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Thematic Review |
Louisiana State University Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA
Published, JLR Papers in Press, September 16, 2003. DOI 10.1194/jlr.R300013-JLR200
1 To whom correspondence should be addressed. e-mail: nbazan{at}lsuhsc.edu
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ABSTRACT |
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Lipidomic neurobiology will advance our knowledge of the brain, spinal cord, retina, and peripheral nerve function and diseases that affect them, and new discoveries on networks of signaling in health and disease will likely lead to novel therapeutic interventions.
Supplementary key words diacylglycerols • docosahexaenoic acid • endocannabinoids • lipidomics • long-term potentiation • phospholipases A2 • photoreceptors • prostaglandins
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INTRODUCTION |
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To highlight the significance of PUFA and of a bioactive phospholipid, platelet-activating factor (PAF), we provide here examples of lipid signaling in synaptic plasticity and memory, as well as in pathologic conditions relevant to retinal degeneration, stroke, epilepsy, and Alzheimer's disease. This article describes certain aspects of a field that is rapidly growing and does not represent a complete account. Only some of the several contributions made to this theme are discussed: omission of papers was unavoidable due to the relative brevity of this article and the large scope of this field.
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CYCLOOXYGENASE-2-GENERATED PROSTAGLANDIN E2 MODULATES POSTSYNAPTIC MEMBRANE EXCITABILITY AND LONG-TERM SYNAPTIC PLASTICITY IN HIPPOCAMPAL NEURONS |
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Basal, "constitutive" COX-2 expression is regulated by synaptic activity and is up-regulated by high-frequency stimulation associated with long-term synaptic plasticity (3). Furthermore, COX-2 is enriched in dendritic spines in excitatory synapses (4). These findings implicate both constitutive and inducible COX-2 in synaptic plasticity.
More direct evidence on the significance of COX-2 in synaptic plasticity was obtained using COX-2 inhibitors and prostaglandins in hippocampal dentate granule neurons (5). These studies demonstrated that selective COX-2 inhibitors, but not COX-1 inhibitors, decrease induction of long-term potentiation (LTP) in hippocampal dentate granule neurons. Prostaglandin E2 (PGE2), but not PGD2 or PGF2
, reverses COX-2 inhibitor-induced suppression of LTP. This is in agreement with the observation that COX-2 preferentially channels the conversion of AA toward PGE2 and prostacyclin (6). PGE2 receptors are expressed in hippocampus, implying that the action of COX-2 inhibition on LTP induction in dentate neurons results from blocking the synthesis of PGE2. Therefore, it is very likely that PGE2 is the effector of COX-2-mediated activity-dependent synaptic plasticity (5).
The phospholipid messenger PAF has been proposed as a retrograde messenger of LTP (7) and a presynaptic site of action has been evidenced (see below). The action of PGE2 on synaptic modification, however, is not on presynaptic endings, but rather on postsynaptic sites. PGE2 regulates membrane excitability by modulating K+, hyperpolarization-activated current, and tetrodotoxin-resistant Na+-channel currents in sensory neurons (8–10). Moreover, spatiotemporal correlation of coincidence of postsynaptic firing and excitatory postsynaptic potentials are key in synaptic efficacy (11–14). In fact, decreasing postsynaptic neuron membrane excitability, which leads to a decrease in the number of postsynaptic action potentials during high-frequency stimulation of the presynaptic ending, decreases the probability of LTP induction. It was found that COX-2 inhibition attenuates postsynaptic membrane excitability. Thus, PGE2 derived from the tonic activity of constitutive COX-2 participates in neuronal membrane excitability. One other important factor in LTP is the active propagation of axonally generated action potentials back into the dendrites, where associated dendritic influx plays a significant role (13). Pharmacologic COX-2 blocking decreases back-propagating dendritic action potential-associated Ca2+ influx (5). Overall, constitutively inducible COX-2 regulates membrane excitability and activity-dependent LTP induction in hippocampus.
Depolarizing concentrations of K+ promote active release of AA in cortical neurons (15), retina (16), and synaptosomes (17). One interpretation of these results is that high K+ promotes a depolarization-dependent Ca2+ influx through voltage-gated Ca2+ channels. This in turn activates presynaptic glutamate release that modulates excitatory glutamate receptors (15). Thus Ca2+ influx through the N-methyl-D-aspartate (NMDA) receptor, and direct Ca2+ entrance through voltage-dependent calcium channels, activate phospholipase A2 (PLA2) to result in AA release via phospholipid hydrolysis. In addition, glutamate may activate metabotropic receptors that, through phospholipase C (PLC) activation, generate diacylglycerol.
Neuronal COX-2 expression is also up-regulated in experimental epileptogenesis, when aberrant synaptic plasticity is thought to be activated. The experimental kindling model resembles aspects of mesial temporal lobe epilepsy (18). Kindling epileptogenesis is triggered by repeated subconvulsive stimulation, which gradually results in intensified seizures. Both COX-2 and cPLA2 expression are activated, indicating that the free AA released is converted into prostaglandins during epileptogenesis (19). Nimesulide, a COX-2 blocker, decreases kindling epileptogenesis. The inability of nimesulide to completely inhibit kindling development suggests either a limited bioavailability of the drug to neuronal COX-2 to attain full blockade and/or a redundancy of the signaling involved. For example COX-1, which is not inhibited by nimesulide, may catalyze the synthesis of prostaglandins, minimizing the action of nimesulide. The exact mechanism by which COX-2 inhibition attenuates kindling epileptogenesis is not understood. Notwithstanding, COX-2 inhibition may diminish prostaglandin(s) and/or PAF synthesis, lipid messengers that are both involved in synaptic facilitation (20). Moreover, kindling epileptogenesis promotes selective neuronal COX-2 expression, initially in the hippocampus and subsequently in the neocortex. The stimulating electrode in this particular experiment was placed in the ventral hippocampus. Taken together, these studies suggest that the spreading of kindling-induced COX-2 expression from hippocampal neurons to neocortical neurons is a major event in the permanent facilitation of aberrant functional connectivity, and that COX-2 is a mediator (19). Kindling is also a model of bipolar disorders, and valproate, a mood stabilizer, when chronically administered to rats, down-regulates AA conversion into prostaglandins by decreasing COX brain expression (21). Lithium, also used to treat bipolar disorders, potentiates brain AA signaling (22).
Astrocytes are also active in the synthesis of prostaglandins, particularly in response to interleukin-1ß(IL-1ß) (23). Astrocytes form an intimate sheath around synapses and increase their intracellular Ca2+ content when excitatory neurotransmission is activated (24). As a consequence, there is a calcium-dependent glutamate release from astrocytes (25), an event that is activated by prostaglandins (Fig. 1) . Thus, these lipid messengers may be an intercellular signal of an integrated glutamatergic cross-talk between neurons and astrocytes (25). At present there are several evolving concepts on the nature of the signaling that allows neurons and astrocytes to communicate. In fact, this communication is bidirectional, and also has consequences on activity-dependent modulation of cerebral blood flow (26, 27) through multiple astrocyte signaling, including possible cytochrome P450 epoxygenase, which synthesizes epoxyeicosatrienoic acids that in turn elicit vasodilatory properties on the cerebral microcirculation (28). Astrocytes also release AA in response to oxidative stress by activation of cPLA2 and Ca2+-independent PLA2 (iPLA2) (29). These cells have complex regulatory mechanisms for cPLA2 activation involving protein kinase C (PKC) and MAP kinases (30). Moreover, the astrocytes' response to proinflammatory cytokines includes induction of secretory PLA2 (sPLA2) expression (31).
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20:. 4-DAG IN SYNAPTIC PLASTICITY |
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Inositol lipid synthesis in neurons is maintained by a de novo route through PA, and the DAG kinase step contributes to their replenishment (by its product PA) after synaptic activity-induced PIP2 hydrolysis. Thus, the DAG
(specific for 20:4-DAG, see below) becomes critical for the synthesis of PIP2 containing 20:4.
Diacylglycerols are messengers that modulate certain PKC isoforms, whereas IP3 releases Ca2+ from intracellular stores. DAG targets may discern DAG fatty acid composition (32). Thus, DAG generated from PC through PLD has different fatty acid composition from that generated from PIP2. PC at sn-2 is mainly oleate, 18:1,n-3 (33), as compared with arachidonate, which is the major sn-2 acyl chain in PIP2. During seizures, the main DAG that transiently accumulates in brain is 20:4-DAG (34–36); however, early and late DAG peaks display different fatty acid composition, strongly implying sources other than PIP2. Thus, it is clear that the fatty acid composition of inositol lipids is important in the generation of 20:4-DAG. To achieve enrichment in 20:4 in PIP2, enzymes for inositol lipid synthesis selectively employ 20:4-containing lipids as substrates (37). A critical enzyme is DAG kinase, which catalyzes the phosphorylation of DAG to PA. There are nine genes encoding these enzymes. DGK, which selectively phosphorylates 20:4-DAG, when deleted has helped to dissect several of these biochemical and neurobiological issues (38).
DGK brain cellular distribution as mGluR1 is localized in Purkinje cerebellar neurons, mitral cells of the olfactory bulb, hippocampal interneurons, and neurons of the thalamus and substantia nigra (39, 40). The neurotransmitter glutamate activates G-protein-coupled mGluR1, promoting PIP2 degradation by PLC and the subsequent activation of PKCß. DGK-deficient mice displayed a marked down-regulation of 20:4-inositol lipid signaling when exposed to electroconvulsive shock (ECS). This was reflected by lower PIP2 degradation and lower accumulation of DAG, free arachidonic, and stearic acids after ECS. These studies on DGK suggest that this signaling pathway participates in synaptic function, long-term potentiation, seizures, and neuroprotection.
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ARACHIDONIC ACID-CONTAINING MESSENGERS IN THE PSYCHOACTIVE ACTIONS OF ENDOCANNABINOIDS |
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Endocannabinoids are postulated to signal another mode of transynaptic interaction, the "depolarization-induced suppression of inhibition" (44–46). This is a retrograde mode of communication, where endocannabinoids disinhibit neuronal activity by blocking neurotransmitter release from gamma aminobutyric acid (GABA) ergic neurons (47). Consequently, the outcome is stimulation of neurotransmission. In different neuronal circuits, endocannabinoids may exert excitatory or inhibitory modulatory actions (46, 48).
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sPLA2: AN INTERCELLULAR MESSENGER |
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sPLA2s binding to N (neural)- and M (muscle)-type receptors were discovered by using various purified snake and bee venom sPLA2s as ligands (55–58). The activation of sPLA2 receptors in primary neurons in culture, using purified sPLA2 as a ligand, promotes a synergy with glutamate, inducing neuronal cell death (59). Moreover, AA metabolism (59), COX-2 activation (60), ischemic neuronal survival (61), and calcium influx (62) are clearly engaged in this response. Figure 1 outlines the potential involvement of sPLA2 at the synapse. It has been suggested that sPLA2 is coreleased along with neurotransmitters (63). This issue needs to be further explored in relation to specific synapses. At any rate sPLA2 in the intercellular space is able to generate lipid mediators, and the enzyme protein itself, when secreted, becomes a messenger. It is of interest that the consequences of sPLA2 acting on cells is the release of lipid messengers, either on the cell surface or intercellularly. It is not clear yet how sPLA2s may act on astrocytes, microglia, and neurons, or whether they are restricted to some cells.
Another remarkable case of a lipid-metabolizing enzyme that is present in the extracellular space is the major component of the cerebrospinal fluid, prostaglandin D synthase (64–66).
sPLA2 receptor activation in neurons induces sustained modifications in neuronal metabolism of arachidonoyl-phospholipids, although the specific messengers formed are not yet defined. sPLA2 receptor activation and glutamate synergize AA mobilization and neurotoxicity. Therefore, excitotoxicity may not only involve glutamate, as often assumed, but also sPLA2 (59). It is also possible that sPLA2 may have modulatory physiological actions at the synapse and other sites of the nervous system.
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DOCOSAHEXAENOIC ACID IN NEURONS AND PHOTORECEPTORS |
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Rhodopsin in photoreceptors is immersed in a lipid environment highly enriched in phospholipids containing DHA. Some DHA is found in close association with rhodopsin (74, 77) and DHA is essential for rhodopsin function (78–80). Moreover, retinal DHA, like brain DHA, is very resistant to n-3 fatty acid dietary deprivation.
Because of this constant systemic flow of DHA via a "long loop," it is highly relevant that retinitis pigmentosa (RP) is associated with alterations in lipoprotein metabolism (73). The most frequently reported phenotype is low plasma and red blood cell levels of DHA (81–84). In Usher's syndrome, an autosomal recessive RP that is associated with hearing loss, lower plasma levels of 22:6- and 20:4-phospholipids are also found (85). Interestingly, changes show a direct correlation to the severity of disease, and are more accentuated in patients with Usher's type I than in those with the less severe type II form (86).
Low plasma levels of 22:6n-3 in RP patients have also been interpreted as a mechanism to protect the retina from oxidative damage resulting from photochemical function of rhodopsin (87). Stress signals originating from retinas undergoing degeneration (e.g., RP) may shut off the communication between the retina and the liver (67), reducing the systemic liver supply of 22:6n-3. In dogs with progressive rod-cone degeneration (prcd) (88) as well as in other retinal-degeneration models (87), low levels of DHA in photoreceptor phospholipids occur. Moreover, the synthesis of DHA from 20:5n-3 in RPE cultures from prcd is not affected by the retinal degeneration (89), and dietary supplementation with DHA failed to prevent the loss of photoreceptor DHA and the prcd phenotype (88). Moreover, cultured hepatocytes from prcd dogs display higher accumulation of 22:6-phospholipids in the liver and impaired hepatocyte secretion of DHA-containing VLDLs (85), supporting the hypothesis that in retinal degenerations a systemic DHA metabolic defect occurs that leads to reduced liver DHA supply to the retina. Whether DHA dietary supplementation protects the retina of RP patients is not known.
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DHA: TARGET OF FREE RADICAL-CATALYZED PEROXIDATION AND PRECURSOR OF DOCOSANOIDS |
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Docosanoids, enzyme-derived DHA metabolites, were identified initially in the retina (94), and have been proposed to elicit neuroprotective actions (78). Very recently it was ascertained by tandem liquid chromatography-photodiode array-electrospray ionization-mass spectrometric-mass spectrometry (LC-PDA-ESI-MS-MS)-based lipidomic analysis that the synthesis of DHA-oxygenation messengers occurs during brain ischemia-reperfusion (95). Two DHA-oxygenation pathways operate: one that gives rise to 10,17S-docosatriene, and the second that results in the synthesis of resolvin-type messengers (17R-DHA). Resolvins were elegantly identified outside the nervous system as a response to aspirin treatment (96). The brain resolvins are also made upon treatment with aspirin (95). Both DHA-oxygenation pathways generate messengers that are counter-proinflammatory signals (96–98). The docosanoid 10,17S-docosatriene is a potent inhibitor of brain ischemia-reperfusion-induced polymorphonuclear leukocyte (PMN) infiltration, as well as of nuclear factor-
B (NF-B) and COX-2 expression (95). Moreover, marked attenuation of the stroke volume was observed when 10,17S-docosatriene was infused into the third ventricle during ischemia-reperfusion (95). Discovery of these DHA-oxygenation messengers sheds new light on how the brain modulates its response to inflammatory injury, and raises the exciting potential for designing new drugs to treat neurologic disorders that have a neuroinflammatory component, such as stroke, traumatic brain injury, or spinal cord injury. In particular, the very high biological activity of the docosanoid 10,17S-docosatriene marks it as potential effector of neuroprotection.
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PAF-MEDIATED CELL SIGNAL TRANSDUCTION IN THE NERVOUS SYSTEM |
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PAF and the free PUFAs released during PAF synthesis accumulate in brain upon stimulation (105). In the retina and in neurons in culture, neurotransmitters trigger Ca2+-independent de novo PAF synthesis through cytidine 5'-diphosphocholine (106, 107). Since PAF stimulates ATP release from PC12 cells, it has been implicated in vesicular release of neurotransmitters (108), perhaps through a mechanism analogous to that engaged in vesicular release of vasoactive substances from platelets and eosinophils (109).
PAF is rapidly degraded by deacetylation to the biologically inactive lipid, lyso-PAF. Several PAF-AH are expressed in the central nervous system (99). Use of the stable PAF analog, methyl carbamyl-PAF (mc-PAF), allows the study of PAF action while avoiding enzyme-mediated inactivation. Bath-applied mc-PAF specifically augments hippocampal excitatory synaptic transmission using synaptic pairs of neurons in culture (100). This study also demonstrated that PAF action is receptor mediated and presynaptically localized, and supported the notion that PAF is a second messenger in the central nervous system. Additional mc-PAF enhanced the amplitude of evoked postsynaptic currents, while diminishing the size of presynaptic action potentials. Interestingly, the mc-PAF effect on excitatory synaptic transmission is very selective, since it does not increase general presynaptic function (100). Also, c-PAF elicts these actions independently of postsynaptic glutamate receptors. Moreover, mc-PAF augmented the frequency of spontaneous miniature excitatory synaptic events, sparing their amplitude and their time course.
Retrograde messengers of LTP are candidates to up-regulate memory. Retrograde messengers released from the postsynaptic neuron are thought to enhance excitatory neurotransmitter release from the presynaptic neuron; this is believed to increase synaptic efficiency of LTP. The signaling that links the postsynaptic neuron to presynaptic modulation of neurotransmitter release is in accord with the Hebbian concept of synaptic potentiation. Several mediators have been postulated to be retrograde messengers, including arachidonic acid, nitric oxide, carbon monoxide, and PAF. In the case of arachidonic acid, even though this fatty acid is released and increases excitatory synaptic transmission when coupled with presynaptic stimulation, it requires relatively high concentrations (110), and in CA1 neurons, AA effects are blocked by DL-2-amino-phosphopentanoic acid (APV) (111, 112), consequently limiting arachidonic acid's potential as a retrograde messenger.
PAF, on the other hand, fulfills several aspects of a retrograde messenger in LTP: it is synthesized in brain during stimulation as well as in neurons in culture, it activates hippocampal excitatory synapses by increasing presynaptic glutamate release, and it augments hippocampal CA1 LTP.
Infusion of PAF into specific brain regions promotes memory facilitation in rats. In experiments using the step-down inhibitory avoidance or spatial-habitation task, PAF infused 10 min before training or immediately after training enhanced retention scores. However, PAF infused 60 min post-training had no effect on retention (113). In PAF-receptor-deficient mice, marked attenuation of LTP was observed. Infusion of PAF into brain regions enhanced memory formation in a time-dependent, neuroanatomically specific fashion. A presynaptic PAF-receptor antagonist had a clear amnesic effect in several memory-task tests.
Post-training intrahippocampal infusion of intracellular forms of the PAF receptor did not modify memory for an inhibitory avoidance task (113, 114). However, post-training injection of PAF into either amygdala, hippocampus, or entorhinal cortex enhances memory in an inhibitory avoidance task (113), whereas injection of a PAF-receptor antagonist that selectively targets the presynaptic PAF receptor impairs memory in this task. Moreover, post-training intrahippocampal and intradorsal striatal injections of either PAF or PAF-receptor antagonists modulate memory in hidden and visible platform water-maze tasks, respectively (115–117).
The NMDA-receptor antagonist MK-801 markedly attenuated the memory-enhancing effects of intradorsal striatal infusion of PAF on the visible platform water-maze task. On the other hand, in a hidden platform water-maze task, intrahippocampal infusion of PAF blocks the memory-perturbing actions of MK-801. The mechanism allowing interactions between the phospholipid messenger and the NMDA receptor in the mnemonic functions of hippocampus and striatum may underlie the participation of the intracellular form of the PAF receptor or of signaling cascades evolving from the cell-surface PAF receptor to transcription factors and genes (118).
PAF-receptor antagonists block LTP in rat hippocampal CA1 neurons, dentate gyrus, and medial vestibular nuclei. PAF itself increases excitatory postsynaptic responses and the frequency of spontaneous excitatory postsynaptic currents, and enhances the receptor-mediated release of the excitotoxic amino acid, glutamate, from presynaptic terminals. Excitatory synaptic transmission is modulated by a variety of signaling systems, including the inhibitory neurotransmitter GABA. In a study of the effects of PAF on GABA neurotransmission in hippocampal neurons in primary culture, extracellular PAF reduced GABA-gated chloride ion current in more than 65% of cells while enhancing it in 
23% of cells. This heterogeneous modulation of inhibitory neurotransmission may be the result of GABA receptor subtypes differing in their subunit composition or in phosphorylation sites responding to intracellular signaling molecules that transduce the extracellular PAF signal to the GABA receptor, or it may be the result of allosteric effects on the receptor regulatory sites (119).
Because PAF predominantly inhibits ionic GABA-receptor activity in hippocampal neurons, it is not surprising that PAF enhances excitatory presynaptic glutamatergic neurotransmission as well as decreases inhibitory GABAergic postsynaptic activity (119).
The observation that PAF-receptor antagonists elicit neuroprotection in the gerbil brain ischemia-reperfusion model (120) suggested that PAF may work at the synapse. In this model, the ischemia-induced accumulation of free PUFA was decreased by the PAF antagonists that were also neuroprotective by restoring cerebral blood flow (120). The ischemia-induced PUFA release is believed to result from synaptic phospholipase(s) A2 activity (116). In addition, the PAF antagonist shown to be neuroprotective in the gerbil ischemia-reperfusion model also selectively displaced radiolabeled PAF binding from synaptic membranes (121). This synaptic membrane binding site was therefore suggested to be the modulator of glutamate neurotransmitter release (100). Moreover, intracellular PAF-binding sites identified in a microsomal fraction were distinct from those at the synaptic membrane fraction insofar as responses to several antagonists (121). At that time it was known that PAF activates early-response genes (122–124), therefore the intracellular receptor was thought to be the signaling linkage to the nucleus. Cloning of the seven-transmembrane domain PAF receptor (125–127) and the discovery of specific PAF receptor-mediated Ca2+ influx into neurons (102) further illuminated neural PAF signaling. In studies of LTP in hippocampal neurons from PAF-receptor-deficient mice, both incidence and size of LTP, defined as increased excitatory postsynaptic potentials, were attenuated in PAF-receptor-knockout mice, as compared with LTP in wild-type mice. Moreover, PAF receptor-deficient mice display a marked attenuation of LTP upon stimulation of the lateral, but not the medial, perforant path (128). In another study, PAF-deficient mice had unaltered LTP; however, there were substantial differences between the experimental conditions of the two studies (129). Furthermore, PAF-receptor antagonists reduced LTP in wild-type mice, but not in PAF-receptor knockout mice. These results further support the hypothesis that PAF is involved in hippocampal synaptic plasticity (128). Most recently, the intracellular PAF receptors were further characterized. One form is confined to the endosomes (130) and the other to the nuclear membrane (131). Both intracellular forms of the receptor may be part of the intracellular microsomal form described earlier (121). At any rate, we know that neurons, astrocytes, and microglia, as well as endothelial cells, express the PAF seven-transmembrane domain receptor. It remains to be defined whether the intracellular PAF receptor(s) have a different molecular structure or whether they are in fact an intracellular state of the cell-surface PAF seven transmembrane domain receptor. Does the cell-surface PAF receptor internalize? Is the cell-surface PAF receptor destined to insertion in the membrane already active, and if so, can PAF itself internalize to access either of these PAF-receptor forms located inside the cell? Finally, regarding PAF's transcriptional actions, at least two mechanisms are possible: the cell surface receptor triggers the signaling cascade, or the intracellular form establishes interactions with specific kinases/phosphatases or transcription factors with or without specific scaffolding proteins.
During ischemia, seizures, and in other pathologic conditions involving oxidative stress, the rates of PAF synthesis and degradation no longer maintain a modulated PAF pool size; consequently, PAF concentration increases and it becomes a pro inflammatory messenger and a mediator of neurotoxicity. As such, PAF activates COX-2 expression (132) as well as that of several early-response genes that encode transcription factors (122, 123). PAF activates apoptosis and PMN and their adhesion to the microvasculature (109). This event has critical consequences for cell survival. Leukocyte infiltration mediates neural injury in head trauma, stroke, spinal cord injury, and other diseases. PAF also enhances the synthesis and release of IL-6, IL-8, IL-10, tumor necrosis factor-, and of other mediators of the inflammatory response. PAF activates phospholipases through its receptor, resulting in additional PAF synthesis, along with that of prostaglandins and leukotrienes. Overall, PAF is a potent neuronal injury messenger. PAF also plays a prominent role in astrocytes and in microglial cells. Many of these actions have been studied in nonneural cells and are assumed to occur in the nervous system as well. Therefore, excessive PAF promotes neuronal damage, and PAF-receptor antagonists elicit neuroprotection in various models of neural injury (120, 133–137).
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PAF DEGRADATION IN THE CENTRAL NERVOUS SYSTEM |
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1, 29 kDa and 2, 30 kDa) and one regulatory ß subunit (45 kDa); the latter gene is analogous to the LIS1 gene, which causes lissencephaly in Miller-Dieker syndrome (104). Because lissencephaly results from defects in neuronal cell migration, PAF-AHIb may modulate neuronal migration during nervous system development. Moreover, PAF has been found to promote growth-cone collapse, implicating further the phospholipid messenger in developmental neurobiology (100). PAF-AH cleaves the acetate moiety of PAF and comprises an "off" signal when PAF is no longer needed to perform a function or when the concentrations of PAF become neurotoxic. We tested this hypothesis using recombinant plasma-type PAF-AH (rPAF-AH) in primary neuronal cultures, and found that rPAF-AH in fact elicits neuroprotection (138). The human form of PAF-AH is effective in inhibiting inflammation in nonneural cells (139). rPAF-AH elicits concentration-dependent neuroprotection against NMDA-induced apoptosis in hippocampal neurons in primary culture (138). The criteria used in this study included electron microscopy to monitor nuclear condensation, histone release, TUNEL staining, and DNA laddering. Therefore, rPAF-AH may be an alternative to PAF antagonists in regulating pathologic accumulation of PAF in several conditions involving excitotoxicity, including epileptic brain damage, head injury, stroke, glaucoma, and neurodegenerative diseases. The development of these concepts for therapeutic interventions may be helpful because rPAF-AH is relatively resistant to proteolytic degradation, contributing to sustained bioavailability after administration. Also rPAF-AH is able to hydrolyze oxidized phospholipids, which are also recognized by the PAF receptor (109). PAF-like oxidized phospholipids accumulate in several pathologic conditions that involve oxidative stress.
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LIPIDOMIC NEUROBIOLOGY ON THE HORIZON |
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An example of an evolving area of the neurosciences is the understanding of the fundamental inner workings of the dendrites, which contain complex intracellular membranes rich in polyunsaturated phospholipids. Dendrites undergo profound changes during neuronal function, including the membrane vesicular transport of neurotransmitter receptors, ion channels, and other proteins destined to the dendritic spine, where critical postsynaptic elements of neurotransmission are located. Definition of the dendritic lipidome will also define the participation of lipid signaling in dendritic development and in the establishment of synaptic contacts as well as overall dendritic plasticity.
Although AA is widely implicated in signaling in brain, there are several gaps in our understanding of the release of this fatty acid from membrane reservoirs. Reports that AA is released primarily by G-protein-mediated PLA2 activation remain to be confirmed (141, 142). In addition, modulation of PLA2 by Ca2+ and protein kinase needs to be better defined. It is clear that NMDA-receptor activation promotes the release of AA (143), and that a variety of eicosanoids are then generated. The modulatory events that channel AA toward specific eicosanoids are not understood. The endocannabinoid family of lipid messengers will remain an active focus of interest because of the growing evidence of their actions in synaptic function, learning, memory, and other forms of behavior (144, 145).
The essential fatty acid of the linolenic acid family, DHA, is most highly concentrated in brain and retina. The significance of this polyunsaturated fatty acid, above and beyond its being a target for nonenzymatic peroxidation under various pathologic conditions, will be a focus of continued research. Clearly, DHA-containing molecular species of phospholipids confer a unique environment for ion channels, receptors, transporters, and protein-protein interactions critical in signaling. How these events are regulated, including the synthesis and remodeling of these highly unsaturated phospholipids, is not clearly understood. The enzyme-mediated synthesis of docosanoids raises the possibility of exploring the specific generation of novel DHA-oxygenation messengers that are neuroprotective (95). How these docosanoid messengers are synthesized, through which receptors they elicit their actions, how they are affected by pharmacologic agents, and how the docosanoids themselves might become a base for new drug design are questions for the near future. The use of tandem LC-PDA-ESI-MS-MS-based lipidomic analysis, in combination with other experimental approaches, will greatly contribute to our understanding of the significance of DHA in health and in pathologic conditions.
The knowledge evolving from lipidomic neurobiology will also be potentiated by multidisciplinary approaches (e.g., multiphoton confocal analysis). Structural neurobiology will also come into play, because the lipidome will provide new insights into the precise stereochemical structure of lipids of excitable membranes, as well as of intracellular membranes. There is also growing evidence of the exquisite signaling interplay among neurons, astrocytes, oligodendrocytes, and microglia. Prostaglandins are among the lipid messengers explored to date as modulators of astrocyte release of glutamate (25). Microglia also actively make prostaglandins in response to injury (146–148), although prostaglandin E2 may be engaged in neuroprotective mechanisms (149). Moreover, the renewed interest in defining the significance of nonneuronal cells in the nervous system (150–152) will be greatly enhanced by lipidomic approaches. Overall, the near future will witness breakthroughs using lipidomic neurobiology to more precisely define synaptic lipid signaling that will contribute to a renewed vista of the function of the nervous system as well as of the neurobiology of diseases.
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ACKNOWLEDGMENTS |
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Manuscript received August 1, 2003 and in revised form September 2, 2003.
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REFERENCES |
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ABSTRACT
INTRODUCTION
