Cholinergic Modulation of Inflammatory CNS Cytokines

描述（由申请人提供）：我们正在研究在促炎细胞因子和烟碱能神经递质系统如何相互作用的背景下神经元-胶质相互作用的机制，以确定神经炎症环境中神经元对兴奋毒素的易感性，这通常存在于神经疾病中。总体假设是：在神经炎症过程中，中枢神经系统细胞预先暴露于胆碱能激动剂尼古丁，改变TNF α启动的信号传导，改变神经元对兴奋毒素的易感性和中枢神经系统反应。这一假设源于几个关键的结果，包括：1。培养的皮质神经元可以免受TNF α或尼古丁的nmda毒性攻击，然而，TNF α和尼古丁诱导的神经保护作用在混合神经元和胶质细胞的培养中被消除。这些药物在富集的神经元培养物中不具有拮抗作用，这表明需要其他非神经元细胞类型。将单核吞噬细胞/小胶质细胞（MP/MG）添加到富集的神经元培养物中可以恢复尼古丁和TNFalpha之间的拮抗作用。4. 培养的MP/MG表达nachr，它们对尼古丁的存在有功能反应；尼古丁给药改变了tnfalpha启动的caspase 8激活动力学，caspase 8是tnfalpha信号传导的重要细胞内介质。我们将在Specific Aim 1中确定尼古丁/TNFalpha对NMDA的神经保护拮抗是否需要中枢神经系统细胞（包括神经元和MP/MG）之间的特定细胞-细胞相互作用，在Specific Aim 2中确定除了nAChRalpha7外，神经元尼古丁受体是否由神经元以外的细胞类型表达。如果尼古丁预处理CNS细胞通过改变caspase/蛋白酶激活和/或功能改变其对TNFalpha的反应，则参与尼古丁/TNFalpha神经保护拮抗的相关机制。这些研究对于理解尼古丁持续存在对中枢神经系统正常神经炎症调节的影响具有直接和新颖的意义，这可能决定了对许多毒素的易感性，并影响正常和病理反应。

DESCRIPTION (provided by applicant): We are examining mechanisms of neuronal-glial interactions within the context of how a proinflammatory cytokines and the nicotinic cholinergic neurotransmitter systems interact to determine neuronal susceptibility to excitotoxins in a neuroinflammatory environment, as is often present in neurological disease. The Overall Hypothesis is: Pre-exposure of CNS cells to the cholinergic agonist, nicotine, modifies signaling initiated by TNF alpha and alters neuronal vulnerability to excitotoxins and the CNS response during neuro-inflammatory processes. This hypothesis stems from several key results that include: 1. Cultured cortical neurons are protected against an NMDA-toxic challenge by TNFalpha or nicotine, however, TNF alpha and nicotine induced neuroprotection is abolished when the agents are present together cultures of mixed neurons and glia, 2. These agents are not antagonistic in enriched neuronal cultures suggesting that other non-neuronal cell types are required, 3. The addition of mononuclear phagocytes/microglial cells (MP/MG) to enriched neuronal cultures restores antagonism between nicotine and TNFalpha. 4. MP/MG in culture express nAChRs, and they respond functionally to the presence of nicotine, and 5. Nicotine administration alters the kinetics of TNFalpha-initiated caspase 8 activation, an important intracellular mediator of TNFalpha-signaling. We will determine in Specific Aim 1 if nicotine/TNFalpha antagonism of neuroprotection to NMDA requires specific cell-cell interactions between cells of the CNS including neurons and MP/MG, In Specific Aim 2 if neuronal nicotinic receptors, in addition to nAChRalpha7, and expressed by cell types other than neurons, participate in mechanism(s) related to nicotine/TNFalpha antagonism of neuroprotection and in Specific Aim 3 if nicotine preconditioning of CNS cells alters their response to TNFalpha through modifying caspase/protease activation and/or function. These studies have direct and novel implications toward understanding the consequences of sustained nicotine presence on the normal regulation of neuro-inflammation in the CNS, which may determine susceptibility to many toxins and influence normal and pathological responses.