Bioactive Lipids in Cancer, Inflammation and Related Diseases
New Orleans, Louisiana
Oct. 30-Nov. 02, 2022
Nicolas G. Bazan, M.D., Ph.D., is the founding Director of the Neuroscience Center of Excellence at the School of Medicine, Louisiana State University Health New Orleans and the inaugural founder of The Ernest C. and Yvette C. Villere Chair for Research in Retinal Degeneration. Dr. Bazan has been appointed to the highest academic rank in the LSU System, a Boyd Professor. He is also a Foreign Adjunct Professor of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Dr. Bazan received his medical degree from the University of Tucuman in Argentina. Afterward, he trained at Columbia University College of Physicians and Surgeons, Department of Physical Medicine and Rehabilitation in New York and at the Massachusetts Mental Health Center/ Department of Biological Chemistry, at the Harvard Medical School. At the age of 26 he was appointed Assistant Professor of Biochemistry University of Toronto and Assistant Director of the Department of Neurochemistry at the Clarke Institute of Psychiatry. He then founded a research institute, a new Biology academic unit, and doctorate and Master of Science graduate programs in Biochemistry in Argentina. In 1981, Dr. Bazan move to New Orleans.
Dr.Bazan was the founding Editor-in-Chief for Springer Nature’s Molecular Neurobiology journal. He was also the founding Senate Member of the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) in der Helmholtz-Gemeinschaft for the neurodegenerative diseases research program (2009-16) in Germany. He served as the Elected Chairman, Board of Governors, ARVO Foundation (2011-14) and the elected President of the American Society for Neurochemistry (1991-2001).
Dr. Bazan’s recognition and awards includes the Javits Neuroscience Investigator Award NINDS, NIH, 1989
He devoted his life to studying fundamental signaling mechanisms in early stages of brain and retinal dysfunctions. He has discovered cellular and molecular principles that reveal novel pro-homeostatic lipid mediators as well as their relevance and implications in early stages of Alzheimer’s disease, in experimental stroke, experimental epilepsy, Parkinson’s disease, ALS, MS, traumatic brain injury, retinitis pigmentosa and age-related macular degeneration.
In his first laboratory at the Clarke Institute of Psychiatry in Toronto, Canada, Dr. Bazan discovered that brain ischemia (like in stroke), seizures (like in epilepsy) or electroconvulsive shock (a therapy for depression) trigger the rapid release of unesterified essential fatty acids (docosahexaenoic and arachidonic acids) from membranes through phospholipase A2. These findings became a citation classic (“Neural Stimulation or Onset of Cerebral Ischemia Activates Phospholipase A2”, Bazan NG, Current Contents/Life Sciences, 30:10, 1991).
Dr. Bazan’s research has opened conceptual in-roads in biology, neuroscience, and medicine by the uncovering signaling mechanisms and novel molecular principles of cell survival and neuroprotection. His contributions are unique and pioneering. From the beginning of his scientific career, he has contributed innovative concepts and has discovered molecular principles that sustain neural cell integrity. He was the first to uncover arachidonic acid (AA) and docosahexaenoic acid (DHA) brain release upon stimulation by ischemia and/or seizures at rates comparable to those of maximal hormonal lipolytic activation in other tissues. At the time, medical sciences were captivated by the discovery of prostaglandins and other eicosanoids from AA (omega-6 essential fatty acid family member) and the elucidation of their functions by B. Samuelsson, S. Bergstrom, and J. Vane. Dr. Bazan took a different focus and approach and began aiming in the late 60’s to understand the significance and consequences of brain release of DHA, a member of the omega-3 essential fatty acid family. During this time, he became aware of studies that observed the beneficial health effects of diets rich in omega-3 fatty acids. Thus, he began conceptualizing and pondering on the biology of DHA, which is prominently concentrated in the central nervous system (CNS), and he formulated hypotheses and tested them under various conditions, as described below. He found that the brain of newborns and of poikilothermic animals (toads) release DHA at much lower rates than that of adults or normothermic animals and suggested that this was a connection to brain vulnerability to ischemia. Based on these observations, unexpected outcomes have since evolved, including his findings on the significance of the phospholipid-mediator, platelet-activating factor (PAF) in the nervous system. Dr. Bazan approached this issue from a different angle because PAF metabolism involves DHA and AA release. Therefore, he and his collegues were the first to find that PAF modulates hippocampal excitatory synaptic transmission and presynaptic glutamate release and that it is a retrograde messenger of long-term potentiation enhancing in turn memory formation. He then began connecting these initial findings with synaptic signaling and brain function, and in the early 1980s, Dr. Bazan developed the concept and initial exploration of bioactive DHA derivatives that he suggested calling docosanoids (22C, in contrast to the 20C eicosanoids from AA). In fact, he showed that the retina generated enzyme-derived DHA products. In groundbreaking fashion, Dr. Bazan discovered the source and mechanisms of retention of retinal DHA. He identified the link between DHA deficiency and inherited retinal dystrophies. This laid the foundation for therapeutic strategies designed to bolster endogenous levels of retinal DHA. Bazan expanded his work to examine mechanisms of release of free DHA by brain and retina and was the first to associate phospholipase-mediated DHA release with disorders of the brain and retina, a phenomenon known as the “Bazan effect.” This has led to a number of discoveries that have impacted our understanding and potential therapies of several forms of dementia and CNS neurodegeneration.
While studying DHA brain release due to stimulation early on, Dr. Bazan began using the retina as a natural-made brain slice since the differentiated neuron, photoreceptor cell, is enriched in DHA, and its neuronal circuitry makes it an integral part of the central nervous system (CNS). Then he uncovered new mechanisms regarding how DHA is acquired to reach such a unique endowment in the retina and brain. Based on these discoveries, Bazan identified the liver-to-retina (and brain) “long loop” for DHA supply and a retinal pigment epithelium/photoreceptor intercellular “short loop” for DHA retention in photoreceptors. This recycling is similar to that seen in retinoids, and he postulated it to be critical for photoreceptor survival; hence, its breakage leads to retinal degeneration. Bazan also found that Acadian Louisiana Usher’s Syndrome patients (born deaf, then blind due to retinitis pigmentosa) have DHA shortage in the blood, implicating the long loop in retinal degeneration. This observation, among others from his lab, led him to further explore the role of DHA in photoreceptor degeneration and to extrapolate it to Alzheimer’s disease. His quest focused on the specific molecular mechanisms engaged and led Bazan and collaborators to the discovery of a specific transmembrane protein (adiponectin receptor 1; AdipoR1) for DHA uptake/retention in retinal pigment epithelial (RPE) cells and photoreceptors necessary for cell functional integrity. This AdipoR1-protein, although it has seven transmembrane domains, is not a G-protein, and thus he demonstrated that its cognate ligand, adiponectin, is not involved. Therefore, the new function is that AdipoR1 represents a key molecular switch for DHA uptake, retention, and conversion into a photoreceptor-specific molecular species of phosphatidylcholine that are decreased in age-related macular degeneration. In fact, when Bazan and his colleagues genetically ablated the protein, retinal degeneration ensued. Bazan’s thinking and work have influenced others. As an example of an additional impact of these discoveries, it was reported that a single amino acid mutation in AdipoR1 causes non-syndromic autosomal dominant retinitis pigmentosa, a finding that was based on Dr. Bazan’s work on AdipoR1
Bazan and collaborators demonstrated in 1984 that DHA is the precursor of docosanoids and predicted that they are endowed with pro-homeostatic cell survival properties. Dr. Bazan contributed to the discovery of the synthesis and bioactivity of neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) in 2003-2004. His work uncovered that NPD1 arrests apoptosis in RPE cells at the pre-mitochondrial level and is neuroprotective in brain ischemia-reperfusion and in cellular models of Alzheimer’s disease. Thus, Bazan and colleagues coined the name “neuroprotectin D1” for this first-identified docosanoid and showed that NPD1 is an oxidative stress/injury response mediator that counteracts disruptions of cellular homeostasis, and it is an active participant in a well-concerted process that effectively modulates neuroinflammation. Esterified DHA from phospholipids is cleaved by phospholipase A2 (PLA2), releasing DHA followed by NPD1 synthesis. Bazan also showed that 15-lipoxygenase-1 (15-LOX-1) catalyzes DHA enzymatic lipoxygenation and conversion into NPD1 and that neurotrophins stimulate this process (e.g., BDNF, NGF, PEDF). They found enhanced cytosolic PLA2 expression and decreased free-DHA in short post-mortem sampled CA1 hippocampal region of early stages of Alzheimer’s disease with a concomitant 25-fold decrease in NPD1. In human neuronal cells in culture, he also showed that NPD1 promotes the downregulation of pro-inflammatory genes and pro-apoptotic Bcl-2 proteins and that it also enhances the abundance of anti-apoptotic proteins to counteract Aβ-mediated neurotoxicity. Among the molecular targets that he found for this bioactive lipid is the triggering of de-phosphorylation of Bcl-xL in a PP2A-dependent fashion during oxidative stress, which induces cell survival.
Bazan and his colleagues demonstrated also that DHA activates long-term restoration of synaptic circuits in models of epileptogenesis. Thus, DHA release has well-defined beneficial effects. He and his colleagues then found increased NPD1 synthesis, as a consequence of DHA administration, in a middle cerebral artery occlusion (MCAo) stroke model that, in turn, prompts selective neuronal cREL translocation followed by BIRC3 gene expression, resulting in remarkable neurological recovery. Thus, cREL was translocated into the nucleus to a greater extent in DHA-treated animals, suggesting that NPD1 produced by the conversion of systemically administered DHA acts through cREL-mediated BIRC3 transcriptional activation to exert its neuroprotective bioactivity. This series of studies also included the use of a cellular model, where Bazan found that when the cREL protein abundance increases, it leads to survival and a decrease in p65/RelA in response to NPD1. These findings helped further unravel the endogenous signaling that sustains cellular integrity, thus providing a new understanding of the mechanisms that could lead to precise therapeutic approaches for neuroprotection.
Bazan and his colleagues recently discovered a new family of lipid messengers, which they coined “elovanoids”. Elovanoids are set apart from all other lipid messengers. Known lipid mediators, such as prostaglandins, leukotrienes, lipoxins, resolvins, and docosanoids, are derived from 18 to 22 carbon-length fatty acid precursors. Elovanoids, on the other hand, have structures derived from 32- or 34-carbon precursors, with different physicochemical and biological properties. Bazan and colleagues reported the complete structures and stereochemistry of the novel elovanoids ELV-N32 (derived from 32:6,n-3) and ELV-N34 (derived from 34:6,n-3), the complete R/S configuration, and the Z/E geometry of the double bonds as generated in retinal cells and neurons. Dr. Bazan furthermore showed that ELVs are cell-specific mediators necessary for neuroprotective signaling for cell integrity.
In addition, Bazan designed and developed several molecules for clinical application (covered by patents assigned to LSU Health New Orleans), including non-narcotic, non-toxic analgesics for a variety of conditions: neuropathic pain; novel neuroprotective compounds, anti-inflammatories, compounds effective for slowing down invasiveness of glioblastoma multiforme; genetically-engineered transdifferentiated fibroblasts for neurons and genetically-engineered adipose tissue cells for neurodegenerative diseases. Currently, he is beginning to apply his discoveries by translating them by means of startup companies that he co- founded: NeuResto Therapeutics, LLC (discoveries for Alzheimer’s, Parkinson’s, retinal degenerations, stroke, ALS, MS, long-COVID-19 and other brain and retina diseases) and South Rampart Pharma, LLC (novel non-addictive painkiller).
Dr. Bazan’s ongoing quest in the fields of biology and medicine is, in a way, reflected as a response to one major challenge to civilization: the growing incidence of the loss of sight and cognition due to increased life expectancy and other factors. His ideas are synergized with a rise in the occurrence of photoreceptor- and neuronal-survival failure, as reflected mainly by age-related macular degeneration (AMD) and Alzheimer’s disease (AD). The development of the nervous system is driven by neuronal apoptotic cell death and, thereafter, for the lifespan, neurons are post-mitotic. In neurodegenerative diseases, apoptosis and other forms of cell death lead to selective neuronal loss. Although age is the main risk factor, not everyone develops these diseases during aging. Thus, Bazan posed the following questions: 1) why can the latency period last for decades without disease manifestation, for example, in inherited familial forms of AD and in retinal degenerations including AMD, and 2) does a cell-specific initial response/s counteract the consequences of mutation/polymorphism expression. There are many factors involved, including developmentally expressed genes, since most inherited neurodegenerative diseases remain asymptomatic during the development and maturation of the nervous system. Bazan clearly began deciphering the molecular logic that sustains neuronal survival by uncovering molecular principles (transcriptional signatures) governed by the docosanoid NPD1 and likely by other key mediators, such as the newly discovered elovanoids. Bazan is untangling issues to be explored, including the decision-making process involved in the storage specificity/retrieval of lipid mediators and the molecular sensors in the early stages of neurodegenerations.
His laboratory has led to the uncovering of new gene regulation and necessary proteins for cell survival in RPE cells, and these molecular events provide unified responses amenable to be harnessed to slow down the onset and early progression of neurodegeneration. Thus, Dr. Bazan uncovered a different signal bifurcation mechanism that aims to sustain cell integrity. Overall, Dr. Bazan is a pioneer in the remarkable current realization of the significance of DHA and related mediators for central nervous system organization, functions, and pathologies. He contributed to revealing molecular principles that include novel pro-homeostatic and neuroprotective lipid-signaling that sustain brain and retina cell integrity and function.