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The onset of neurodegenerations and nervous system injury both trigger cell signaling perturbations that lead to damage of neuronal circuits and synapic connections, as well as protective signaling that aims to halt disease onset. Here we review recent findings that support the role of the docosanoid mediator neuroprotectin D1 (NPD1) as an early response or sentinel during the initial phase of nervous system damage. NPD1 is derived from docosahexaenoic acid that is selectively concentrated and retained in the nervous system. The protein misfolding triggers the biosynthesis of NPD1 which in turn downregulates pathways that lead to cell death and changes the outcome to cell survival. Proteotoxic stress as a result of protein misfolding is a widespread event in many neurodegenerative diseases. Therefore, mechanisms and mediators such as NPD1 that curtail consequences of these events are of interest as leads in the search for novel preventive and or therapeutic approaches., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The identification of neuroprotectin D1 (NPD1), a biosynthetic product of docosahexaenoic acid (DHA), in brain and retina as well as the characterization of its bioactivity, is generating a renewed interest in the functional role and pathophysiological significance of omega-3 fatty acids in the central nervous system. Neurotrophins, particularly pigment epithelium-derived factor (PEDF), induce NPD1 synthesis and its polarized apical secretion, implying paracrine and autocrine bioactivity of this lipid mediator. Also, DHA and PEDF synergistically activate NPD1 synthesis and antiapoptotic protein expression and decreased proapoptotic Bcl-2 protein expression and caspase 3 activation during oxidative stress. In experimental stroke, endogenous NPD1 synthesis was found to be upregulated, and the infusion of the lipid mediator into the brain under these conditions revealed neuroprotective bioactivity of NPD1. The hippocampal CA1 region from Alzheimer's disease (AD) patients (rapidly sampled) shows a major reduction in NPD1. The interplay of DHA-derived neuroprotective signaling aims to counteract proinflammatory, cell-damaging events triggered by multiple, converging cytokine and amyloid peptide factors, as in the case of AD. Generation of NPD1 from DHA thereby appears to redirect cellular fate toward successful preservation of retinal pigment epithelial (RPE)-photoreceptor cell integrity and brain cell aging. The Bcl-2 pro- and antiapoptotic proteins, neurotrophins, and NPD1, lie along a cell fate-regulatory pathway whose component members are highly interactive, and have potential to function cooperatively in cell survival. Agents that stimulate NPD1 biosynthesis, NPD1 analogs, or dietary regimens may be useful as new preventive/therapeutic strategies for neurodegenerative diseases.

Platelet-activating factor (PAF), a bioactive lipid (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) derived from phospholipase A(2) and other pathways, has been implicated in neural plasticity and memory formation. Long-term potentiation (LTP) can be induced by the application of PAF and blocked by a PAF receptor (PAF-R) inhibitor in the hippocampal CA1 and dentate gyrus. To further investigate the role of PAF in synaptic plasticity, we compared LTP in dentate granule cells from hippocampal slices of adult mice deficient in the PAF-R and their age-matched wild-type littermates. Whole cell patch-clamp recordings were made in the current-clamp mode. LTP in the perforant path was induced by a high-frequency stimulation (HFS) and defined as >20% increase above baseline of the amplitude of excitatory postsynaptic potentials (EPSPs) from 26 to 30 min after HFS. HFS-induced enhancement of the EPSP amplitude was attenuated in cells from the PAF-R-deficient mice (163 +/- 14%, mean +/- SE; n = 32) when compared with that in wild-type mice (219 +/- 17%, n = 32). The incidence of LTP induction was also lower in the cells from the deficient mice (72%, 23 of 32 cells) than in the wild-type mice (91%, 29 of 32 cells). Using paired-pulse facilitation as a synaptic pathway discrimination, it appeared that there were differences in LTP magnitudes in the lateral perforant path but not in the medial perforant path between the two groups. BN52021 (5 microM), a PAF synaptosomal receptor antagonist, reduced LTP in the lateral path in the wild-type mice. However, neither BN52021, nor BN50730 (5 microM), a microsomal PAF-R antagonist, reduced LTP in the lateral perforant path in the receptor-deficient mice. These data provide evidence that PAF-R-deficient mice are a useful model to study LTP in the dentate gyrus and support the notion that PAF actively participates in hippocampal synaptic plasticity.

Platelet-activating factor (PAF), one of the most potent bioactive lipids, has been implicated in modulating long-term potentiation (LTP) and neurotoxicity. In the CNS, glutamate and GABA are the major excitatory and inhibitory neurotransmitters, respectively. Previous work has focused on the effects of PAF on glutamatergic receptor responses. The purpose of the present study was to investigate the possible actions of PAF on ionotropic GABA receptor responses in primary cultured hippocampal neurons using the whole-cell and single channel patch clamp techniques. Extracellular application of PAF induced a reduction of the GABA gated Cl- current in a majority of cells (29 of 44 cells), while it caused an enhancement in 10 of 44 cells. A similar heterogeneous modulation of PAF on the GABA receptor activities was also observed in outside-out patch recordings. Moreover, the cell-attached single channel recordings showed that PAF decreased the GABA channel activity. Therefore, PAF may modulate synaptic activity by inhibiting GABA receptor channels. During seizures and neural injury, when enhanced synthesis of this lipid mediator takes place, the actions of PAF on inhibitory GABA receptors may contribute to synaptic dysfunction.

Interleukin-1 beta (IL-1beta) is an inflammatory cytokine whose expression is elevated in brain during seizures, ischemia, and injury. Expression of IL-1beta and its receptor can also be observed in normal brain. Platelet-activating factor (PAF) is also a dual mediator that promotes neuronal plasticity responses as well as inflammation. We have determined the role of PAF in the regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes by IL-1beta in rat primary hippocampal cultures. As assessed by reverse transcriptase/polymerase chain reaction (RT/PCR), recombinant mouse IL-1beta (1 nM) led to an induction of COX-2 mRNA which peaked at 2 hours, declined to baseline levels by 4 hours, began to rise again by 6 hours, and remained elevated at 24 hours post-treatment. iNOS mRNA was also induced, but unlike COX-2, its abundance peaked at 4 hours and decreased by 6 hours to a plateau lasting through 24 hours. Pretreatment with PAF antagonist BN50730 blocked induction of COX-2 mRNA by 2-hour IL-1beta treatment, and 2-hour treatment with the PAF analog mcPAF mimicked the effects of IL-1beta on COX-2 mRNA levels. Following injury, synaptic plasticity changes may be affected by IL-1beta-PAF-COX-2 neuronal signaling., (Copyright 1999 Wiley-Liss, Inc.)

The secretory phospholipases A2 (sPLA2) OS2 (10, 20 and 50 pmol) or OS1, (50 pmol) purified from taipan snake Oxyuranus scutellatus scutellatus venom, and the excitatory amino acid glutamate (Glu) (2.5 and 5.0 micromol) were injected into the right striatum of male Wistar rats. Injection of 10 and 20 pmol OS2 caused no neurological abnormalities or tissue damage. OS2 (50 pmol) caused apathy and circling towards the injection side. Histology revealed an infarct at the injection site. Injection of 50 pmol OS1 showed very little or no signs of neurotoxicity. Injection of 2.5 micromol Glu caused no tissue damage or neurological abnormality. After injection of 5.0 micromol Glu, the animals initially circled towards the side of injection, and gradually developed generalized clonic convulsions. These animals showed a well demarcated striatal infarct. When non-toxic concentrations of 20 pmol OS2 and 2.5 micromol Glu were co-injected, a synergistic neurotoxicity was observed. Extensive histological damage occurred in the entire right hemisphere, and in several rats comprising part of the contralateral hemisphere. These animals were apathetic in the immediate hours following injection, with circling towards the side of injection in the following days. Thus, OS2 greatly potentiates glutamate excitoxicity in vivo.

Pigment epithelial-derived factor (PEDF) has been shown to be a survival factor for cerebellar granule neurons. Here we investigated the ability of PEDF to enhance the survival of hippocampal neurons in culture, and to protect these neurons against acute glutamate toxicity. Hippocampal neurons prepared from 1- to 3-day postnatal rat brain were cultured for either 7 or 14 days in vitro (DIV). At 14 DIV, neurons were only slightly protected (13% +/- 4%) against 50 microM glutamate toxicity when treated with 1 microg/ml of PEDF for 3 successive days before glutamate exposure as measured by lactate dehydrogenase (LDH) release. In comparison, basic fibroblast growth factor (bFGF) at 10 ng/ml for the same treatment period protected 58% +/- 8% of the neurons against glutamate. Using quantitative image analysis of digitized micrographs, we found that the average size of neurons in young, developing hippocampal cultures (7 DIV), was greatly decreased by treatment with 50 microM glutamate. Treatment for up to 5 successive days with 1 microg/ml of PEDF before glutamate addition dramatically increased the average hippocampal neuron soma size, compared to cells treated with glutamate alone. Thus, PEDF may promote the growth of hippocampal neurons, and, if added to developing hippocampal neurons, can also protect these cells from subsequent injury, such as the excitotoxicity of glutamate.

The bioactive lipid platelet-activating factor (PAF) accumulates in brain during injury, seizures and ischemia and may, in addition, be significant in AIDS dementia and in other neurodegenerative diseases. We have used plasma-type recombinant PAF acetylhydrolase (rPAF-AH) to test the hypothesis that PAF accumulation is involved in early events leading to neuronal apoptosis during excitotoxic neuronal injury. Neuronal cultures were labeled with FITC-12-dUTP (TUNEL technique) and propidium iodide, digitized using fluorescence microscopy and a chilled 3CCD color camera, and analyzed with 2D graphics analysis software. N-methyl-D-aspartate (NMDA) (50 microM, 2 hr) induced a 2.5-fold increase in apoptosis of hippocampal neurons compared with controls when analyzed 24 hr after NMDA treatment. Hippocampal neurons receiving rPAF-AH (20 microg/ml) before, during, and after NMDA treatment demonstrated a concentration-dependent neuroprotective effect which resulted in 47% and 30% neuroprotection against 50 and 100 microM NMDA, respectively. The noncompetitive NMDA receptor antagonist MK-801(300 nM) completely inhibited apoptosis caused by NMDA. The neuroprotective effect of rPAF-AH against NMDA-induced apoptosis was confirmed using as additional criteria, histone release, electron microscopy, and DNA laddering. Neuroprotection elicited by rPAF-AH demonstrates that PAF is an injury mediator in NMDA-induced neuronal apoptosis and that the recombinant protein is potentially useful as a therapeutic approach.

Excitatory amino acids transduce physiological and pathological signals to neurons. Similarly, the neuroactive lipid platelet-activating factor (PAF) has been implicated in modulating long-term potentiation and neuronal survival. Excitatory amino acids and PAF have been shown to increase mitogen-activated protein (MAP) kinases in different cell types. Here, we have investigated the similarities and differences between PAF and kainate in activating MAP kinases in primary hippocampal neurons in vitro. Extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 kinases were activated by kainate or PAF in hippocampal neurons. This activation was blocked by the receptor antagonists CNQX and BN 50730 for kainate and PAF, respectively. The PAF receptor antagonist BN 50730 also blocked kainate activation. CNQX had no effect on PAF activation of the kinases, indicating that PAF is downstream of kainate activation. Coapplication of submaximal concentrations of PAF and kainate resulted in a less than additive activation, suggesting similar routes of activation by the two agonists. Both CNQX and BN 50730 blocked kainate-induced neurotoxicity. These results indicate that PAF and kainate activate similar kinase pathways. Therefore, PAF acts downstream of the kainate subtype of glutamate receptors, and when excessive receptor activation takes place, this bioactive lipid may contribute to neuronal cell death.

Secretory and cytosolic phospholipases A2 (sPLA2 and cPLA2) may contribute to the release of arachidonic acid and other bioactive lipids, which are modulators of synaptic function. In primary cortical neuron cultures, neurotoxic cell death and [3H]arachidonate metabolism was studied after adding glutamate and sPLA2 from bee venom. sPLA2, at concentrations eliciting low neurotoxicity (

The physical nature of neuronal cells, particularly in the functional and morphological segregation of synapse, soma, and dendrites, imparts special importance on the integrity of their cell membranes for the localization of function, generation of intrinsic second messengers, and plasticity required for adaptation and repair. The component phospholipids of neural membranes are important sources of bioactive mediators that participate in such diverse phenomena as memory formation and cellular damage following trauma. A common role for PAF in these processes is established through the suppressive effects of its antagonists. Furthermore, being both an extracellular and intracellular agonist of phospholipase activation, in addition to being a product of phospholipase activity, PAF assumes a centralized role in the cellular metabolism following neural stimulation. The linkage of PAF to neural immediate-early gene expression, both in vitro and in vivo, suggests that its effects are initiating to long-term formative and reparative processes. Such a common link between destructive and plastic responses provides an important view of cellular and tissue maintenance in the nervous system.

The author reflects on the role of the nucleolus in the neuroprotection response in neurodegeneration. The author states that nucleolus is the cellular center of ribosome biogenesis required for neuronal survival. He also mentions that the challenging role of the nucleolus in cellular homeostasis is its anticipation in sensing cellular stress signals and sending them to the stabilization system.

The article presents an abstract of the research "PAF Decreases Postsynaptic Ionotropic GABA Receptor Activity in Hippocampal Neurons," which will be presented at the American Society for Neurochemistry's 30th Annual Meeting to be held in New Orleans, Louisiana on March 14-17, 1999. Platelet activating factor has been implicated in modulating long-term potentiation and neurotoxicity and, therefore, may play an important role in epileptogenesis.

The article presents an abstract of the research "Modulation of Stress-Sensitive Map Kinases and Neuronal Cell Death by Glutamate Receptor Signaling Interplay," which will be presented at the American Society for Neurochemistry's 30th Annual Meeting to be held in New Orleans, Louisiana on March 14-17, 1999. It has been noted that overactivation of the glutamate ionotropic receptors leads to excitotoxic cell death while NMDA receptor antagonism provides neuroprotection.

The article presents an abstract of the research "Significance of Nitric Oxide Synthase and Platelet-Activating Factor in the Activation of Stress Sensitive Mitogen-Acivated Protein Kinases in Neurons in Culture," which will be presented at the American Society for Neurochemistry's 30th Annual Meeting to be held in New Orleans, Louisiana on March 14-17, 1999. The study was conducted by P.K. Mukherjee and colleagues.

The article presents an abstract of the article "Cytokine-Responsive NF-KB-Induced Kinase and Inhibitor of KB Kinase Activation by NMDA Through PAF in Primary Neuronal Culture," by A. Castellano, P.K. Mukherjee, W.J. Lukiw, M.A. DeCoster and N.G. Bazan. The abstract will be presented during the 30th Annual Meeting of the American Society for Neurochemistry to be held in New Orleans, Louisiana during March 14-17, 1999.