Neuronal Injury; Neuronal Plasticity; Neurons; Neuropsychology; Outcome; Pharmaceutical Preparations; Phase; Physiological; Physiology; Pyramidal Cells; Quality of life; Recovery; Recovery of Function; Regulation; Role; Stimulus; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Time; United States; calcineurin phosphatase; cognitive function; disability; glycogen synthase kinase 3 beta; imaging study; improved; improved outcome; inhibitor/antagonist; mortality; neuroprotection; novel; prevent; public health relevance; sulfated glycoprotein 2; synaptic function; synaptic inhibition

 DESCRIPTION (provided by applicant): Cardiac arrest (CA) occurs in approximately 600,000 people each year in the United States alone and is a major cause of mortality and morbidity1. Cardiac arrest results in global cerebral ischemia and hypoxic-ischemic injury, and the consequent neuronal damage results in long-term cognitive impairments. The memory disorders commonly observed following CA are readily explained by the selective vulnerability of CA1 pyramidal cells of the hippocampus. However, recent imaging studies in humans indicate that hippocampal injury per se may not correlate with memory dysfunction9, implicating altered physiology following ischemia. Indeed, our recent study indicates that surviving neurons in the hippocampus exhibit physiological changes that likely contribute to cognitive deficits10. This is significant because several interventional clinical trials aimed at reducing neuronal injury have failed to improve outcome following ischemic insults, making it clear that alternative approaches are needed to improve functional recovery. An optimal therapeutic intervention would have the capacity to reduce neuronal injury, maintain functional neuronal networks, and even recover function if administered in the subacute to late chronic phase. Our preliminary data indicate that inhibition of the ion channel TRPM2 fits these criteria. We show that inhibition of TRPM2 during the acute phase (30 min) after cardiac arrest provides neuroprotection and delayed inhibition (6-7 days) reverses CA-induced impairment of neuronal function and plasticity. Memory deficits and hippocampal dysfunction are well accepted sequelae of global cerebral ischemia. Evidence of hippocampal dysfunction following ischemia is provided using electrophysiological recordings of the remaining synaptic network. Synaptic plasticity, in the form of strengthening following physiological stimuli (long-term potentiation; LTP) is a well-established cellular model of learnin and memory. Our recent studies and preliminary studies indicate that CA/CPR causes prolonged impairment (at least 30 days) of hippocampal LTP10 that is prevented by inhibition of TRPM2 channels during the acute phase (30 min) after CA/CPR. Most surprisingly, inhibition of TRPM2 one week after CA/CPR results in reversal of deficits in LTP and enhance memory function. TRPM2 channels have recently been observed to contribute to synaptic inhibition via activation of glycogen synthase kinase 3β (GSK3β); therefore we hypothesize that prolonged activation of TRPM2 channels within hippocampal synapses activates GSK3β, thereby inhibiting the induction of LTP and thus new memories. Our new preliminary data indicates that inhibition of TRPM2 has the potential reduce cognitive impairments and potentially provide a new restorative therapy. The current proposal is aimed at determining the mechanism underlying the regulation of TRPM2 channels during the subacute and chronic phase following ischemia and most-importantly the mechanism of TRPM2-mediated inhibition of synaptic plasticity. We hypothesize that 1) ischemia causes sustained activation of TRPM2 channels, 2) inhibiting synaptic plasticity and 3) that delayed administration of TRPM2 inhibitors will reverse deficits in synaptic plasticity and recover memory function following cardiac arrest.

 描述(申请人提供)：心脏骤停(CA)每年仅在美国就有大约60万人发生，是死亡和发病的主要原因1。心脏骤停导致全脑缺血和缺氧缺血性损伤，继而引起的神经元损伤导致长期的认知损害。CA后常见的记忆障碍很容易被海马区CA1锥体细胞的选择性易损性解释。然而，最近对人类的成像研究表明，海马体损伤本身可能与记忆功能障碍无关，这意味着缺血后的生理改变。事实上，我们最近的研究表明，海马体中存活的神经元表现出可能导致认知缺陷的生理变化。这一点意义重大，因为一些旨在减少神经元损伤的介入性临床试验未能改善缺血损伤后的结果，这清楚地表明，需要替代方法来改善功能恢复。如果在亚急性期到慢性期应用，最佳的治疗干预将具有减少神经元损伤、维持功能神经元网络、甚至恢复功能的能力。我们的初步数据表明，对离子通道TRPM2的抑制符合这些标准。我们发现，在心脏骤停后的急性期(30分钟)抑制TRPM2可提供神经保护，延迟抑制(6-7天)可逆转CA引起的神经元功能和可塑性损害。记忆障碍和海马区功能障碍是公认的全脑缺血的后遗症。通过对剩余突触网络的电生理记录，提供了缺血后海马体功能障碍的证据。突触可塑性，以在生理刺激(长时程增强；LTP)后加强的形式，是一个成熟的学习和记忆的细胞模型。我们最近的研究和初步研究表明，CA/CPR导致海马LTP10的长时间损伤(至少30天)，这种损伤是通过在CA/CPR后的急性期(30分钟)抑制TRPM2通道来防止的。最令人惊讶的是，CA/CPR后一周抑制TRPM2可逆转LTP的缺陷并增强记忆功能。最近观察到TRPM2通道通过激活糖原合成酶激酶3β(GSK3β)参与突触抑制，因此我们推测，海马区突触内TRPM2通道的长时间激活激活了GSK3β，从而抑制了LTP的诱导，从而抑制了新的记忆。我们新的初步数据表明，抑制TRPM2有可能减少认知障碍，并有可能提供一种新的恢复性治疗。目前的建议旨在确定TRPM2通道在缺血后的亚急性和慢性期的调节机制，以及最重要的是TRPM2介导的突触可塑性抑制的机制。我们假设1)缺血导致TRPM2通道的持续激活，2)抑制突触的可塑性，3)延迟给予TRPM2抑制剂将逆转 心脏骤停后突触的可塑性和记忆功能的恢复。