ArticleLiterature Review

Lipid signaling: Sleep, synaptic plasticity, and neuroprotection

Authors:
  • Louisiana State University Health, New Orleans, LA 70112
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Abstract

Increasing evidence indicates that bioactive lipids participate in the regulation of synaptic function and dysfunction. We have demonstrated that signaling mediated by platelet-activating factor (PAF) and cyclooxygenase (COX)-2-synthesized PGE2 is involved in synaptic plasticity, memory, and neuronal protection [Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron 1992; 9:1211; Kato K, Clark GD, Bazan NG, Zorumski CF. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 1994; 367:175; Izquierdo I, Fin C, Schmitz PK, et al. Memory enhancement by intrahippocampal, intraamygdala or intraentorhinal infusion of platelet-activating factor measured in an inhibitory avoidance. Proc Natl Acad Sci USA 1995; 92:5047; Chen C, Magee CJ, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 2002; 87:2851]. Recently, we found that prolonged continuous wakefulness (primarily rapid eye movement (REM)-sleep deprivation, SD) causes impairments in hippocampal long-term synaptic plasticity and hippocampus-dependent memory formation [McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci 2003; 23:9687]. To explore the mechanisms underlying SD-induced impairments, we have studied several bioactive lipids in the hippocampus following SD. It appears that SD causes increases in prostaglandin D2 (PGD2) and 2-arachidonylglycerol (2-AG), and a decrease in PGE2, suggesting that these lipid messengers participate in memory consolidation during REM sleep. We have also explored the formation of endogenous neuroprotective lipids. Toward this aim, we have used ischemia-reperfusion damage and LC-PDA-ESI-MS-MS-based lipidomic analysis and identified docosanoids derived from synaptic phospholipid-enriched docosahexaenoic acid. Some of the docosanoids exert potent neuroprotective bioactivity [Marcheselli VL, Hong S, Lukiw WJ, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003; 278:43807; Mukherjee PK, Marcheselli VL, Serhan CN, Bazan, NG. Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Nat Acad Sci USA 2004; 101:8491). Taken together, these observations that signaling lipids participate in synaptic plasticity, cognition, and survival indicate that lipid signaling is closely associated with several functions (e.g; learning and memory, sleep, and experimental stroke) and pathologic events. Alterations in endogenous signaling lipids or their receptors resulting from drug abuse lead to changes in synaptic circuitry and induce profound effects on these important functions. In the present article, we will briefly review bioactive lipids involved in sleep, synaptic transmission and plasticity, and neuroprotection, focusing mainly on our experimental studies and how these signaling molecules are related to functions and implicated in some neurologic disorders.

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... When associated to phospholipids, PUFAs play important role in the structure of membranes, by determining its curveting and flexibility [27,28]. More importantly, PUFAs can be released by phospholipase enzymes to be metabolized by cyclooxygenase (COX) / lipoxygenase (LOX) pathways in a huge variety of derivates [3,[29][30][31] (Figure 1). These derivates are mainly involved in neuroinflammatory processes and the classical picture is that derivates from ω-6 PUFAs, in particular ARA, are pro-inflammatory whereas ω-3 PUFAs derivates, mainly EPA (ecosapentaenoic acid) and DHA, are antiinflammatory and pro-resolutive factors. ...
... These derivates are mainly involved in neuroinflammatory processes and the classical picture is that derivates from ω-6 PUFAs, in particular ARA, are pro-inflammatory whereas ω-3 PUFAs derivates, mainly EPA (ecosapentaenoic acid) and DHA, are antiinflammatory and pro-resolutive factors. The main enzymes involved in these processes are COX, LOX and cytochrome P450 [3,[29][30][31]. In the brain, it is still unclear whether neurons and/ or glial cells are the main cellular type involved in the production of PUFA derivates with pro or anti-inflammatory activities. ...
... In parallel, the role of PUFAs on inflammation is well documented [98,99]. Globally, we can summarize that ω-6 PUFAs, such as ARA, are metabolized in pro-inflammatory derivates while ω-3 PUFAs, such as DHA and EPA, are metabolized in anti-inflammatory and proresolution derivates [3,[29][30][31]. PUFAs play thus a central role in the immune response of the organism. ...
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Omega-3 (omega-3) and omega-6 (omega-6) are polyunsaturated fatty acids (PUFAs) that play critical role in human health and have to be provided by food. In the brain, PUFAs are also precursors of endocannabinoids. The aim of this chapter is to review the existing literature on how dietary PUFAs impact on the endocannabinoid system in the brain and what are the consequences for brain function and dysfunction. In this chapter, we will first describe how PUFAs enter the brain, what are their metabolism processes and roles in brain function. We will describe the pathways from PUFAs to endocannabinoid production. Then, we will review the literature on how dietary omega-6/omega-3 ratio impacts the endocannabinoid system, in terms of endocannabinoid levels, proteins and endocannabinoid-dependent synaptic plasticity. In the next part, we will describe what we know about the interactions between PUFAs and endocannabinoids in neurological and neuropsychiatric disorders. Finally, we will conclude on the possible implications of the interactions between dietary PUFAs and endocannabinoids in the normal and pathological brain. In particular, we will discuss how dietary PUFAs, as homeostatic regulators of endocannabinoids, can constitute interesting therapeutic strategies for the prevention and/or treatment of neurological disorders with endocannabinoids impairment.
... When associated to phospholipids, PUFAs play important role in the structure of membranes, by determining its curveting and flexibility [27,28]. More importantly, PUFAs can be released by phospholipase enzymes to be metabolized by cyclooxygenase (COX) / lipoxygenase (LOX) pathways in a huge variety of derivates [3,[29][30][31] (Figure 1). These derivates are mainly involved in neuroinflammatory processes and the classical picture is that derivates from ω-6 PUFAs, in particular ARA, are pro-inflammatory whereas ω-3 PUFAs derivates, mainly EPA (ecosapentaenoic acid) and DHA, are antiinflammatory and pro-resolutive factors. ...
... These derivates are mainly involved in neuroinflammatory processes and the classical picture is that derivates from ω-6 PUFAs, in particular ARA, are pro-inflammatory whereas ω-3 PUFAs derivates, mainly EPA (ecosapentaenoic acid) and DHA, are antiinflammatory and pro-resolutive factors. The main enzymes involved in these processes are COX, LOX and cytochrome P450 [3,[29][30][31]. In the brain, it is still unclear whether neurons and/ or glial cells are the main cellular type involved in the production of PUFA derivates with pro or anti-inflammatory activities. ...
... In parallel, the role of PUFAs on inflammation is well documented [98,99]. Globally, we can summarize that ω-6 PUFAs, such as ARA, are metabolized in pro-inflammatory derivates while ω-3 PUFAs, such as DHA and EPA, are metabolized in anti-inflammatory and proresolution derivates [3,[29][30][31]. PUFAs play thus a central role in the immune response of the organism. ...
Chapter
Full-text available
Omega-3 (ω-3) and omega-6 (ω-6) are polyunsaturated fatty acids (PUFAs) that play critical role in human health and have to be provided by food. In the brain, PUFAs are also precursors of endocannabinoids. The aim of this chapter is to review the existing literature on how dietary PUFAs impact on the endocannabinoid system in the brain and what are the consequences for brain function and dysfunction. In this chapter, we will first describe how PUFAs enter the brain, what are their metabolism processes and roles in brain function. We will describe the pathways from PUFAs to endocannabinoid production. Then, we will review the literature on how dietary ω-6/ω-3 ratio impacts the endocannabinoid system, in terms of endocannabinoid levels, proteins and endocannabinoid-dependent synaptic plasticity. In the next part, we will describe what we know about the interactions between PUFAs and endocannabinoids in neurological and neuropsychiatric disorders. Finally, we will conclude on the possible implications of the interactions between dietary PUFAs and endocannabinoids in the normal and pathological brain. In particular, we will discuss how dietary PUFAs, as homeostatic regulators of endocannabinoids, can constitute interesting therapeutic strategies for the prevention and/or treatment of neurological disorders with endocannabinoids impairment.
... Regarding the adult brain, the knockdown of cytoplasmic PLA 2 has the same effects as the Cox-2 inhibition in that both block long-term depression (LTD) in the brain slices and attenuate the short-term adaptation of optokinetic eye movements [65]. Disturbances of the PLA 2 -Cox-2 tandem may thus have profound effects in synaptic circuitry [66], brain plasticity [67], and motor learning [65]. In addition, PLA 2 enzymes have also been associated with the Fig. 1 Schematic representation of cyclooxygenase-2-mediated synaptic activity. ...
... Neuronal plasticity is essential not only for learning and memory [80] but also for the stability of neuronal networks during neurodevelopment [32,81,82]. The Cox-2 metabolite PGE 2 directly participates in the homeostatic plasticity of the brain [31,32,66,73,83] and spinal cord [9]. Cox-2 also supports adult neurogenesis [84] and the neurovascular coupling in the cortex [34,35,85,86]. ...
Article
Full-text available
Cyclooxygenases are a group of heme-containing isozymes (namely Cox-1 and Cox-2) that catalyze the conversion of arachidonic acid to largely bioactive prostaglandins (PGs). Cox-1 is the ubiquitous housekeeping enzyme, and the mitogen-inducible Cox-2 is activated to cause inflammation. Interestingly, Cox-2 is constitutively expressed in the brain at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Neuronal Cox-2 is activated in response to synaptic excitation to yield PGE2, the predominant Cox-2 metabolite in the brain, which in turn stimulates the release of glutamate and neuronal firing in a retrograde fashion. Cox-2 is also engaged in the metabolism of new endocannabinoids from 2-arachidonoyl-glycerol to modulate their actions at presynaptic terminals. In addition to these interactions, the induction of neuronal Cox-2 is coupled to the trans-synaptic activation of the dopaminergic mesolimbic system and some serotoninergic receptors, which might contribute to the development of emotional behavior. Although much of the focus regarding the induction of Cox-2 in the brain has been centered on neuroinflammation-related neurodegenerative and psychiatric disorders, some evidence also suggests that Cox-2 release during neuronal signaling may be pivotal for the fine tuning of cortical networks to regulate behavior. This review compiles the evidence supporting the homeostatic role of neuronal Cox-2 in synaptic transmission and plasticity, since neuroinflammation is originally triggered by the induction of glial Cox-2 expression. The goal is to provide perspective on the roles of Cox-2 beyond neuroinflammation, such as those played in memory and anxiety, and whose evidence is still scant.
... Regarding the adult brain, the knockdown of cytoplasmic PLA 2 has the same effects as the Cox-2 inhibition in that both block long-term depression (LTD) in the brain slices and attenuate the short-term adaptation of optokinetic eye movements [65]. Disturbances of the PLA 2 -Cox-2 tandem may thus have profound effects in synaptic circuitry [66], brain plasticity [67], and motor learning [65]. In addition, PLA 2 enzymes have also been associated with the Fig. 1 Schematic representation of cyclooxygenase-2-mediated synaptic activity. ...
... Neuronal plasticity is essential not only for learning and memory [80] but also for the stability of neuronal networks during neurodevelopment [32,81,82]. The Cox-2 metabolite PGE 2 directly participates in the homeostatic plasticity of the brain [31,32,66,73,83] and spinal cord [9]. Cox-2 also supports adult neurogenesis [84] and the neurovascular coupling in the cortex [34,35,85,86]. ...
Article
Ascorbic acid (AA) is a water-soluble vitamin (C) found in all bodily organs. Most mammals synthesize it, humans are required to eat it, but all mammals need it for healthy functioning. AA reaches its highest concentration in the brain where both neurons and glia rely on tightly regulated uptake from blood via the glucose transport system and sodium-coupled active transport to accumulate and maintain AA at millimolar levels. As a prototype antioxidant, AA is not only neuroprotective, but also functions as a cofactor in redox-coupled reactions essential for the synthesis of neurotransmitters (e.g., dopamine and norepinephrine) and paracrine lipid mediators (e.g., epoxiecoisatrienoic acids) as well as the epigenetic regulation of DNA. Although redox capacity led to the promotion of AA in high doses as potential treatment for various neuropathological and psychiatric conditions, ample evidence has not supported this therapeutic strategy. Here, we focus on some long-neglected aspects of AA neurobiology, including its modulatory role in synaptic transmission as demonstrated by the long-established link between release of endogenous AA in brain extracellular fluid and the clearance of glutamate, an excitatory amino acid. Evidence that this link can be disrupted in animal models of Huntington´s disease is revealing opportunities for new research pathways and therapeutic applications (e.g., epilepsy and pain management). In fact, we suggest that improved understanding of the regulation of endogenous AA and its interaction with key brain neurotransmitter systems, rather than administration of AA in excess, should be the target of future brain-based therapies.
... They are direct mediators of inflammatory responses [11,12]. Prostaglandin E 2 (PGE 2 ) is synthesized by the COX-2 pathway and is a crucial mediator of responses to injuries in the brain [12][13][14]. PGE 2 also plays an important role in dynamically maintaining membrane excitability, synaptic transmission, integration, and plas-ticity in the hippocampus. Notably, depletion of endogenous PGE 2 in hippocampal CA1 pyramidal neurons results in a significant reduction of the membrane input resistance and frequency of firing. ...
... Notably, depletion of endogenous PGE 2 in hippocampal CA1 pyramidal neurons results in a significant reduction of the membrane input resistance and frequency of firing. Such a decrease of membrane excitability is reversed by the exogenous application of PGE 2 [13]. In addition, PGE 2 facilitates pentylenetetrazole (PTZ)-and methylmalonate-induced seizures [15,16]. ...
Article
Full-text available
Neuroinflammation plays a major role in brain excitability and may contribute to the development of epilepsy. Prostaglandin E2(PGE2) is a direct mediator of inflammatory responses and, through EP receptors, plays an important role in neuronal excitability. Pharmacological evidence supports that centrally-administered EP1 and EP3 receptor antagonists reduced acutely evoked seizures in rats. Translation of these findings would benefit from evidence of efficacy with a more clinically relevant route of delivery and validation in another species. In the current study we investigated whether the systemic administration of EP1 and EP3 agonists and antagonists modulate pentylenetetrazole (PTZ)-induced seizures in mice. In addition, it was examined whether these compounds alter Na+, K+-ATPase activity, an enzyme responsible for the homeostatic ionic equilibrium and, consequently, for the resting membrane potential in neurons. While the systemic administration of EP1 and EP3 antagonists (ONO-8713 and ONO-AE3-240, respectively) attenuated, the respective agonists (ONO-DI-004 and ONO-AE-248) potentiated PTZ-induced seizures (all compounds injected at the dose of 10 µg/kg, s.c., 30 min before PTZ challenge). Co-administration of either EP1 or EP3 agonist with the respective antagonists nullified the anticonvulsant effects of EP1/3 receptor blockade. In addition, EP1 and EP3 agonists exacerbated PTZ-induced decrease of Na+, K+-ATPase activity in both cerebral cortex and hippocampus, whereas, EP1 and EP3 antagonists prevented PTZ-induced decrease of Na+, K+-ATPase activity in both structures. Our findings support and extend evidence that EP1 and EP3 receptors may be novel targets for the development of anticonvulsant drugs.
... This is particularly relevant because Johnson and colleagues (10) have demonstrated that short-term (over several days) exposure to ANG II in rats can produce long-term neuroplastic changes in the brain that promote increased neurogenic pressor activity and BP on subsequent exposure of the animals to ANG II, salt, or aldosterone. Because COX-1derived prostanoids are capable of inducing neuroplastic changes in the brain (5,9,40), together, these observations indicate that the timing of prostanoid generation in the brain may be a critical element in their ability to cause HTN. ...
... Some evidence exists that prostanoid products can act in the brain to increase sympathetic activity and BP (28). In addition, there is evidence that prostanoids can cause adaptive changes in brain pathways that could lead to prolonged alterations in brain function (5,9). Therefore, we tested the hypothesis that transcriptional and translational products of the prostanoid pathway could be transiently activated early during the development of ANG II-salt HTN, with possible consequences for long-term BP regulation. ...
Article
Prostanoids generated by the cyclooxygenase (COX) pathway appear to contribute to the neurogenic hypertension (HTN) in rats. The first goal of this study was to establish the time frame during which prostanoids participate in AngII-salt HTN. We induced HTN using AngII (150 ng/kg/min, sc) infusion for 14 days in rats on a high salt (2% NaCl) diet. When ketoprofen pretreatment was combined with treatment during the first 7 days of AngII infusion, development of HTN and increased neurogenic pressor activity (indexed by the depressor response to ganglion blockade) were significantly attenuated for the entire AngII infusion period. This suggest that prostanoid generation caused by administration of AngII and salt leads to an increase in neurogenic pressor activity and blood pressure (BP) via a mechanism that persists without the need for continuing prostanoid input. Second goal of this study was to determine if prostanoid products specifically in the brain contribute to HTN development. Expression of prostanoid pathway genes was measured in brain regions known to affect neurogenic BP regulation. AngII treated rats exhibited changes in gene expression of phospholipase A2 (upregulated in organum vasculosum of the lamina terminalis, paraventricular nucleus, nucleus of the solitary tract, and middle cerebral artery) and lipocalin type prostaglandin D synthase (upregulated in the organum vasculosum of the lamina terminalis). Based on our results we propose that activation of the brain prostanoid synthesis pathway both upstream and downstream from COX at early stages plays an important role in the development of the neurogenic component of AngII-salt HTN.
... Overall, our network pharmacology approach indicates that the beneficial effect of SAFI on IS is likely due to its anti-inflammatory properties via direct inhibition of PTGS1 and PTGS2. It should be noted that PTGS1 and PTGS2 are involved in inflammation not only via the arachidonic acid (AA) metabolic pathway, but also through the maintenance of cerebral blood flow, synaptic plasticity, and cerebrovascular regulation (Niwa et al., 2000;Chen and Bazan, 2005;Jayaraj et al., 2020). Due to the advantages of multiple components, multiple targets and multiple pathways, other potential effects of SAFI in the treatment of IS should be further explored. ...
Article
Full-text available
Ischemic stroke (IS) is an acute neurological injury that occurs when a vessel supplying blood to the brain is obstructed, which is a leading cause of death and disability. S alvia miltiorrhiza has been used in the treatment of cardiovascular and cerebrovascular diseases for over thousands of years due to its effect activating blood circulation and dissipating blood stasis. However, the herbal preparation is chemically complex and the diversity of potential targets makes difficult to determine its mechanism of action. To gain insight into its mechanism of action, we analyzed “Salvianolic acid for injection” (SAFI), a traditional Chinese herbal medicine with anti-IS effects, using computational systems pharmacology. The potential targets of SAFI, obtained from literature mining and database searches, were compared with IS-associated genes, giving 38 common genes that were related with pathways involved in inflammatory response. This suggests that SAFI might function as an anti-inflammatory agent. Two genes associated with inflammation ( PTGS1 and PTGS2 ), which were inhibited by SAFI, were preliminarily validated in vitro . The results showed that SAFI inhibited PTGS1 and PTGS2 activity in a dose-dependent manner and inhibited the production of prostaglandin E2 induced by lipopolysaccharide in RAW264.7 macrophages and BV-2 microglia. This approach reveals the possible pharmacological mechanism of SAFI acting on IS, and also provides a feasible way to elucidate the mechanism of traditional Chinese medicine (TCM).
... Docosanoids effectively constrain the expression of proinflammatory gene and leukocyte infiltration mediated by the ischemia-reperfusion of brain. Moreover, it also protects the cells of retinal pigment epithelium in humans from the oxidative stress [157]. Finally, EPA is a significant component of the nerve cells and serves as the precursor for the production of thromboxane-3, leukotriene-5 and prostaglandin-3 [158]. ...
Chapter
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Lipids are abundant in the nervous system which is second only to adipose tissue. A major part of the lipids of the nervous system is found in myelin with about 70–80% of its dry mass. The major class of brain lipids is phospholipids and others include sphingolipids, gangliosides and cholesterol. These lipids are involved in the structure and function of cell membranes in the brain and display a variety of biological functions to maintain vital cellular processes at various levels; they are source of energy, serve as signalling molecules, and withstand structural integrity of cellular compartment and membranes. Lipids in the form of fatty acids participate actively in the development of the nervous system at embryonic and early postnatal stage and are crucial for its maintenance throughout adulthood. Dyslipidaemia is extensively considered as biomarker of diseases of the nervous system. It is therefore believed that these changes contribute in their own right by as yet incompletely understood mechanisms to those pathological processes. Human body is incapable to synthesize both LA and ALA endogenously, so their provision is exogenous with food and are classified as essential fatty acids. Correction of altered lipids level by exogenous supply is considered a most promising therapeutic approach.
... [31][32][33][34] Normal COX2/ PGE2-mediated signaling is involved in fundamental brain functions such as dendritic spine formation, synaptic plasticity and memory and learning. 22,30,[35][36][37] Various abnormalities in key components of the COX2/PGE2 pathway due to both genetic and environmental influences have been implicated in clinical studies on ASD 20,21 (Figure 1). For instance, increased and decreased ratios of AA to omega-3 and omega-6 fatty acids, [38][39][40] increased PLA2 activity, 41 decreased total AA and increased PGE2 levels 42 have been reported in blood samples of human patients with ASD. ...
... Fatty acids (FAs), particularly the long-chain polyunsaturated FAs (PUFAs), have been proposed to play a role in sleep processes, by exerting effects directly on neuronal membrane structure or indirectly on the dynamics of biochemical compounds (complex lipids, prostaglandins, neurotransmitters, amino acids, interleukins) necessary for the initiation and maintenance of sleep [15]. For instance, 20:4n-6 derived prostaglandin D2 (PGD2) was an inducer of sleep [16,17], while prostaglandin I2 (PGI2) was a promotor of alertness in mammalian brains [18]. The 22:6n-3 could facilitate the release of serotonin [19,20], which is known as the precursor of a sleep-inducing indolamine, melatonin. ...
Article
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The relationship between circulating fatty acid (FA) composition and childhood sleep disturbance remains largely unclear. We aimed to investigate the association of erythrocyte membrane FA composition with prevalence of sleep disturbance in Chinese children and adolescents. A cross-sectional survey was conducted among 2337 school-aged children and adolescents who completed a clinical assessment in Beijing, China. Presence of sleep disturbance was self-reported or parent-reported by questionnaires. Erythrocyte FAs were measured by gas chromatography, and desaturase activities were estimated by FA ratios. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for sleep disturbance across FA quartiles were calculated by a logistical regression model. We found higher proportions of erythrocyte phospholipid 24:0, 24:1n-9, and lower proportions of total n-3 polyunsaturated FA (PUFA), 22:5n-3 and 22:6n-3 in participants with sleep disturbance compared with those without. In the logistical regression models, significant inverse associations were found for total n-3 PUFA, 22:5n-3 and 22:6n-3, the highest versus lowest quartile ORs and 95% CIs were 0.57 (0.40, 0.82), 0.67 (0.47, 0.97) and 0.69 (0.49, 0.96), respectively. For per 1 SD difference of proportion, OR and 95% CI of prevalence of sleep disturbance was 0.91 (0.86, 0.97) for total n-3 PUFA, 0.90 (0.82, 0.98) for 22:5n-3, and 0.92 (0.86, 0.99) for 22:6n-3, respectively. No significant association was found for saturated fatty acids, monounsaturated fatty acids, n-6 polyunsaturated fatty acids or FA ratios. The present study suggested that erythrocyte n-3 PUFAs, especially 22:5n-3 and 22:6n-3, are inversely associated with prevalence of sleep disturbance in Chinese children and adolescents.
... Such regulatory function of VLC-SFA in synaptic transmission is novel and markedly different from other lipid or lipophilic substances previously tested that acted via a receptor. For instance, platelet-activating factor (PAF) has been shown to serve a critical modulatory effect on pre-synaptic events, but all of its effects, including an influence on long-term potentiation and memory formation, were prevented by PAF receptor inhibitors [65][66][67][68]. ...
Article
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Lipids are essential components of the nervous system. However, the functions of very long-chain fatty acids (VLC-FA; ≥ 28 carbons) in the brain are unknown. The enzyme ELOngation of Very Long-chain fatty acids-4 (ELOVL4) catalyzes the rate-limiting step in the biosynthesis of VLC-FA (Agbaga et al., Proc Natl Acad Sci USA 105(35): 12843–12848, 2008; Logan et al., J Lipid Res 55(4): 698–708, 2014), which we identified in the brain as saturated fatty acids (VLC-SFA). Homozygous mutations in ELOVL4 cause severe neuropathology in humans (Ozaki et al., JAMA Neurol 72(7): 797–805, 2015; Mir et al., BMC Med Genet 15: 25, 2014; Cadieux-Dion et al., JAMA Neurol 71(4): 470–475, 2014; Bourassa et al., JAMA Neurol 72(8): 942–943, 2015; Aldahmesh et al., Am J Hum Genet 89(6): 745–750, 2011) and are post-natal lethal in mice (Cameron et al., Int J Biol Sci 3(2): 111–119, 2007; Li et al., Int J Biol Sci 3(2): 120–128, 2007; McMahon et al., Molecular Vision 13: 258–272, 2007; Vasireddy et al., Hum Mol Genet 16(5): 471–482, 2007) from dehydration due to loss of VLC-SFA that comprise the skin permeability barrier. Double transgenic mice with homozygous knock-in of the Stargardt-like macular dystrophy (STDG3; 797-801_AACTT) mutation of Elovl4 with skin-specific rescue of wild-type Elovl4 expression (S⁺Elovl4mut/mut mice) develop seizures by P19 and die by P21. Electrophysiological analyses of hippocampal slices showed aberrant epileptogenic activity in S⁺Elovl4mut/mut mice. FM1-43 dye release studies showed that synapses made by cultured hippocampal neurons from S⁺Elovl4mut/mut mice exhibited accelerated synaptic release kinetics. Supplementation of VLC-SFA to cultured hippocampal neurons from mutant mice rescued defective synaptic release to wild-type rates. Together, these studies establish a critical, novel role for ELOVL4 and its VLC-SFA products in regulating synaptic release kinetics and epileptogenesis. Future studies aimed at understanding the molecular mechanisms by which VLC-SFA regulate synaptic function may provide new targets for improved seizure therapies. Electronic supplementary material The online version of this article (10.1007/s12035-017-0824-8) contains supplementary material, which is available to authorized users.
... Additionally, essential fatty acids have been involved with the production of prostaglandins. Prostaglandins are believed to be the most potent endogenous sleep-promotion substance and are well known to mediate sleep/wake regulation 27 and responses of synaptic circuitry to sleep deprivation 28 . Epidemiological studies have also demonstrated significant associations between increased fish intake and improved sleep measures in adults 29,30 as well as infants 25,26 and children 31 . ...
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Greater fish consumption is associated with improved cognition among children, but the mediating pathways have not been well delineated. Improved sleep could be a candidate mediator of the fish-cognition relationship. This study assesses whether 1) more frequent fish consumption is associated with less sleep disturbances and higher IQ scores in schoolchildren, 2) such relationships are not accounted for by social and economic confounds, and 3) sleep quality mediates the fish-IQ relationship. In this cohort study of 541 Chinese schoolchildren, fish consumption and sleep quality were assessed at age 9-11 years, while IQ was assessed at age 12. Frequent fish consumption was related to both fewer sleep problems and higher IQ scores. A dose-response relationship indicated higher IQ scores in children who always (4.80 points) or sometimes (3.31 points) consumed fish, compared to those who rarely ate fish (all p < 0.05). Sleep quality partially mediated the relationship between fish consumption and verbal, but not performance, IQ. Findings were robust after controlling for multiple sociodemographic covariates. To our knowledge, this is the first study to indicate that frequent fish consumption may help reduce sleep problems (better sleep quality), which may in turn benefit long-term cognitive functioning in children.
... Excesul de PAF favorizează degradarea neuronilor. Astfel acțiunea inhibatorie a trilactonelor joacă un rol important în protejarea neuronilor și prevenirea atacurilor ischemice la nivel cerebral (Smith et al. 1996;Smith & Luo, 2004;Chen & Bazan, 2005;Ramassamy et al. 2007;Balayev et al. 2008;Ude et al. 2013). De asemenea, în studiile realizate pe șobolani, trilactonele au prezentat activitate de blocare a canalelor de ioni de la nivelul neuronilor din hipocamp (Kressmann et al. 2002). ...
Article
The aim of this review is to describe Ginkgo biloba (Ginkgoaceae) morphology, main bioactive compounds and pharmaceutical properties. Ginkgo is the only surviving tree species of the order Ginkgoales and it has been used for hundred years in order to treat various diseases. Nowadays, G. biloba extracts have become one of the most studied and sold herbal medicinal products. Leaves contain terpene trilactones, biflavones, flavonol glycosides, alkylphenols, proanthocyanidins, simple phenolic acids, polyprenols, 4-O-methylpyridoxine. There are numerous studies published about the in vitro and in vivo pharmacological effects and mechanisms of these extracts and its components. G. biloba cures cognitive deficits and also has antioxidant and free radical scavenging activities in animals. The extracts are wideused for treating or preventing cognitive decline, claudication, dementia, and cerebral insufficiency. Ginkgo biloba L., denumit popular Arborele pagodelor, este singura specie a genului Ginkgo din familia Ginkgoaceae. Poate fi descris ca un arbore cu ramificația simpodială, cu talia de aproximativ 30 m, frunze caduce în formă de evantai, pieloase, bilobate, uneori aproape semicirculare, cu nervațiune dicotomică, neregulat incizate, dințate sau sinuate, pețiolate, de 5-8 cm lungime, grupate pe microblaste. Cilindrul central variază de la protostel la eustel în funcție de vârstă. Lemnul secundar este format din traheide cu punctuațiuni areolate, iar scoarța și măduva tulpinii sunt prevăzute cu canale secretoare de substanțe mucilaginoase. Florile sunt unisexuate, repartizate dioic; microsporofilele florilor bărbătești au aspectul unor filamente ce poartă în vârf câte doi saci polenici și sunt reunite pe un ax amentiform. Grăuncioarele de polen sunt lipsite de saci aeriferi. Macrosporofilele, la florile femeiești au aspectul unor pedunculi cu doi lobi foarte scurți, care susțin în vârf două ovule ortotrope mari cu cameră polenică. Fecundația se petrece ca și la cicadopside, iar embrionul este slab diferențiat. Sarcotesta este partea externă a
... In addition, ETS capacity (VO 2 rate induced by FCCP) was lower in the TG compared with the CG (online Supplementary Data). This reduction in ETS capacity also caused a decrease in respiratory reserve capacity (Fig. 4), indicating that liver mitochondria from TG offspring is already working near their bioenergetics limit, possibly because of alterations in mitochondrial architecture (42) and/or respiratory complex activities (7) . The respiratory parameters in the IG were not significantly affected when compared with the CG and PG ( Fig. 2 and 3), despite the same alterations in unsaturated FA composition and glucose homoeostasis observed in the TG (Tables 3 and 4). ...
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The quality of dietary lipids in the maternal diet can programme the offspring to diseases in later life. We investigated whether the maternal intake of palm oil or interesterified fat, substitutes for trans -unsaturated fatty acids (FA), induces metabolic changes in the adult offspring. During pregnancy and lactation, C57BL/6 female mice received normolipidic diets containing partially hydrogenated vegetable fat rich in trans -unsaturated fatty acids (TG), palm oil (PG), interesterified fat (IG) or soyabean oil (CG). After weaning, male offspring from all groups received the control diet until day 110. Plasma glucose and TAG and liver FA profiles were ascertained. Liver mitochondrial function was accessed with high-resolution respirometry by measuring VO 2 , fluorimetry for detection of hydrogen peroxide (H 2 O 2 ) production and mitochondrial Ca ²⁺ uptake. The results showed that the IG offspring presented a 20 % increase in plasma glucose and both the IG and TG offspring presented a 2- and 1·9-fold increase in TAG, respectively, when compared with CG offspring. Liver MUFA and PUFA contents decreased in the TG and IG offspring when compared with CG offspring. Liver MUFA content also decreased in the PG offspring. These modifications in FA composition possibly affected liver mitochondrial function, as respiration was impaired in the TG offspring and H 2 O 2 production was higher in the IG offspring. In addition, mitochondrial Ca ²⁺ retention capacity was reduced by approximately 40 and 55 % in the TG and IG offspring, respectively. In conclusion, maternal consumption of trans -unsaturated and interesterified fat affected offspring health by compromising mitochondrial bioenergetics and lipid metabolism in the liver.
... The mechanism of action of ibuprofen largely depends on its inhibition of COX [23] and the main products of COX activity are the prostaglandins, which in turn are lipid mediators important in modulation of many brain activities. For instance, the activity of COX-2, one of two isoforms of COX, is involved in synaptic activity and plasticity, hippocampal long-term potentiation (LTP) and maturation of the brain (reviewed: [24,25]). In one of the aforementioned epidemiology studies of acetaminophen, ibuprofen was ruled out as a possible confounding cause of the developmental neurotoxic effects [19]. ...
Article
Both Δ(9)-tetrahydrocannabinol (THC) and ibuprofen have analgesic properties by interacting with the cannabinoid receptor type 1 (CB1R) and the cyclooxygenase (COX) systems, respectively. Evaluation of these analgesics is important not only clinically, since they are commonly used during pregnancy and lactation, but also to compare them with acetaminophen, with a known interaction with both CB1R and the COX systems. Short-term exposure of neonatal rodents to acetaminophen during the first weeks of postnatal life, which is comparable with a period from the third trimester of pregnancy to the first years of postnatal life in humans, induces long-term behavioral disturbances. This period, called the brain growth spurt (BGS) and is characterized by series of rapid and fundamental changes and increased vulnerability, peaks around postnatal day (PND) 10 in mice. We therefore exposed male NMRI mice to either THC or ibuprofen on PND 10. At 2 month of age, the mice were subjected to a spontaneous behavior test, consisting of a 60min recording of the variables locomotion, rearing and total activity. Mice exposed to THC, but not ibuprofen, exhibited altered adult spontaneous behavior and habituation capability in a dose-dependent manner. This highlights the potency of THC as a developmental neurotoxicant, since a single neonatal dose of THC was enough to affect adult cognitive function. The lack of effect from ibuprofen also indicates that the previously seen developmental neurotoxicity of acetaminophen is non-COX-mediated. These results might be of importance in future research as well as in the ongoing risk/benefit assessment of THC.
... Another aspect that deserves further investigation is the possible modulation of neurotrophins, including BDNF, by dietary PUFAs [14]. The mammalian central nervous system is enriched in docosahexaenoic acid (DHA) [22:6 omega-3] and arachidonic acid (AA) [20:4(n-6)], which not only have a role as sources for membrane synthesis and energy production, but are also involved in cell signalling, gene transcription and neuronal plasticity [30]. In particular, DHA and BDNF may be associated with the same signalling pathway to promote neurogenesis in the adult primate brain [31]. ...
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Purpose: A gluten-free diet (GFD) has been reported to negatively impact the quality of life (QoL) of coeliac disease (CD) patients. The gut-brain axis hormones ghrelin and leptin, with the brain-derived neurotrophic factor (BDNF), may affect QoL of CD patients undergoing GFD. Our aims were to evaluate whether: (a) the circulating concentrations of leptin, ghrelin and BDNF in CD patients were different from those in healthy subjects; (b) GFD might induce changes in their levels; (c) BDNF Val66Met polymorphism variability might affect BDNF levels; and (d) serum BDNF levels were related to dietary docosahexaenoic acid (DHA) as a neurotrophin modulator. Methods: Nineteen adult coeliac patients and 21 healthy controls were included. A QoL questionnaire was administered, and serum concentrations of ghrelin, leptin, BDNF and red blood cell membrane DHA levels were determined at the enrolment and after 1 year of GFD. BDNF Val66Met polymorphism was analysed. Results: Results from the questionnaire indicated a decline in QoL after GFD. Ghrelin and leptin levels were not significantly different between groups. BDNF levels were significantly (p = 0.0213) lower in patients after GFD (22.0 ± 2.4 ng/ml) compared to controls (31.2 ± 2.2 ng/ml) and patients at diagnosis (25.0 ± 2.5 ng/ml). BDNF levels correlated with DHA levels (p = 0.008, r = 0.341) and the questionnaire total score (p = 0.041, r = 0.334). Conclusions: Ghrelin and leptin seem to not be associated with changes in QoL of patients undergoing dietetic treatment. In contrast, a link between BDNF reduction and the vulnerability of CD patients to psychological distress could be proposed, with DHA representing a possible intermediate.
... The neuroprotective effects of lipids have been well documented in the literature (see [49] and [50] for review). Previous studies indicated that the down-regulation of sphingolipids (which include SM lipids) with C18-C24 fatty acid side chains were linked to the degeneration of cerebellar Purkinje and granule cells in the cerebellum, and the accumulation of lipofuscin and ubiquitin in the CA3 hippocampal region of mice [51,52]. ...
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Slight changes in the abundance of certain lipid species in the brain may drastically alter normal neurodevelopment via membrane stability, cell signalling, and cell survival. Previous findings have demonstrated that postnatal exposure to di (2-ethylhexyl) phthalate (DEHP) disrupts normal axonal and neural development in the hippocampus. The goal of the current study was to determine whether postnatal exposure to DEHP alters the lipid profile in the hippocampus during postnatal development. Systemic treatment with 10 mg/kg DEHP during postnatal development led to elevated levels of phosphatidylcholine and sphingomyelin in the hippocampus of female rats. There was no effect of DEHP exposure on the overall abundance of phosphatidylcholine or sphingomyelin in male rats or of lysophosphatidylcholine in male or female rats. Individual analyses of each identified lipid species revealed 10 phosphatidylcholine and six sphingomyelin lipids in DEHP-treated females and a single lysophosphatidylcholine in DEHP-treated males with a two-fold or higher increase in relative abundance. Our results are congruent with previous work that found that postnatal exposure to DEHP had a near-selective detrimental effect on hippocampal development in males but not females. Together, results suggest a neuroprotective effect of these elevated lipid species in females.
... Some of the neuroprotective effects of DHA involve sub-products of its metabolism called docosanoids, especially neuroprotectin D1 (NPD1). Under conditions of inflammation and/or oxidative stress, NPD1 is able to reduce pro-apoptotic agents such as caspase-3, Bad and Bax, as well as to inhibit cyclooxigenase-2 activation and the pro-inflammatory factor NF-kB (Marcheselli et al., 2003;Chen and Bazan, 2005;Bazan et al., 2011;Mukherjee et al., 2004). Recent evidence has also shown that an ethanolamide derivative of DHA, called Ndocosahexaenoylethanolamide (DEA) is a mediator of the DHA-induced increase in neurite outgrowth and synaptogenesis in hippocampal neurons (Kim et al., 2011a,b). ...
... Alternatively, pharmacological inhibition of Cox-1 using Valeryl Salicylate in a model of global cerebral ischemia with 5 min occlusion increased the number of healthy neurons in the hippocampal CA1 even after 7 days post-ischemia [232]. Under normal conditions, Cox-2 is involved in synaptic plasticity and cerebrovascular regulation [233,234]. Whereas, under disease conditions, their reaction products have a major role in glutamate excitotoxicity [235]. Cox-2, an essential isoform for prostanoid synthesis, has been reported to be enhanced within the ischemic border zone in rat models of focal cerebral ischemia [236]. ...
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Abstract Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration. The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit. Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage. In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses. Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury. Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.
... Lipids partake in diverse and critical biological roles, such as in cell signaling [1][2][3], membrane function and integrity [4], alveoli functioning [5], energy storage [6], and water retention in the skin [7] and eyes [8]. These varied biological roles are achieved through the vast heterogeneity and complexity in lipid structure, distribution, and concentration. ...
Article
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Background Lipidomics, the comprehensive measurement of lipids within a biological system or substrate, is an emerging field with significant potential for improving clinical diagnosis and our understanding of health and disease. While lipids diverse biological roles contribute to their clinical utility, the diversity of lipid structure and concentrations prove to make lipidomics analytically challenging. Without internal standards to match each lipid species, researchers often apply individual internal standards to a broad range of related lipids. To aid in standardizing and automating this relative quantitation process, we developed LipidMatch Normalizer (LMN) http://secim.ufl.edu/secim-tools/ which can be used in most open source lipidomics workflows. Results LMN uses a ranking system (1–3) to assign lipid standards to target analytes. A ranking of 1 signifies that both the lipid class and adduct of the internal standard and target analyte match, while a ranking of 3 signifies that neither the adduct or class match. If multiple internal standards are provided for a lipid class, standards with the closest retention time to the target analyte will be chosen. The user can also signify which lipid classes an internal standard represents, for example indicating that ether-linked phosphatidylcholine can be semi-quantified using phosphatidylcholine. LMN is designed to work with any lipid identification software and feature finding software, and in this study is used to quantify lipids in NIST SRM 1950 human plasma annotated using LipidMatch and MZmine. Conclusions LMN can be integrated into an open source workflow which completes all data processing steps including feature finding, annotation, and quantification for LC-MS/MS studies. Using LMN we determined that in certain cases the use of peak height versus peak area, certain adducts, and negative versus positive polarity data can have major effects on the final concentration obtained.
... For example, PGE2 has been shown to be proconvulsive and neurotoxic (Kunz and Oliw, 2001;Oliveira et al., 2008), while PGF2alpha has inhibitory action on seizures (Kim et al., 2008). The application of PGE2 to pyramidal CA1 neurons increases frequency of firing and excitatory postsynaptic potentials amplitude, most likely by reducing K + currents in neurons (Chen and Bazan, 2005). PGE2 synthesis leads also to the production of reactive oxygen species (ROS) as intermediate products, that in turn can potentiate glutamate-mediated effects (Dawson et al., 1991). ...
Article
Neuroinflammation and reactive oxygen and nitrogen species are rapidly induced in the brain after acute cerebral injuries that are associated with an enhanced risk for epilepsy in humans and related animal models. These phenomena reinforce each others and persist during epileptogenesis as well as during chronic spontaneous seizures. Anti-inflammatory and anti-oxidant drugs transiently administered either before, or shortly after the clinical onset of symptomatic epilepsy, similarly block the progression of spontaneous seizures, and may delay their onset. Moreover, neuroprotection and rescue of cognitive deficits are also observed in the treated animals. Therefore, although these treatments do not prevent epilepsy development, they offer clinically relevant disease-modification effects. These therapeutic effects are mediated by targeting molecular signaling pathways such as the IL-1β−IL-1 receptor type 1 and TLR4, P2X7 receptors, the transcriptional anti-oxidant factor Nrf2, while the therapeutic impact of COX-2 inhibition for reducing spontaneous seizures remains controversial. Some anti-inflammatory and anti-oxidant drugs that are endowed of disease modification effects in preclinical models are already in medical use and have a safety profile, therefore, they provide potential re-purposed treatments for improving the disease course and for reducing seizure burden. Markers of neuroinflammation and oxidative stress can be measured in blood or by neuroimaging, therefore they represent testable prognostic and predictive biomarkers for selecting the patient‘s population at high risk for developing epilepsy therefore eligible for novel treatments. This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.
... For example, PGE2 has been shown to be proconvulsive and neurotoxic (Kunz and Oliw, 2001;Oliveira et al., 2008), while PGF2alpha has inhibitory action on seizures (Kim et al., 2008). The application of PGE2 to pyramidal CA1 neurons increases frequency of firing and excitatory postsynaptic potentials amplitude, most likely by reducing K + currents in neurons (Chen and Bazan, 2005). PGE2 synthesis leads also to the production of reactive oxygen species (ROS) as intermediate products, that in turn can potentiate glutamate-mediated effects (Dawson et al., 1991). ...
... COX-2 inhibition prevents long-term potentiation of the perforant-path synapse to the dentate granule cells (Chen et al., 2002). After selective inhibition of COX-2, the excitability of hippocampal CA1 pyramidal neurons and dendritic membranes significantly reduced, which may be due to alterations in potassium currents (Chen and Bazan, 2005). COX-2 can also transform arachidonic acid into prostaglandin and other harmful substances to promote inflammation (Xu et al., 2020). ...
Article
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The transcriptional regulator nuclear factor kappa B (NF-κB) modulates cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. The NF-κB pathway plays a major role in the expressing genes related to inflammation, including chemokines, interleukins, and tumor necrosis factor. It also transcribes genes that can promote neuronal survival or apoptosis. Epilepsy is one of the most common brain disorders and it not only causes death worldwide but also affects the day-to-day life of affected individuals. While epilepsy has diverse treatment options, there remain patients who are not sensitive to the existing treatment methods. Recent studies have implicated the critical role of NF-κB in epilepsy. It is upregulated in neurons, glial cells, and endothelial cells, due to neuronal loss, glial cell proliferation, blood-brain barrier dysfunction, and hippocampal sclerosis through the glutamate and γ-aminobutyric acid imbalance, ion concentration changes, and other mechanisms. In this review, we summarize the functional changes caused by the upregulation of NF-κB in the central nervous system during different periods after seizures. This review is the first to deconvolute the complicated functions of NF-κB, and speculate that the regulation of NF-κB can be a safe and effective treatment strategy for epilepsy.
... They generally act locally, close to the place of synthesis through G-protein-coupled receptors [4]. In the brain, eicosanoids and other oxylipins play an important role in many physiological processes [5], such as neuroinflammation [6], cerebral blood flow regulation [7], neuroprotection [8], regulation of temperature [9] and sleep [10], maturation of brain [11] and pain [12], thus making these pathways critical targets in drug discovery. They can also be used as possible biomarkers of pathological processes such as oxidative stress [13] and inflammation [14]. ...
Article
Oxylipins are key lipid mediators of important brain processes, including pain, sleep, oxidative stress and inflammation. For the first‐time, an in‐depth profile of up to 52 oxylipins can be obtained from the brains of awake moving animals using in vivo solid‐phase microextraction (SPME) chemical biopsy tool in combination with liquid chromatography – high resolution mass spectrometry. Among these, 23 oxylipins are detectable in the majority of healthy wildtype samples. This new approach successfully eliminates the changes in oxylipin concentrations routinely observed during the analysis of post‐mortem samples, allows time‐course monitoring of their concentrations with high spatial resolution in specific brain regions of interest and can be performed using the same experimental set‐up as in vivo microdialysis (MD) thus providing a new and exciting tool in neuroscience and drug discovery.
... It appears that SD and insomnia lead to overproduction of COX-2 then increasing in PGD2 and decreasing in PGE2. This suggests that these lipid molecules participate in memory consolidation during REM sleep [300]. For mentioning the effects of these events on neurons and synapse plasticity, a study shows blocking COX-2 by synthetic and soluble Aβ prevents the inhibition of hippocampal long-term plasticity (LTP) and leads to restoration of synaptic function [301]. ...
Article
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Alzheimer’s disease (AD) is the most common type of dementia and a neurodegenerative disorder characterized by memory deficits especially forgetting recent information, recall ability impairment, and loss of time tracking, problem-solving, language, and recognition difficulties. AD is also a globally important health issue but despite all scientific efforts, the treatment of AD is still a challenge. Sleep has important roles in learning and memory consolidation. Studies have shown that sleep deprivation (SD) and insomnia are associated with the pathogenesis of Alzheimer’s disease and may have an impact on the symptoms and development. Thus, sleep disorders have decisive effects on AD; this association deserves more attention in research, diagnostics, and treatment, and knowing this relation also can help to prevent AD through screening and proper management of sleep disorders. This study aimed to show the potential role of SD and insomnia in the pathogenesis and progression of AD.
... Interestingly, the gene CCDC68, coiledcoil domain containing 68, has been shown to be significantly associated with the sleep disturbance phenotype in genome wide association studies (81)(82)(83). Moreover, PLSCR2, phospholipid scramblase 2, and TNK1, tyrosine kinase non-receptor 1, are involved in phospholipid metabolism, which is significant because lipid signaling and is associated with both sleep and synaptic function (84). ACSF3, an acyl co-A synthetase, was also identified as differentially methylated and plays a role in fatty acid synthesis (85), which is a critical process that sustains brain energy metabolism during sleep (86). ...
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Background: Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigation of blast-related neurotrauma. We have undertaken human studies involving military “breachers” —exposed to controlled, low-level blast during a 3-days explosive breaching course. Methods: We screened epigenetic profiles in peripheral blood samples from 59 subjects (in two separate U.S. Military training sessions) using Infinium MethylationEPIC BeadChips. Participants had varying numbers of exposures to blast over their military careers (empirically defined as high ≥ 40, and conversely, low < 39 breaching exposures). Daily self-reported physiological symptoms were recorded. Tinnitus, memory problems, headaches, and sleep disturbances are most frequently reported. Results: We identified 14 significantly differentially methylated regions (DMRs) within genes associated with cumulative blast exposure in participants with high relative to low cumulative blast exposure. Notably, NTSR1 and SPON1 were significantly differentially methylated in high relative to low blast exposed groups, suggesting that sleep dysregulation may be altered in response to chronic cumulative blast exposure. In comparing lifetime blast exposure at baseline (prior to exposure in current training), and top associated symptoms, we identified significant DMRs associated with tinnitus, sleep difficulties, and headache. Notably, we identified KCNN3, SOD3, MUC4, GALR1, and WDR45B, which are implicated in auditory function, as differentially methylated associated with self-reported tinnitus. These findings suggest neurobiological mechanisms behind auditory injuries in our military warfighters and are particularly relevant given tinnitus is not only a primary disability among veterans, but has also been demonstrated in active duty medical records for populations exposed to blast in training. Additionally, we found that differentially methylated regions associated with the genes CCDC68 and COMT track with sleep difficulties, and those within FMOD and TNXB track with pain and headache. Conclusion: Sleep disturbances, as well as tinnitus and chronic pain, are widely reported in U.S. military service members and veterans. As we have previously demonstrated, DNA methylation encapsulates lifetime exposure to blast. The current data support previous findings and recapitulate transcriptional regulatory alterations in genes involved in sleep, auditory function, and pain. These data uncovered novel epigenetic and transcriptional regulatory mechanism underlying the etiological basis of these symptoms. © Copyright © 2020 Wang, Wilson, Ge, Nemes, LaValle, Boutté, Carr, Kamimori and Haghighi.
... PAF is also a potent activator of inflammatory cells involved in the innate immune system, including neutrophils, macrophages and platelets. It is also a potent neuromodulator 37 . Both LPC and PAF are glycerophospholipids that are derived from the parent lipid phosphatidylcholine (PC) (Fig. 3A). ...
Article
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Blood serum is enriched in lipids and has provided a platform to understand the pathogenesis of a number of human diseases with improved diagnosis and development of biomarkers. Understanding lipid changes in neurodegenerative diseases is particularly important because of the fact that lipids make up >50% of brain tissues. Frontotemporal dementia (FTD) is a common cause of early onset dementia, characterized by brain atrophy in the frontal and temporal regions, concomitant loss of lipids and dyslipidemia. However, little is known about the link between dyslipidemia and FTD pathophysiology. Here, we utilized an innovative approach – lipidomics based on mass spectrometry – to investigate three key aspects of FTD pathophysiology – mitochondrial dysfunction, inflammation, and oxidative stress. We analyzed the lipids that are intrinsically linked to neurodegeneration in serum collected from FTD patients and controls. We found that cardiolipin, acylcarnitine, lysophosphatidylcholine, platelet-activating factor, o-acyl-ω-hydroxy fatty acid and acrolein were specifically altered in FTD with strong correlation between the lipids, signifying pathophysiological changes in FTD. The lipid changes were verified by measurement of the common disease markers (e.g. ATP, cytokine, calcium) using conventional assays. When put together, these results support the use of lipidomics technology to detect pathophysiological changes in FTD.
... They generally act locally, close to the place of synthesis through G-protein-coupled receptors [4]. In the brain, eicosanoids and other oxylipins play an important role in many physiological processes [5], such as neuroinflammation [6], cerebral blood flow regulation [7], neuroprotection [8], regulation of temperature [9] and sleep [10], maturation of brain [11] and pain [12], thus making these pathways critical targets in drug discovery. They can also be used as possible biomarkers of pathological processes such as oxidative stress [13] and inflammation [14]. ...
Article
Oxylipins are key lipid mediators of important brain processes, including pain, sleep, oxidative stress and inflammation. For the first‐time, an in‐depth profile of up to 52 oxylipins can be obtained from the brains of awake moving animals using in vivo solid‐phase microextraction (SPME) chemical biopsy tool in combination with liquid chromatography – high resolution mass spectrometry. Among these, 23 oxylipins are detectable in the majority of healthy wildtype samples. This new approach successfully eliminates the changes in oxylipin concentrations routinely observed during the analysis of post‐mortem samples, allows time‐course monitoring of their concentrations with high spatial resolution in specific brain regions of interest and can be performed using the same experimental set‐up as in vivo microdialysis (MD) thus providing a new and exciting tool in neuroscience and drug discovery.
... Además, el DHA inhibe la formación de PGE2 en neuroblastomas73 .La acción de COX2 en el sistema nervioso permite la síntesis de PGE2 que tiene efectos sobre la plasticidad neuronal, sináptica, sobre la memoria y aumenta la actividad excitatoria del hipocampo. Sin embargo, el aumento de PGD2 y disminución de PGE2 favorece la consolidación de la memoria durante el sueño en la fase de movimientos oculares rápidos (REM)74 .Recientemente se ha demostrado que a partir de DHA se genera un derivado llamado Maresina (MaR1) con potente actividad antiinflamatoria en macrófagos ...
Article
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The functionality of the eukaryotic cell depends on the cell membrane, the genetic information and action of different organelles with or without the presence of membranes. The functionality of the cell membrane and organelles containing it depends primarily on the type and location of fatty acids in the phospholipids and the type of enzymes associated with them, this allows the fatty acids to be metabolized to new species that exert various functions. From this perspective, some essential fatty acids (EFAs) that produce metabolites that exert health benefits are identified, (for example antiinflammatory, neuroprotection, etc) and exert negative effects metabolites (eg inflammation, necrosis promoters, atheroma, etc.) are also generated. In general, these adverse or beneficial effects depend on the ratio of omega-6/omega-3 obtained in the diet. Thus, the higher this ratio is more negative effect; therefore the challenge of the current supply is obtained through food consumption, lower ratios in these fatty acids. The present review aims to present recent evidence on the effects of some AGEs, and the role of diet in maintaining health. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.
Article
Current first-line treatments for major depressive disorder (MDD), i.e., antidepressant drugs and psychotherapy, show delayed onset of therapeutic effect as late as 2-3 weeks or more. In the clinic, the speed of beginning of the actions of antidepressant drugs or other interventions is vital for many reasons. Late-onset means that depression, its related disability, and the potential danger of suicide remain a threat for some patients. There are some rapid-acting antidepressant interventions, such as sleep deprivation, ketamine, acute exercise, which induce a significant response, ranging from a few hours to maximally one week, and most of them share a common characteristic that is the activation of the endocannabinoid (eCB) system. Activation of this system, i.e., augmentation of eCB signaling, appears to have anti-depressant-like actions. This article puts the idea forward that the activation of eCB signaling represents a critical mechanism of rapid-acting therapeutic interventions in MDD, and this system might contribute to the development of novel rapid-acting treatments for MDD.
Article
Polyunsaturated fatty acids (PUFAs) are essential for brain development and function. Increasing evidence has shown that an imbalance of PUFAs is associated with various human psychiatric disorders, including autism and schizophrenia. However, the mechanisms underlying the effects of PUFAs on brain functions at cellular and molecular levels remain unclear. Since PUFAs are insoluble in water, specific transporters are required to deliver PUFAs to appropriate intracellular compartments. Fatty acid-binding proteins (FABPs), the cellular chaperones of PUFAs, are involved in PUFA intracellular trafficking, signal transduction, and gene transcription. Therefore, we focused on the relationship between FABP-regulated PUFA homeostasis in the brain and neuronal plasticity. The authors previously reported that FABP3, which preferentially binds to n-6 PUFAs, is strongly expressed in the gamma-aminobutyric acid (GABAergic) inhibitory interneurons of the adult mouse anterior cingulate cortex (ACC), which is a component of the limbic cortex and is important for the coordination of cognitive and emotional behaviors. Interestingly, Fabp3 KO mice show increased GABA synthesis and abnormal excitatory/inhibitory balance in the ACC. In addition, studies have indicated that FABP7, which preferentially binds to n-3 PUFAs, controls lipid raft function in astrocytes, and astrocytic Fabp7 deficiency results in an altered response of astrocytes to external stimuli. Furthermore, Fabp7 KO mice exhibit aberrant dendritic morphology, and decreased spine density and excitatory synaptic transmission in pyramidal neurons. This review summarizes relationship between PUFAs or FABPs and human psychiatric disorders and discusses recent progress in elucidating the function of FABPs, especially FABP3 and 7, in the brain.
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The endocannabinoid (EC) system, consisting of ECs, their synthesizing and degrading enzymes, specific transmembrane EC transporters and receptors, is located in both excitatory and inhibitory synapses of all the classical neurotransmitter types throughout the central and peripheral nervous systems, where it acts as a retrograde signaling mechanism to inhibit further release of transmitter. This form of synaptic plasticity is a major component of both rapid short-term and sustained long-term adaptive responses that underlie such processes as homeostasis, learning, memory, and extinction. The functional effects on any given pathway can be either inhibitory or excitatory, depending on whether excitatory (e.g., glutamatergic) or inhibitory (e.g., GABAergic) modulation normally predominates in that pathway. However, the dose-effect curves of EC activity are in many instances biphasic, because sustained strong activity leads to EC receptor desensitization and down-regulation, resulting in progressive loss or even reversal of the effect. Therefore the effects of cannabis and exogenous cannabinoids, of both plant and synthetic origin, are in many cases different from, or even opposite to, those of the EC system.
Article
In recent years, interesterified fat (IF) has largely replaced trans fat in industrialized food. Studies of our research group showed that IF consumption may not be safe for central nervous system (CNS) functions. Our current aim was to evaluate IF maternal consumption before conception on cognitive performance of adult rat offspring. Female Wistar rats were fed with standard chow plus 20% soybean and fish oil mix (control group) or plus 20% IF from weaning until adulthood (before mating), when the diets were replaced by standard chow only. Following the gestation and pups' development, locomotion and memory performance followed by neurotrophin immunocontent and fatty acids (FA) profile in the hippocampus of the adulthood male offspring were quantified. Maternal IF consumption before conception decreased hippocampal palmitoleic acid incorporation, proBDNF and BDNF levels, decreasing both exploratory activity and memory performance in adult offspring. Considering that, the adult male offspring did not consume IF directly, further studies are needed to understand the molecular mechanisms and if the IF maternal preconception consumption could induce the epigenetic changes observed here. Our outcomes reinforce an immediate necessity to monitor and / or question the replacement of trans fat by IF with further studies involving CNS functions.
Article
An increasing number of studies show that both inflammation and neural plasticity act as key players in the vulnerability and recovery from psychiatric disorders and neurodegenerative diseases. However, the interplay between these two players has been limitedly explored. In fact, while a few studies reported an immune activation, others conveyed an immune suppression, associated with an impairment in neural plasticity. Therefore, we hypothesized that deviations in inflammatory levels in both directions may impair neural plasticity. We tested this hypothesis experimentally, by acute treatment of C57BL/6 adult male mice with different doses of two inflammatory modulators: lipopolysaccharide (LPS), an endotoxin, and ibuprofen (IBU), a nonselective cyclooxygenase inhibitor, which are respectively a pro- and an anti-inflammatory agent. The results showed that LPS and IBU have different effects on behavior and inflammatory response. LPS treatment induced a reduction of body temperature, a decrease of body weight and a reduced food and liquid intake. In addition, it led to increased levels of inflammatory markers expression, both in the total hippocampus and in isolated microglia cells, including Interleukin (IL)-1β, and enhanced the concentration of prostaglandin E2 (PGE2). On the other hand, IBU increased the level of anti-inflammatory markers, decreased tryptophan 2,3-dioxygenase (TDO2), the first step in the kynurenine pathway known to be activated during inflammatory conditions, and PGE2 levels. Though LPS and IBU administration differently affected mediators related with pro- or anti-inflammatory responses, they produced overlapping effects on neural plasticity. Indeed, higher doses of both LPS and IBU induced a statistically significant decrease in the amplitude of long-term potentiation (LTP), in Brain-Derived Neurotrophic Factor (BDNF) expression levels and in the phosphorylation of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluR1, compared to the control group. Such effect appears to be dose-dependent since only the higher, but not the lower, dose of both compounds led to a plasticity impairment. Overall, the present findings indicate that acute treatment with pro- and anti-inflammatory agents impair neural plasticity in a dose dependent manner.
Chapter
During postnatal development, connections between retinal ganglion cells and their subcortical targets form precise topographical maps that are normally achieved through the selective elimination of misplaced axons and the stabilization of correct sets of axon terminals. Most of the fine tuning of visual connections is dependent on neural activity and occurs during a critical period that is defined as a fairly limited time window when developing neural connections display a maximal ability to sculpt highly specific circuits. We discuss the role of omega-3 fatty acids in the development of visual connections and the consequences of the nutritional restriction of such essential fatty acids in animal models. As a result of omega-3/docosahexaenoic acid (DHA) restriction, malnourished litters displayed abnormal wiring patterns with increased innervation density in major subcortical visual targets - the lateral geniculate nucleus and superior colliculus - that suggests both a delay in axonal elimination and also impairment in mechanisms involved in synaptic maintenance. We also suggest that a low omega-3 diet produces an abnormally extended critical period that might impair the normal ability to develop precisely connected neuronal populations. Since our results point to a delay in the formation of sensory visual circuits, we raise concerns about the impact of such nutritional imbalance in the development of visual acuity and other sensory, motor, and cognitive skills.
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As lipids account for about half of the brain tissue dry weight, it is not surprising that lipid biochemistry, neurochemistry, membrane structure and function have evolved together with our knowledge of brain function, including studies on ageing.The lipids in the brain are both a structural component of cell membranes and act as regulators. The amount of lipids in the brain varies spatially, from one region to another, and temporally, with age. The main lipids in the brain are phospholipids, of which phosphatidyl-ethanolamines (including plasmalogens) are the most abundant and are most affected by age. They are followed by phosphatidyl-choline, phosphatidyl-serine and phospho-inositides. Although these last two are the least abundant, they are important in signal transduction. The phosphatidyl-glycerols, mainly cardiolipins, are present in mitochondrial membranes. Sphingolipids (sphingomyelin, cerebrosides, sulfatides) are mainly found in myelin, while others, like gangliosides, are found in all structures. Ceramides could be involved in apoptose during brain ageing. Lastly, there are very few triglycerides in the brain.Lipids containing long chain fatty acids (and their derivatives) and some essential fatty acids, like ALA, LA and DHA should be part of the diet. Therefore, diet is a key environmental factor that influences the structure and function of the nervous system - and consequently ageing. The fatty acid profile changes with age and each phospholipid in a given tissue (central or peripheral nervous system, retina, white or grey matter), cell, and organelle has a characteristic fatty acid composition. This is particularly so for myelin, which has typically very long chains of saturated, mono-unsaturated and alpha-hydroxylated fatty acids, and nerve-endings (synaptosomes, highly polyunsaturated).The brain has a very high content of omega-3 polyunsaturated fatty acids and these fats are involved in several neuropsychiatric diseases (depression, Alzheimer's disease) and in the cognitive decline that occurs with age. There is growing evidence from observational, epidemiological, biological biochemical studies that omega-3 polyunsaturated fatty acids can protect the brain against ageing and dementia. They may act by protecting neurones, and/or have anti-amyloid, anti-oxidant, anti-inflammatory and anti-atherogenic properties.As docosahexaenoic acid (DHA) is a primary component of membrane phospholipids in the brain, an adequate omega-3 polyunsaturated fatty acid status is needed to maintain membrane integrity and neurone function; it may also protect against disease.Most reliable studies have been performed on animals, as the composition of human tissues, including brain lipid and fatty acid composition, may change post-mortem, due to cause of death, duration of any disease, delay before analysis, or temperature.
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Effects of strong stress inducing diffuse damage of the brain tissue on subsequent sleep were studied in rats preliminary implanted with chronic electrodes for the neocortical and hippocampal EEG as well as EMG of the neck muscles. An acute and three chronic experimental models were used: general cerebral ischemia induced by a permanent unilateral occlusion of the common carotid artery, hypoxic hypoxia, hypoglycemia, and "penicillinium" epilepsy. Polysomnographic recording was performed either continuously within 24 hrs (in case of the chronic stress model) or 3 hrs daily: from 09 to 12 a.m. (for three acute stress models). In all the models, a significant increase in the paradoxical sleep (PS) percentage was found which reached its maximum within 1-3 days since stress exposure. The following changes were found to be dependent upon the character of the stress factor. In acute stress models, the PS percentage returned to the baseline level within 5-6 days. In the chronic model, the PS percentage returned to baseline level on the 40-45th day after the day of occlusion. The sharp increase in the PS percentage following the exposure to stress factors inducing cerebral tissue damage corroborate the hypothesis of an increase in neural tissue restitution processes during PS periods.
Chapter
Unabated neuroinflammation plays a pathogenic role in various CNS diseases. In epilepsy, neuroinflammation is not a bystander phenomenon of the diseased brain but contributes to neuronal hyperexcitability underlying seizure generation, cell loss, and neurological comorbidities. Several molecules that constitute the inflammatory milieu in the epileptogenic area activate intracellular signaling pathways in neurons, glia, and cellular components of the blood-brain barrier, resulting in pathologic modifications of cell function. These molecular entities ultimately lead to alterations in synaptic transmission and plasticity. The mechanisms activated by inflammatory molecules include rapid posttranslational changes in voltage-gated and receptor-coupled ion channels and transcriptional regulation of immune and nonimmune gene expression. These modes of action highlight an emerging neuromodulatory role of inflammatory molecules that differs from their classical functions as immune activation effectors in infection or autoimmunity. We review the main actions exerted by inflammatory molecules on target cells by selecting those with a demonstrated role in experimental seizures and discuss their relevance for human epilepsy.
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The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3-4-year recurring cycle of topics. These topics will be presented at the 2020 Virtual Conference. Below is the adult sleep medicine core that includes topics pertinent to sleep-disordered breathing and insomnia.
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Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling mediators that are engaged in both physiological and pathological processes in the brain. Recently, their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression. The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of proinflammatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins. Thus, AA metabolites have double-edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a contributor or even the basis for chronic neuroinflammatory effects. This review focuses on important evidence regarding eicosanoid-related pathways (with special emphasis on prostaglandins and lipoxins) that has added a new layer of complexity to the idea of targeting the double-edged AA-derivative pathways for therapeutic benefits in depression. We also sought to explore future research directions that can support a pro-resolving response to control the balance between eicosanoids and thus to reduce the chronic neuroinflammation that underlies at least a portion of depressive disorders.
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With the help of particulate matter, Benzo(a)pyrene (BaP) has become a widely distributed environmental contaminant. In addition to the well-known carcinogenicity, a growing number of studies have focused on the neurotoxicity of BaP, especially on adverse neurobehavioral effects. However, the molecular modulating mechanisms remain unclear. In this paper, we confirmed that BaP exposure produced a neuronal insult via its metabolite Benzo(a)pyrene diol epoxide (BPDE) on the primary cultured cortical neuron in vitro and mice in vivo models, and the effects were largely achieved by activating cyclooxygenases-2 (COX-2) enhancement. Also, the action of BaP on elevating COX-2 was initiated by BPDE firmly binding to the active pockets of COX-2, then followed by the production of prostaglandin E2 (PGE2) and upregulation of its EP2 and EP4 receptors, finally stimulating cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway. Our results reveal a mechanistic association underlying BaP exposure and increased risk for neurological dysfunction, and clarify the ways to prevent and treat brain injuries in polluted environments.
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We present an united-atom model (gb-fb15) for the molecular dynamics simulation of hydrated liquid-crystalline dipalmitoylphosphatidylcholine (DPPC) phospholipid bilayers. This model was constructed through the parameter-space minimization of a regularized least squares objective function via the ForceBalance method. The objective function was computed using a training set of experimental bilayer area per lipid and deuterium order parameter. This model was validated by comparison to experimental volume per lipid, x-ray scattering form factor, thermal area expansivity, area compressibility modulus and lipid lateral diffusion coefficient. These comparisons demonstrate that gb-fb15 is robust to temperature variation and an improvement over the original model for both the training and validation properties.
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A novel simple and selective electrochemical procedure is utilized for the determination of Dinoprostone (DIN) in drug substance and pharmaceutical preparation with good recovery and without interference with other excipient. Herein, the electrochemical sensing platform based upon preparing gold nanoparticle sensor on silica modified carbon paste electrode. The surface morphology of the modified electrode was characterized by scanning electron microscope. Different experimental conditions, including electrode composition, effect of pH and scan rate were estimated carefully by cyclic voltammetry to obtain the highest electrochemical response. By using square wave voltammetry a good linear response was obtained in the range of, 2 x 10-5-4 x10-4 mol L-1, and 2 x 10-7-1.6 x 10-4 mol L-1, with low detection limit of 5 x 10-6 mol L-1, and 4.9 x 10-8 mol L-1 by CPE and GNP/SMCPE respectively. The obtained results are in good agreement with those obtained by official method. No electrochemical method was reported before for determination of DIN. The developed method was simple, rapid, economic and challenging to green analytical chemistry.
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Neuroscience, Ophthalmology, Stroke, Epilepsy
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The cellular and molecular events that take place during brain development play an important role in governing function of the mature brain. Lipid signalling molecules such as prostaglandin E2 (PGE2) play an important role in healthy brain development. Abnormalities along the COX/PGE2 signalling pathway due to genetic or environmental causes have been linked to Autism Spectrum Disorders (ASDs). This study aims to evaluate the effect of altered COX/PGE2 signalling on development and function of the prenatal brain using male mice lacking cyclooxygenase-1 and -2 (COX-1-/- and COX-2-/-) as potential model systems of ASD. Microarray analysis was used to determine global changes in gene expression during embryonic days 16 (E16) and 19 (E19). Gene Ontology: Biological Process (GO:BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were implemented to identify affected developmental genes and cellular processes. We found that in both knockouts the brain at E16 had nearly twice as many differentially expressed genes and affected biological pathways containing various ASD associated genes important in neuronal function. Interestingly, using GeneMANIA and Cytoscape we also show that the ASD-risk genes identified in both COX-1-/-and COX-2-/- models belong to protein-interaction networks important for brain development despite of different cellular localization of these enzymes. Lastly, we identified 8 genes that belong to the Wnt signalling pathways exclusively in the COX-2-/- mice at E16. The level of PKA-phosphorylated β-catenin (S552), a major activator of the Wnt pathway, was increased in this model, suggesting cross-talk between the COX-2/PGE2 and Wnt pathways during early brain development. Overall, these results provide further molecular insight into the contribution of the COX/PGE2 pathways to ASD and demonstrate that COX-1-/- and COX-2-/- animals might be suitable new model systems for studying the disorders.
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Epilepsy is a brain disease associated with epileptic seizures as well as with neurobehavioral outcomes of this condition. In the last century, inflammation emerged as a crucial factor in epilepsy etiology. Various brain insults through activation of neuronal and non-neuronal brain cells initiate a series of inflammatory events. Growing observations strongly suggest that abnormal activation of critical inflammatory processes contributes to epileptogenesis, a gradual process by which a normal brain transforms into the epileptic brain. Increased knowledge of inflammatory pathways in epileptogenesis has unveiled mechanistic targets for novel antiepileptic therapies. Molecules specifically targeting the pivotal inflammatory pathways may serve as promising candidates to halt the development of epilepsy. The present paper reviews the pieces of evidence conceptually supporting the potential role of inflammatory mechanisms and the relevant blood-brain barrier (BBB) disruption in epileptogenesis. Also, it discusses the mechanisms underlying inflammation-induced neuronal-glial network impairment and highlights innovative neuroregulatory actions of typical inflammatory molecules. Finally, it presents a brief analysis of observations supporting the therapeutic role of inflammation-targeting tiny molecules in epileptic seizures.
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Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) are involved in the pathogenesis of Alzheimer's disease (AD), which is characterized by the accumulation of β-amyloid protein (Aβ) and tau hyperphosphorylation. However, the gaps in our knowledge of the roles of COX-2 and PGs in AD have not been filled. Here, we summarized the literature showing that COX-2 dysregulation obviously influences abnormal cleavage of β-amyloid precursor protein, aggregation and deposition of Aβ in β-amyloid plaques and the inclusion of phosphorylated tau in neurofibrillary tangles. Neuroinflammation, oxidative stress, synaptic plasticity, neurotoxicity, autophagy, and apoptosis have been assessed to elucidate the mechanisms of COX-2 regulation of AD. Notably, an imbalance of these factors ultimately produces cognitive decline. The current review substantiates our understanding of the mechanisms of COX-2-induced AD and establishes foundations for the design of feasible therapeutic strategies to treat AD.-Guan, P.-P. and Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer's disease.
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Traumatic brain injury (TBI) leads to changes in ion fluxes, alterations in mitochondrial function and increased generation of reactive oxygen species, resulting in secondary tissue damage. Mitochondria play important signaling roles in coordination of multiple metabolic platforms in addition to their well-known role in bioenergetics. Mitochondrial signaling strongly depends on cardiolipin (CL), a mitochondria-specific structurally unusual anionic phospholipid containing four fatty acyl chains. While our previous reports indicated that CL is selectively oxidized and presents itself as a target for the redox therapy following TBI, the topography of changes of CL in the injured brain remained to be defined. Here we present a MALDI imaging study which reports regio-specific changes in CL, in a controlled cortical impact (CCI) model of TBI in rats. MALDI imaging revealed that TBI caused early decreases in CL in the contusional cortex, ipsilateral hippocampus and thalamus with the most highly unsaturated CL species being most susceptible to loss. Phosphatidylinositol was the only other lipid species that exhibited a significant decrease, albeit to a lesser extent than CL. Signals for other lipids remained unchanged. This is the first study evaluating the spatial distribution of CL loss after acute brain injury. We propose that the CL loss may constitute an upstream mechanism for CL-driven signaling in different brain regions as an early response mechanism and may also underlie the bioenergetic changes that occur in hippocampal, cortical and thalamic mitochondria after TBI. This article is protected by copyright. All rights reserved.
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The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.
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Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.
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Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and up-regulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia. Using rat models for SD and focal ischemia we investigated the expression of cyclooxygenase-1 (COX-1), the constitutive form, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme in prostaglandin biosynthesis and the target enzymes for nonsteroidal anti-inflammatory drugs. Whereas COX-1 mRNA levels were undetectable and uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia. The cortical induction was reduced by MK-801, an N-methyl-d-aspartic acid-receptor antagonist, and by dexamethasone and quinacrine, phospholipase A2 (PLA2) inhibiting compounds. MK-801 acted by blocking SD whereas treatment with PLA2 inhibitors preserved the wave propagation. NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-receptor antagonist, did not affect the SD-induced COX-2 expression, whereas COX-inhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, NG-nitro-l-arginine methyl ester, tended to enhance the COX-2 mRNA expression. In addition, ischemia induced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells. Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-d-aspartic acid-receptors and PLA2, most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.
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Marijuana is known to affect learning and memory in humans, and cannabinoids block long-term potentiation in the hippocampus, a model for the synaptic changes that are believed to underlie memory at the cellular level. We have now examined the physiological properties of the Schaffer collateral-CA1 synapses in mutant mice in which the CB1 receptor gene has been invalidated and found that these animals exhibit a half-larger long-term potentiation than wild-type controls. Other properties of these synapses, such as paired-pulse facilitation, remained unchanged. This indicates that disrupting CB1 receptor-mediated neurotransmission at the genome level produces mutant mice with an enhanced capacity to strengthen synaptic connections in a brain region crucial for memory formation.
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Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), which is thought to be a retrograde messenger in long-term potentiation (LTP), enhances glutamate release and LTP through an action on presynaptic nerve endings. The PAF antagonist BN 52021 blocks CA1 LTP in hippocampal slices, and, when infused into rat dorsal hippocampus pre- or posttraining, blocks retention of inhibitory avoidance. Here we report that memory is affected by pre- or posttraining infusion of the PAF analog 1-O-hexadecyl-2-N-methylcarbamoyl-sn-glycerol-3-phosphocholine (mc-PAF) into either rat dorsal hippocampus, amygdala, or entorhinal cortex. Male Wistar rats were implanted bilaterally with cannulae in these brain regions. After recovery from surgery, the animals were trained in step-down inhibitory avoidance or in a spatial habituation task and tested for retention 24 h later. mc-PAF (1.0 microgram per side) enhanced retention test performance of the two tasks when infused into the hippocampus before training without altering training session performance. In addition, mc-PAF enhanced retention test performance of the avoidance task when infused into (i) the hippocampus 0 but not 60 min after training; (ii) the amygdala immediately after training; and (iii) the entorhinal cortex 100 but not 0 or 300 min after training. In confirmation of previous findings, BN 52021 (0.5 microgram per side) was found to be amnestic for the avoidance task when infused into the hippocampus or the amygdala immediately but not 30 or more minutes after training or into the entorhinal cortex 100 but not 0 or 300 min after training. These findings support the hypothesis that memory involves PAF-regulated events, possibly LTP, generated at the time of training in hippocampus and amygdala and 100 min later in the entorhinal cortex.
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A molecule isolated from the cerebrospinal fluid of sleep-deprived cats has been chemically characterized and identified as cis-9,10-octadecenoamide. Other fatty acid primary amides in addition to cis-9,10-octadecenoamide were identified as natural constituents of the cerebrospinal fluid of cat, rat, and human, indicating that these compounds compose a distinct family of brain lipids. Synthetic cis-9,10-octadecenoamide induced physiological sleep when injected into rats. Together, these results suggest that fatty acid primary amides may represent a previously unrecognized class of biological signaling molecules.
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Marijuana has been in use for over 4000 years as a therapeutic and as a recreational drug. Within the past decade, two cannabinoid receptor types have been identified, their signal transduction characterized, and an endogenous lipid agonist isolated from mammalian tissues. The CB1 cannabinoid receptor is widely distributed in mammalian tissues, with the highest concentrations found in brain neurons. CB1 receptors are coupled to modulation of adenylate cyclase and ion channels. The CB2 receptor is found in cells of the immune system and is coupled to inhibition of adenylate cyclase. Both receptor types selectively bind delta 9-THC, the active principle in marijuana, and anandamide (arachidonylethanolamide), an endogenous cannabimimetic eicosanoid. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity, mice with genetic deletion of the cannabinoid receptors, and receptor-specific antibodies, which should help in providing a better understanding of the physiological role of the cannabinoid receptors.
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Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.
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The localization of cannabinoid (CB) receptors to GABAergic interneurons in the hippocampus indicates that CBs may modulate GABAergic function and thereby mediate some of the disruptive effects of marijuana on spatial memory and sensory processing. To investigate the possible mechanisms through which CB receptors may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage-clamp recordings were performed on CA1 pyramidal neurons in rat brain slices. Stimulus-evoked GABA(A) receptor-mediated IPSCs were reduced in a concentration-dependent manner by the CB receptor agonist WIN 55,212-2 (EC(50) of 138 nM). This effect was blocked by the CB1 receptor antagonist SR141716A (1 microM) but not by the opioid antagonist naloxone. In contrast, evoked GABA(B)-mediated IPSCs were insensitive to the CB agonist. WIN 55,212-2 also reduced the frequency of spontaneous, action potential-dependent IPSCs (sIPSCs), without altering action potential-independent miniature IPSCs (mIPSCs), measured while sodium channels were blocked by tetrodotoxin (TTX). Blockade of voltage-dependent calcium channels (VDCCs) by cadmium also eliminated the effect of WIN 55,212-2 on sIPSCs. Depolarization of inhibitory terminals with elevated extracellular potassium caused a large increase in the frequency of mIPSCs that was inhibited by both cadmium and WIN 55,212-2. The presynaptic effect of WIN 55,212-2 was also investigated using the potassium channel blockers barium and 4-aminopyridine. Neither of these agents significantly altered the effect of WIN 55,212-2 on evoked IPSCs. Together, these data suggest that presynaptic CB1 receptors reduce GABA(A)- but not GABA(B)-mediated synaptic inhibition of CA1 pyramidal neurons by inhibiting VDCCs located on inhibitory nerve terminals.
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Cyclooxygenase isozymes (COX-1 and COX-2) are found to be constitutively expressed in brain, with neuronal expression of COX-2 being rapidly induced after numerous insults, including cerebral ischemia. Because overactivation of N-methyl-D-aspartate (NMDA) receptors has been implicated in the cell loss associated with ischemia, we characterized the expression of the COX isozymes in murine mixed cortical cell cultures and used isozyme-selective inhibitors to determine their relative contribution to NMDA receptor-stimulated prostaglandin (PG) production and excitotoxic neuronal cell death. Immunocytochemical analysis of mixed cortical cell cultures revealed that COX-2 expression was restricted to neurons, whereas COX-1 was expressed in both neurons and astrocytes. Brief exposure to NMDA (5 min; 100 microM) elicited a time-dependent accumulation of PGs in the culture medium that preceded neuronal cell death and correlated with the induction of COX-2 mRNA. COX-1 expression remained unchanged. Flurbiprofen, a nonselective COX-1/COX-2 inhibitor, blocked NMDA-stimulated PG production and attenuated neuronal death in a concentration-dependent manner. Similar results were obtained with the specific COX-2 inhibitor NS-398 (10-30 microM) but not with the selective COX-1 inhibitor valeryl salicylate (10-300 microM). Inhibition of total constitutive COX activity with aspirin (100 microM, 1.5 h) before NMDA exposure did not prevent subsequent NMDA-mediated neuronal cell death. However, neuronal injury in aspirin-pretreated cultures was attenuated by flurbiprofen administration after NMDA exposure. Finally, the protection afforded by COX-2 inhibition was specific for NMDA because neither flurbiprofen nor NS-398 protected neurons against kainate-mediated neurotoxicity. Together, these results support the conclusion that newly synthesized COX-2 protein contributes to NMDA-induced neuronal injury.
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Platelet-activating factor (PAF) is a phospholipid with potent, diverse physiological actions, particularly as a mediator of inflammation. The synthesis, transport, and degradation of PAF are tightly regulated, and the biochemical basis for many of these processes has been elucidated in recent years. Many of the actions of PAF can be mimicked by structurally related phospholipids that are derived from nonenzymatic oxidation, because such compounds can bind to the PAF receptor. This process circumvents much of the biochemical control and presumably is regulated primarily by the rate of degradation, which is catalyzed by PAF acetylhydrolase. The isolation of cDNA clones encoding most of the key proteins involved in regulating PAF has allowed substantial recent progress and will facilitate studies to determine the structural basis for substrate specificity and the precise role of PAF in physiological events.
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Whole-cell patch-clamp and intracellular recording techniques have been used to study the action of prostaglandin E2 (PGE2) on neurons in adult rat transverse spinal cord slices. Bath-applied PGE2 (1-20 microm) induced an inward current or membrane depolarization in the majority of deep dorsal horn neurons (laminas III-VI; 83 of 139 cells), but only in a minority of lamina II neurons (6 of 53 cells). PGE2 alone never elicited spontaneous action potentials; however, it did convert subthreshold EPSPs to suprathreshold, leading to action potential generation. PGE2-induced inward currents were unaffected by perfusion with either a Ca(2+)-free/high Mg(2+) (5 mm) solution or tetrodotoxin (1 microm), indicating a direct postsynaptic action. Both 17-phenyl trinor prostaglandin E2 (an EP1 agonist) and sulprostone (an EP3 agonist) had little effect on membrane current, whereas butaprost methyl ester (an EP2 agonist) mimicked the effect of PGE2. Depolarizing responses to PGE2 were associated with a decrease in input resistance, and the amplitude of inward current was decreased as the holding potential was depolarized. PGE2-induced inward currents were reduced by substitution of extracellular Na(+) with N-methyl-d-glucamine and inhibited by flufenamic acid (50-200 microm), which is compatible with activation of a nonselective cation channel. These results suggest that PGE2, acting via an EP2-like receptor, directly depolarizes spinal neurons. Moreover, these findings imply an involvement of spinal cord-generated prostanoids in modulating sensory processing through an alteration in dorsal horn neuronal excitability.
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The functional significance of cyclooxygenases (COX-1 and -2), the key enzymes that convert arachidonic acid (AA) to prostaglandins (PGs) in brain, is unclear, although they have been implicated in cellular functions and in some neurologic disorders, including stroke, epilepsy, and Alzheimer's disease. Recent evidence that COX-2 is expressed in postsynaptic dendritic spines (which are specialized structures involved in synaptic signaling) and is regulated by synaptic activity implies participation of COX-2 in neuronal plasticity. However, direct evidence is lacking. Here we demonstrate that selective COX-2 inhibitors significantly reduced postsynaptic membrane excitability, back-propagating dendritic action potential-associated Ca ²⁺ influx, and long-term potentiation (LTP) induction in hippocampal dentate granule neurons, while a COX-1 inhibitor is ineffective. All of these actions were effectively reversed by exogenous application of PGE 2 but not of PGD 2 or PGF 2α . Our results indicate that COX-2-generated PGE 2 regulates membrane excitability and long-term synaptic plasticity in hippocampal perforant path-dentate gyrus synapses.
Chapter
Arachidonic acid is known to be metabolized into a number of bioactive eicosanoids such as prostaglandins, thromboxanes, leukotrienes, lipoxins and mono-and dihydroxyeicosatetraenoic acids. It is well known that these bioactive eicosanoids are involved in diverse physiological and pathophysiological processes in mammalian tissues. In the last decade of the 20th century, two remarkable derivatives of arachidonic acid, i.e., N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) (Fig. 1) were reported to be new members of the bioactive lipids. Anandamide and 2-AG have unique structural characteristic in that they contain an intact arachidonoyl moiety in their molecules, thus differing from other eicosanoids. Both anandamide and 2-AG have been shown to act as endogenous cannabinoid receptor ligands. In this review, we focused on anandamide and 2-AG and described the metabolism and possible physiological significance of these molecules in mammalian tissues and cells including inflammatory cells and immune competent cells.
Chapter
The prostaglandin endoperoxide H2 synthase (PGHS) isozymes 1 and 2 are membrane bound, heme-dependent enzymes that catalyze the committed step in the conversion of polyunsaturated fatty acids to prostanoids and thromboxanes. The PGHS isozymes, which are also known as cyclooxygenases, produce prostaglandin H2 in two sequential enzymatic steps – a bis-oxygenase (cyclooxygenase) reaction generates prostaglandin G2 from arachidonic acid and a hydroperoxidase reaction creates the final product, prostaglandin H2. The PGHS isozymes are also the primary targets of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and recent pharmacological research efforts have led to the development of isoform selective drugs like Celebrex® and Vioxx®. In this chapter, we discuss the biochemistry, enzymology, and the structural biology of the PGHS isozymes and their relevance to prostanoid physiology and NSAID pharmacology.
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Abstract A current hypothesis of sleep–wake regulation proposes that a sleep process would start with the activation of sleep-promoting neurons located in the preoptic area of the anterior hypothalamus. This activation leads to the inhibition of wake-promoting neurons located in the posterior hypothalamus, basal forebrain and mesopontine tegmentum, which, in turn, removes inhibition from the sleep-promoting structures, thereby enhancing the sleep process. Sleep-promoting neurons are supposed to contain γ-aminobutyric acid and inhibit cholinergic, noradrenergic, serotonergic or histaminergic wake-promoting neurons at sleep onset and during sleep. By comparison with this current active hypothesis of sleep, the present mini-review gives an overview of experimental evidence supporting the old passive reticular hypothesis of sleep, indicating that sleep may result from functional deafferentation from the tonic ascending reticular activity, the idea of which was advanced in the last century by Kleitman, Bremer, and Moruzzi and Magoun. We propose that sleep would start with a small reduction of the activity of the lower brain stem, in particular medullary monoaminergic and non-monoaminergic wake-active neurons, as a result of a decrease in external and internal stimuli exerting excitatory influences on these neurons. By the mechanism of a cascade of disfacilitating processes, this reduction of activity may lead to the inactivation of whole wake-promoting structures in the brain, resulting in the initiation of sleep; the disfacilitation hypothesis of sleep.
Article
We have characterized the rat prostanoid EP1, EP2, EP3alpha and EP4 receptor subtypes cloned from spleen, hepatocyte and/or kidney cDNA libraries. Comparison of the deduced amino acid sequences of the rat EP receptors with their respective homologues from mouse and human showed 91% to 98% and 82% to 89% identity, respectively. Radioreceptor binding assays and functional assays were performed on EP receptor expressing human embryonic kidney (HEK) 293 cells. The KD values obtained with prostaglandin E2 for the prostanoid receptor subtypes EP1, EP2, EP3alpha and EP4 were approximately 24, 5, 1 and 1 nM, respectively. The rank order of affinities for various prostanoids at the prostanoid receptor subtypes EP2, EP3alpha and EP4 receptor subtypes was prostaglandin E2 = prostaglandin E1 > iloprost > prostaglandin F2alpha > prostaglandin D2 > U46619. The rank order at the prostanoid EP1 receptor was essentially the same except that iloprost had the highest affinity of the prostanoids tested. Of the selective ligands, butaprost was selective for prostanoid EP2, M&B28767 and sulprostone were selective for EP3alpha and enprostil displayed dual selectivity, interacting with both prostanoid receptor subtypes EP1 and EP3alpha. All four receptors coupled to their predominant signal transduction pathways in HEK 293 cells. Notably, using a novel aequorin luminescence assay to monitor prostanoid EP1 mediated increases in intracellular calcium, both iloprost and sulprostone were identified as partial agonists. Finally, by Northern blot analysis EP3 transcripts were most abundant in liver and kidney whereas prostanoid EP2 receptor mRNA was expressed in spleen, lung and testis and prostanoid EP1 receptor mRNA transcripts were predominantly expressed in the kidney. The rat prostanoid EP1 probes also detected additional and abundant transcripts present in all the tissues examined. These were found to be related to the expression of a novel protein kinase gene and not the prostanoid EP1 gene [Batshake, B., Sundelin, J., 1996. The mouse genes for the EP1 prostanoid receptor and the novel protein kinase overlap. Biochem. Biophys. Res. Commun. 227. 1329-1333].
Article
Platelet-activating factor (PAF), an alkylether phospholipid, is produced in the brain when it is subjected to various stimuli. Using a Xenopus oocyte expression system, we obtained evidence for functional PAF receptor mRNA expression in rat brain. The presence of the PAF receptor was confirmed and shown to be quite ubiquitous in the CNS by RNA blot and radioligand binding studies. To investigate the neuronal functions of PAF, intracellular Ca2+ increase elicited by nanomolar PAF application was analyzed in cultured rat hippocampal cells. Fractions of NMDA-responsive cells and non-NMDA-responsive cells were shown to respond to PAF, suggesting a potential role for PAF in the Ca2+ signaling pathway in the hippocampus.
Article
The biologically active lipid platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine; PAF) is a mediator of inflammatory and immune responses, and it accumulates in the brain during convulsions or ischemia. We have examined whether PAF may play a second messenger role in the central nervous system by studying effects on synaptic transmission in cultured hippocampal neurons. Carbamyl-PAF, a nonhydrolyzable PAF analog with a similar pharmacologic profile, augmented glutamate-mediated, evoked excitatory synaptic transmission and increased the frequency of spontaneous miniature excitatory synaptic events without increasing their amplitude or altering their time course. This compound had no significant effect on gamma-aminobutyric acid-mediated inhibitory synaptic responses. Lyso-PAF, the biologically inactive metabolic intermediate, had no effect on synaptic transmission. Moreover, the enhancement of excitatory synaptic transmission by carbamyl-PAF was blocked by a PAF receptor antagonist. These results indicate a specific presynaptic effect of PAF in enhancing excitatory synaptic transmission in cultured rat hippocampal neurons.
Article
Platelet-activating factor (PAF) is a naturally occurring phospholipid that serves as a critical mediator in diverse biological and pathophysiological processes. In this study of the interactions of PAF with neuronal cells, it was found that PAF increased the intracellular levels of free calcium ions in cells of the clones NG108-15 and PC12. The increase was dependent on extracellular calcium and was inhibited by the antagonistic PAF analog CV-3988 and by the calcium-influx blockers prenylamine and diltiazem. A functional consequence of this interaction was revealed by measuring a PAF-elicited, Ca2+-dependent secretion of adenosine triphosphate from PC12 cells. Exposure of NG108-15 cells for 3 to 4 days to low concentrations of PAF induced neuronal differentiation; higher concentrations were neurotoxic. Thus, by influencing Ca2+ fluxes, PAF may play a physiological role in neuronal development and a pathophysiological role in the degeneration that occurs when neurons are exposed to circulatory factors as a result of trauma, stroke, or spinal cord injury.
Article
Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (IA) in cultured hippocampal cells. Because cannabinoid receptors inhibit adenylate cyclase, the present study explored whether cAMP played a role in mediating this effect on IA. The specific issue of whether cannabinoid receptor modulation of voltage-dependent IA acts via a cAMP-dependent process was investigated. The cAMP analog, 8-bromo-cAMP, as well as the adenylate cyclase stimulant forskolin, produced concentration-dependent shifts in IA that were opposite those produced by cannabinoid receptor ligands. Moreover, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also produced a marked negative shift in the steady-state voltage dependence of IA and increased the effect of forskolin on IA. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased IA via a decrease in steady-state voltage-dependent inactivation of IA. WIN 55,212-2 also reversed the effects of forskolin on IA. The electrophysiological studies were paralleled by direct assays of cAMP in these cells, where cannabinoids inhibited forskolin-stimulated cAMP by 50% in a pertussis toxin-sensitive manner. The results confirmed that pertussis toxin-sensitive cannabinoid receptor-mediated changes in IA were probably the result of inhibition of adenylate cyclase. The findings are discussed in terms of modulation of IA conductance properties via cannabinoid receptor-mediated inhibition of cAMP levels within the cell.
Article
Long-term potentiation (LTP) refers to a persisting enhancement of neurotransmission that follows high-frequency activation of certain synapses. Although both pre- and postsynaptic mechanisms contribute to LTP, it is believed that the enhanced release of neurotransmitter that accompanies this process results from the production of a diffusible messenger in postsynaptic neurons which traverses the synaptic cleft and alters the function of presynaptic terminals. One candidate for such a messenger is arachidonic acid, a metabolite produced by phospholipase A2 which augments synaptic transmission when coupled with presynaptic stimulation. However, the effects of arachidonic acid require activation of the postsynaptic receptor for N-methyl-D-aspartate. Previously we found that platelet-activating factor (1 O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), another phospholipase A2-derived messenger, selectively enhances excitatory postsynaptic currents in hippocampal neurons by a presynaptic mechanism. We now present evidence that platelet-activating factor, acting at a receptor localized to synaptic regions, participates in LTP in the CA1 region of rat hippocampal slices and may serve as part of a retrograde signalling cascade.
Article
Prostaglandins play important and diverse roles in the CNS. The first step in prostaglandin synthesis involves enzymatic oxidation of arachidonic acid, which is catalyzed by prostaglandin H(PGH) synthase, also referred to as cyclooxygenase. We have cloned an inducible form of this enzyme from rat brain that is nearly identical to a murine, mitogen-inducible cyclooxygenase identified from fibroblasts. Our studies indicate that this gene, here termed COX-2, is expressed throughout the forebrain in discrete populations of neurons and is enriched in the cortex and hippocampus. Neuronal expression is rapidly and transiently induced by seizures or NMDA-dependent synaptic activity. No expression is detected in glia or vascular endothelial cells. Basal expression of COX-2 appears to be regulated by natural synaptic activity in the developing and adult brain. Both basal and induced expression of COX-2 are inhibited by glucocorticoids, consistent with COX-2 regulation in peripheral tissues. Our studies indicate that COX-2 expression may be important in regulating prostaglandin signaling in brain. The marked inducibility in neurons by synaptic stimuli suggests a role in activity-dependent plasticity.
Article
Platelet-activating factor (PAF) is an ether phospholipid that serves as an autacoid in a wide range of biological processes. We found that when PAF was added to hippocampal slices, it induced a stable and concentration-dependent increase in excitatory postsynaptic potential and population spike recordings (long-term potentiation [LTP]). The PAF effect was blocked by the PAF receptor antagonists BN 52021 and WEB 2086 and the N-methyl-D-aspartate receptor antagonists MK 801 and 2-amino-5-phosphonovalerate. However, these PAF receptor antagonists did not block LTP induced by high frequency stimulation. The facilitation induced by PAF could not be reversed by PAF receptor antagonists. Induction of either PAF-or tetanus-triggered facilitation occluded the subsequent expression of the other, suggesting a common pathway. LTP is a type of synaptic plasticity associated with the formation of memory, and PAF may play an important modulatory role in this process.
Article
The effects of the central (CB1) cannabinoid receptor antagonist SR 141716A on the sleep-waking cycle were investigated in freely-moving rats using time scoring and power spectral analysis of the electroencephalogram (EEG). Over a 4-hour recording period, SR 141716A (0.1, 0.3, 1, 3, and 10 mg/kg I.P.) dose-dependently increased the time spent in wakefulness at the expense of slow-wave sleep (SWS) and rapid eye movement sleep (REMS), delayed the occurrence of REMS but did not change the mean duration of REMS episodes. Moreover, the compound induced no change in motor behavior. At the efficient dose of 3 mg/kg I.P., SR 141716A reduced the spectral power of the EEG signals typical of SWS but did not affect those of wakefulness. Taken together, these results demonstrate that the EEG effects of SR 141716A reflect arousal-enhancing properties. In addition, the present study suggests that an endogenous cannabinoid-like system is involved in the control of the sleep-waking cycle.
Article
Postnatal development and adult function of the central nervous system are dependent on the capacity of neurons to effect long-term changes of specific properties in response to neural activity. This neuronal response has been demonstrated to be tightly correlated with the expression of a set of regulatory genes which include transcription factors as well as molecules that can directly modify cellular signaling. It is hypothesized that these proteins play a role in activity-dependent response. Previously, we described the expression and regulation in brain of an inducible form of prostaglandin synthase/cyclooxygenase, termed COX-2. COX-2 is a rate-limiting enzyme in prostanoid synthesis and its expression is rapidly regulated in developing and adult forebrain by physiological synaptic activity. Here we demonstrate that COX-2 immunoreactivity is selectively expressed in a subpopulation of excitatory neurons in neo-and allocortices, hippocampus, and amygdala and is compartmentalized to dendritic arborizations. Moreover, COX-2 immunoreactivity is present in dendritic spines, which are specialized structures involved in synaptic signaling. The developmental profile of COX-2 expression in dendrites follows well known histogenetic gradients and coincides with the critical period for activity-dependent synaptic remodeling. These results suggest that COX-2, and its diffusible prostanoid products, may play a role in postsynaptic signaling of excitatory neurons in cortex and associated structures.
Previously the involvement of platelet-activating factor (PAF) as a retrograde messenger in the induction of long-term potentiation (LTP) in CA1 region of rat hippocampus has been reported (Kato, K. et al. (1994) Nature 367, 175-179). In this report, the effect of PAF receptor antagonist on LTP in the dentate gyrus has been demonstrated and suggests the existence of common mechanisms of LTP in Ca1 and dentate gyrus. The site responsible for the expression of LTP induced by PAF has also been examined. The frequency of miniature EPSCs were enhanced by application of a PAF analog, but median amplitude were unaffected, suggesting that PAF preferentially affects presynaptic sites. Evoked synaptic responses were also monitored and the potentiation by the PAF analog was observed. Interestingly, there is a discrepancy between the results observed in the miniature and evoked potential studies in terms of dose effect of PAF. This discrepancy could have resulted from repeated synaptic stimulations required for studying evoked responses. The requirement for a monitoring stimulation in the evoked response measurement could activate additional biological process that enhance LTP expression.
Article
Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predominately located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent (K(1/2) = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (omega-conotoxin-GVIA-sensitive) and P/Q-type (omega-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.