Bioactive derivative of docosahexaenoic acid is a homeostatic cell survival sentinel in the nervous system.
The brainy lipid from fish
It’s not unusual to find health-food advocates singing the praises of omega-3 fatty acids that are present predominately in cold-water fish. One of these fatty acids, called DHA, has received a great deal of attention for its reported roles in neuronal physiology, pathophysiology, and repair. In this article, Nicholas Bazan highlights some of the reasons for the excitement generated by the discovery of a particular DHA derivative called neuroprotectin D1.
The complexities of cell function in the central nervous system are sustained by intra- and intercellular signaling networks driven by synaptic activity, neurotrophins, gene programs and other factors. The molecular organization and functional contribution of cellular membranes are pivotal in the myriad of molecular circuitries of the CNS. Docosahexaenoic acid, an omega-3 fatty acid, is concentrated and avidly retained in membrane phospholipids of the nervous system, notably in photoreceptors and synapses. DHA is implicated in brain and retina function, aging, and neurological and psychiatric/behavioral illnesses. The discovery of neuroprotectin D1, the first docosanoid (a bioactive derivative of DHA), is allowing scientists to address fundamental questions concerning the biology of omega-3 fatty acids and their significance to brain function and the mechanisms of action in disease models such as stroke, epilepsy and neurodegeneration. The name “neuroprotectin D1” was suggested based on the molecule’s neuroprotective bioactivity in oxidatively stressed retinal pigment epithelial cells and its potent ability to inactivate pro-apoptotic and pro-inflammatory signaling (1). ‘D1’ refers to its being the first identified mediator derived from DHA (1).
The following are disease models and experimental conditions where the protective bioactivity of NPD1 has been found. In all of these instances, NPD1 is made on demand soon after signals are needed to sustain homeostasis. Brain ischemia reperfusion leads to the transient synthesis of NPD1. Since brain damage is proportional to the magnitude of the ischemic insult, we administered NPD1 after experimental stroke with the idea that the amount produced endogenously might be insufficient to exert protection. Thus, we found that infused NPD1 counteracts polymorphonuclear neutrophil infiltration, nuclear factor κB (NF-κB) induction, up-regulation of cyclooxygenase-2 (COX-2) expression, decreased infarct size and neurobehavioral recovery (2).
In retinal pigment epithelial(RPE) cells, the most active phagocytes of the body, NPD1 potently elicits protection against oxidative stress. RPE cells support photoreceptors through the daily shedding, internalization and phagocytosis of photoreceptor outer segment (membrane disc) tips. Notably among neurotrophins, pigment epithelium derived factor, a member of the serine protease inhibitor (serpin) family, is the most potent stimulator of synthesis and selective apical release of NPD1.
DHA deficiency is associated with cognitive decline and possibly Alzheimer’s disease. NPD1 abundance was found to be decreased in Alzheimer’s disease brains as well as cytosolic phospholipase A2 and 15-lipoxygenase-1 (3). NPD1 bioactivity promotes brain cell survival via the induction of neuroinflammatory downregulation and anti-apoptotic and neuroprotective gene-expression programs that suppress Aβ42 production and its neurotoxicity. Moreover, DHA and NPD1 modulate expression of Bcl-xl (4), Bcl-2 and Bfl-1(A1), anti-apoptotic members of the Bcl-2 gene family, and pro-apoptotic Bcl-2 proteins (3).
Excessive oxidative stress turns on multiple signaling pathways that participate in the pathophysiology of neurodegenerative diseases that lead to cell death. Lipidomic-based analysis has allowed researchers to begin decoding CNS omega-3 fatty acid-derived signals (highlighted by the discovery of NPD1 (2)), defining their bioactivity (Fig. 1) and furthering our understanding of their significance for neuroinflammation resolution, sustenance of synaptic circuitry integrity and cell survival. The experimental manipulation of NPD1-mediated signaling to slow or halt the initiation and progression of neurodegenerative diseases represents an emerging target for pharmaceutical intervention and clinical translation.
Biosynthesis and bioactivity of neuroprotectin D1. A membrane phospholipid containing a docosahexaenoyl chain at sn-2 is hydrolyzed by phospholipase A2, generating free (unesterified) DHA (22:6). Lipoxygenation (5) is then followed by epoxidation and hydrolysis to generate NPD1 (10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid). Thus far, a binding site for NPD1 has been identified in retinal pigment epithelial cells and polymorphonuclear cells.
1. Bazan, N.G. (2007) Homeostatic regulation of photoreceptor cell integrity: significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: the Proctor Lecture. Invest. Ophthalmol. Vis. Sci. 48, 4866 – 4881.
2. Belayev, L., Khoutorova, L., Atkins, K.D., Eady, T.N., Hong, S., Lu, Y., Obenaus, A., and Bazan, N.G. (2011) Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke. Transl. Stroke Res. 2, 33 – 41.
3. Lukiw, W.J., Cui, J.G., Marcheselli, V.L., Bodker, M., Botkjaer, A., Gotlinger, K., Serhan, C.N. and Bazan, N.G. (2005) A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774 – 2783.
4. Antony, R., Lukiw, W.J., and Bazan, N.G. (2010) Neuroprotectin D1 induces dephosphorylation of Bcl-xL in a PP2A-dependent manner during oxidative stress and promotes retinal pigment epithelial cell survival. J. Biol. Chem. 285, 18301 – 18308.
5. Calandria, J.M., Marcheselli, V.L., Mukherjee, P.K., Uddin, J., Winkler, J.W., Petasis, N.A., and Bazan, N.G. (2009) Selective survival rescue in 15-lipoxygenase-1-deficient retinal pigment epithelial cells by the novel docosahexaenoic acid-derived mediator, neuroprotectin D1. J. Biol. Chem. 284, 17877 – 17882.