These findings reveal how receptor signaling takes place between receptors of synapses (gaps between neurons through which chemical or electrical signals pass permitting cells to "talk" to each other) and the mechanisms involved in initiating disease. The receptors, called NMDARs, are located both inside and outside of the synapses. Activation of the NMDRs inside (synaptic) allows the synapse to adjust response to signals and activation of the synaptic NMDRs is also required for survival of the cell. In contrast, activation of the receptors outside the synapse (extrasynaptic) leads to cell death.
The LSUHSC research team believed that activation of the extrasynaptic NMDRs promotes the pathological effects of cyclooxygenase 2 (COX-2), a protein known to contribute to inflammation associated with neurotoxicity. They found that activating the synaptic NMDRs greatly increased levels of COX-2, but not of the chemical (arachidonic acid) upon which COX-2 acts. Conversely, activating the extrasynaptic NMDRs increased the levels of arachidonic acid, but not COX-2. The researchers discovered, however, when synaptic and extrasynaptic NMDARs were sequentially activated, the levels of both COX-2 and arachidonic acid increased, as did neurotoxic inflammation.
"We have discovered a fascinating relationship regarding the "conversations" that occur between these two receptors in the brain," said Dr. Nicolas G. Bazan, Professor and Director, LSUHSC Neuroscience Center of Excellence.
"In this paper, we demonstrate how these signals affect cell functions and how they lead to diseases, including stroke, epilepsy and other neurodegenerative disorders. Targeting mechanisms that couple sequential synaptic then extrasynaptic NMDAR stimulations may lead to new anti-inflammatory/neuroprotective approaches."
The research was supported by grants from the National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, and the National Center for Complementary and Alternative Medicine.
"I have a very gifted and talented young MD/Ph.D student in my lab, David Stark, who has a National Institutes of Health award, performed exemplary experiments and co-authored the paper with me," said Dr. Bazan.
LSU Health Sciences Center New Orleans educates Louisiana's health care professionals. The state's academic health leader, LSUHSC consists of a School of Medicine, the state's only School of Dentistry, Louisiana's only public School of Public Health, the only School of Nursing within an academic health center in Louisiana, and Schools of Allied Health Professions, and Graduate Studies. LSUHSC faculty take care of patients in public and private hospitals and clinics throughout the region. In the vanguard of biosciences research in a number of areas in a worldwide arena, the LSUHSC research enterprise generates jobs and enormous economic impact. LSUHSC faculty have made lifesaving discoveries and continue to work to prevent, advance treatment, or cure disease. To learn more, visit http://www.lsuhsc.edu and http://www.twitter.com/LSUHSCHealth.
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