The onset of brain injury and neurodegeneration triggers the synthesis of docosanoid neuroprotective signaling

Abstract

Bioactive lipid messengers are formed through phospholipase-mediated cleavage of specific phospholipids from membrane reservoirs. Effectors that activate the synthesis of lipid messengers, include ion channels, neurotransmitters, membrane depolarization, cytokines, and neurotrophic factors. In turn, lipid messengers regulate and interact with multiple pathways, participating in the development, differentiation, function (e.g., long-term potentiation and memory), protection, and repair of cells of the nervous system. Overall, bioactive lipids participate in the regulation of synaptic function and dysfunction. Platelet-activating factor (PAF) and COX-2-synthesized PGE(2) modulate synaptic plasticity and memory. Oxidative stress disrupts lipid signaling, fosters lipid peroxidation, and initiates and propagates neurodegeneration. Lipid messengers participate in the interactions among neurons, astrocytes, oligodendrocytes, microglia, cells of the microvasculature, and other cells. A conglomerate of interrelated cells comprises the neurovascular unit. Signaling at the neurovascular unit is clearly altered in the early stages of cerebrovascular disease as well as in neurodegenerations. Here we will provide examples of how signaling by lipids regulates critical events essential for neuronal survival. We will highlight a newly identified, DHA-derived messenger, neuroprotectin D1, which attenuates oxidative stress-induced apoptosis. The specificity and potency of this novel docosanoid (neuroprotectin D1) indicate a potentially important target for therapeutic intervention.

Fig. 1.

Members of the initial LSU Neuroscience Center of Excellence External Advisory Committee (1988). Pictured (l-r): Robert Collins (UCLA), John Dowling (Harvard), Julius Axelrod (NIH), Nicolas Bazan (LSU Neuroscience Center), Fred Plum (Cornell), Michael Stryker (UCSF), Mortimer Miskin (NIH).

Fig. 2.

Neuroprotectin D1 Synthesis and Bioactivity. PLA₂ releases DHA membrane phoshopolipids. Then, a lipooxygenase catalyzes the synthesis of 17S-H(p)DHA, which, in turn, is converted to a 16(17)-epoxide that is enzymatically converted to NPD1. Some of the agonists for NPD1 synthesis are indicated. NPD1 decreases PMN infiltration; Bax, Bad, Bid and Bik induction; Bcl-2, Bcl-xl and Bfl-1/A1 abundance: decreases caspase 3 activation; and, inhibits proinflamatory gene expression. The outcome of NPD1 action is cytoprotection and overall enhancement of cell survival. The presence and bioactivity of NPD1 was found in retinal pigment epithelial cells (Mukherjee et al 2004), rat (Belayev et al., 2005) and mouse (Marcheselli et al., 2003) brain undergoing ischemia-reperfusion, human brain (Lukiw et al., 2005), and human neural progenitor cells (Lukiw et al., 2005).