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

 描述（由申请人提供）：仅在美国，每年约有60万人发生心脏骤停（CA），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，并且随后的神经元损伤导致长期的认知障碍。CA后通常观察到的记忆障碍很容易解释为海马CA 1区锥体细胞的选择性脆弱性。然而，最近对人类的成像研究表明，海马损伤本身可能与记忆功能障碍无关9，这涉及缺血后生理学的改变。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10。这是重要的，因为一些旨在减少神经元损伤的干预性临床试验未能改善缺血性损伤后的结果，这表明需要替代方法来改善功能恢复。如果在亚急性至慢性晚期给药，最佳治疗干预将具有减少神经元损伤、维持功能性神经元网络、甚至恢复功能的能力。我们的初步数据表明，抑制离子通道TRPM 2符合这些标准。我们表明，在心脏骤停后的急性期（30分钟）抑制TRPM 2可提供神经保护作用，而延迟抑制（6-7天）可逆转CA诱导的神经元功能和可塑性损伤。 记忆缺陷和海马功能障碍是公认的全脑缺血后遗症。缺血后海马功能障碍的证据是使用剩余的突触网络的电生理记录。突触可塑性，在生理刺激后的强化形式（长时程增强; LTP）是一个完善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LTP 10的长期损害（至少30天），这是通过在CA/CPR后的急性期（30分钟）抑制TRPM 2通道来防止的。最令人惊讶的是，在CA/CPR后一周抑制TRPM 2导致LTP缺陷的逆转并增强记忆功能。TRPM 2通道最近被观察到通过激活糖原合成酶激酶3β（GSK 3 β）来促进突触抑制;因此我们假设海马突触内TRPM 2通道的长期激活激活GSK 3 β，从而抑制LTP的诱导，从而抑制新记忆。我们新的初步数据表明，抑制TRPM 2有可能减少认知障碍，并可能提供一种新的恢复性治疗。目前的建议旨在确定在缺血后的亚急性和慢性阶段TRPM 2通道的调节机制，最重要的是TRPM 2介导的突触可塑性抑制的机制。我们假设1）缺血导致TRPM 2通道的持续激活，2）抑制突触可塑性，3）延迟给予TRPM 2抑制剂将逆转TRPM 2通道的缺陷。 突触可塑性和恢复心脏骤停后记忆功能。

 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.