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.
Miguel F. Molina (firstname.lastname@example.org) is a graduate student at the Louisiana State University Health Sciences Center.
Nicolas G. Bazan (email@example.com) holds the Ernest C. and Yvette C. Villere endowed chair for the study of retinal degenerations at the Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center.