讲座题目：Involvement of NR2B-containing NMDA receptors in HIV-1-assciated neurotoxicity and cognitive impairment.

主讲人：Huangui Xiong,MD, PhD, Professor （Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA）

讲座时间： 2013-10-17周四 上午10:00

地  点：医学部护理楼多功能厅

讲座领域：Pharmacology；Neuroscience

内容简介：  In the highly active anti-retroviral therapy (HAART) era, chronic low level persistent viral infection of mononuclear phagocytes (MP; blood-borne tissue and perivascular macrophages and microglia) has supplanted high level productive HIV-1 replication as the pivotal mechanism for the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Thus, studies on the changing mechanisms for MP-induced neuronal damage are needed. This is imperative for the development of effective therapeutics.  We posit that neuronal damage caused by chronic viral infection of MP can be ameliorated by NMDA receptor antagonists that work through extra-synaptic NR2B-containing NMDARs (NR2BRs). A scheme was developed for this neuroprotective mechanism in the face of prior failures. Indeed, functional NMDARs are multimers composed of at least one obligatory NR1 subunit and one or more NR2 or NR3 subunits.  Each of the NR2 subunits (A, B, C and D) confers distinct electrophysiological and pharmacological properties on the NMDARs. Which subtype(s) of NMDAR is(are) activated by infected cells, whether this activation state changes as a result of restricted infection, and whether HIV-1 infected MP directly activates synaptic or extrasynaptic NMDARs (or both) will be discerned through these works. This is especially noteworthy with respect to the final pathways of neuronal demise. Perhaps most importantly, such pathways may underlie the pathogenesis of a broad range of neurodegenerative disorders. We hypothesize that infection of MP elicits activation of extrasynaptic NR2BRs and their signal transduction pathways affecting neuronal and cognitive function. This idea is based on recent observations that the location of NMDARs makes the key difference,  survival promoting signals derive from synaptic NMDARs, which consist of predominant NR2A-containing NMDARs (NR2ARs), whereas a cell-death signal comes from extrasynaptic NMDARs, which contain mostly NR2BRs. Indeed, it has been shown that activation of NR2BRs results in excitotoxicity and neuronal degeneration. The NR2BR has been implicated in several types of synaptic signaling, modulation of learning and memory processing, and in a number of neurodegenerative disorders in humans. To uncover the mechanisms for HAND pathogenesis (and perhaps other neurodegenerative disorders) and to identify potential therapeutic targets for HAND, we examined the involvement of NR2BRs in HIV/MP-associated neuropathology and its link to neuronal injury and cognitive decline. The aim of this seminar is to report the results obtained in recent years.

 

                                医学部

                              2013年10月14日