Nicolas G. Bazan Lab

Neuroprotection and neural plasticity: unraveling cell signaling in injury and neurodegeneration

During development and throughout life, the nervous system, including the retina, continually modifies itself. These modifications reflect plasticity in terms of synaptic reorganization and other cellular events. Plasticity may also result from insult to the brain: stroke leads to reorganization of synaptic circuitry and epilepsy may lead to the establishment of aberrant circuits.

Bazan Lab MembersA major goal of the N. Bazan laboratory is to understand the endogenous responses of the retina and brain to injury and neurodegeneration. A convergence of approaches, including cell, neurochemical and molecular tools are used. These are complemented primary cell cultures (e.g. hippocampal neurons) and animal models of neurological (epilepsy, stroke, head injury, Alzheimer’s disease) and retinal diseases (age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy). The central hypothesis being explored is that lipid messengers modulate both synaptic receptors, as well as downstream signaling. In addition there is strong emphisis on unraveling endogenous lipid neuroprotective signaling (e.g. docosanoids). Sites of pharmacological action, as well as novel drugs, acting on these informational pathways are being identified.

We are exploring a gene, the inducible prostaglandin synthase, the product of which accumulates in hippocampus in models of epilepsy, as well as in retina in light-induced photoreceptor degeneration. The lab is also studying membrane biogenesis, in terms of the supply and trafficking of docosahexaenoic acid, a key building block, in synapses and photoreceptors. In our studies of excitable membrane biogenesis, we have discovered that the essential fatty acid, docosahexaenoic acid, which is a major component of photoreceptors, is conserved by means of metabolic loops involving the liver and the interstitial space surrounding photoreceptors. These loops are altered in certain retinal degenerations, and, possibly, also in some neurological diseases. This essential fatty acid in addition is the precursor of docosanoids that were identified in the retina in this laboratory in 1984 as a product of lipoxygenation of docosanoidic acid. Very recently the sterospecific neuroprotectin D1 was discovered as a docosanoid mediator. This new messegner is anti-inflammatory, a potent upregulator of Bcl-2 anti-apoptotic and a downregulator of Bcl-2 pro-apoptotic proteins. Our goal is to determine the crosstalk between synapses and genes, and between neurons and astrocytes, that modulate long-term responses, which could perhaps be pharmacologically manipulated to prevent or repair synaptic plasticity deficits occurring in disease.

Bazan Lab Discoveries

Eric J. Knott, William C. Gordon, Bokkyoo Jun, Khanh Do, Nicolas G. Bazan. Retinal Pigment Epithelium and Photoreceptor Preconditioning Protection Requires Docosanoid Signaling. Cell Mol Neurobiol (2017), 1-17, https://doi.org/10.1007/s10571-017-0565-2,
Link for press page for this article

A novel key molecular mechanism leading to visual degeneration and blindness.
This research reveals events that may be harnessed for prevention, as well as to slow down progression, of retinal degenerative diseases. The paper is published in Nature Communication (Rice et al., Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival.Nat Commun. 2015 Mar 4;6:6228. See link for more.

Novel gene-regulated neuroprotection disease-modifying mechanism for vision and stroke
Research led by Nicolas Bazan, MD, PhD, has discovered gene interactions that determine whether cells live or die in the retina and brain. They have uncovered a stereospecific mediator that targets gene interactions leading to cell survival relevant to retinal degenerative diseases, including age-related macular degeneration. Moreover, they also found that this key event halts progression of experimental ischemic stroke damage by activating a neuronal selective event.  The molecular mechanisms identified seem to be critical for vision (RPE-photoreceptor cell) and brain integrity (selectively neuronal). The paper is published online in Cell Death & Differentiation, a Nature journal athttp://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd2014233a.html. See link for more.

Discovery of neuronal architecture protection by neuroprotection D1 in a novel Parkinson’s disease dish model
In a recent report published by our lab, we developed a model of Parkinson’s disease in a dish using the primary mesencephalic neurons in culture from mouse. This model has the advantage of focusing on neurons affected by the disease and to be able to chemically damage the neuronal architecture, recapitulating aspects of the disease process. In addition, the model can be used to identify novel disease-modifying molecular mechanisms and to screen potentially useful therapeutic agents. In fact, using this model, we discovered that the lipid mediator neuroprotectin D1 (D1) remarkably protects the neuronal architecture. See link  for more.

Protection of hippocampal dendritic spines and synaptic plasticity in experimental epilepsy by a docosanoid

In a recent publication, the N. Bazan lab reported the uncovering of naturally-occurring molecules hippocampal neuronal networks in the pilocarpine post-status epilepticus model of limbic epileptogenesis. The data demonstrate that the docosahexaenoic acid (DHA)-derived docosanoid mediator, neuroprotectin D1 (NPD1), prevents experimental epileptogenesis. The paper reports that the structure and function of hippocampal neuronal networks are restored by measuring brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis, and we found that systemically-injected NPD1 led to a reduction in spontaneous recurrent seizures. The results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis, which may contribute to the development of anti-epileptogenic therapeutic strategies. See link for more.

Targeting Neuroprotection in Epilepsy by a Docosanoid

In an editorial update, the Nicolas Bazan lab just published in the journal Future Neurology highlights regarding the therapeutic potential of neuroprotectin D1 (NPD1) for epilepsy. NPD1 is a docosanoid mediator because it is derived from docosahexaenoic acid (DHA) and displays neuroprotective and pro-homeostatic bioactivity. Emphasis is placed on depicting this docosanoid as a major cell survival mediator made “on demand.” This article also discusses ways to effectively deliver NPD1 to the brain, or to enhance its bioavailability, which could contribute to a therapeutic paradigm shift by enhancing the intrinsic potential of brain cells to protect and repair themselves in epilepsy. See link  for more.