Increasing evidence suggests that cyclooxygenase-2 (COX-2) is involved in synaptic transmission and plasticity, and prostaglandin E2 (PGE2) is a key molecule in COX-2-meduated synaptic modification. However, the precise mechanisms, in particular, which subtypes of PGE2 receptors (EPs) mediate the PGE2-induced synaptic response, are not clear. Recently, we demonstrated that EPs are expressed heterogeneously in the hippocampus, and EP2/4 are mainly expressed in presynaptic terminals. Here, we report that PGE2 increased synaptic stimulus-evoked amplitudes of EPSPs in hippocampal slices and frequency of miniature EPSCs (mEPSCs) in hippocampal neurons in culture. These actions were mimicked by an EP2 agonist and attenuated by protein kinase A inhibitors. Decrease of EP2 expression through silencing the EP2 gene eliminated PGE2-induced increase of the frequency of mEPSCs. COX-2 and microsomal PGE synthase-1 (mPGES-1) and mPGES-2 are present in postsynaptic dendritic spines, because they are colocalized with PSD-95 (postsynaptic density-95), a postsynaptic marker. In addition, the frequency of mEPSCs was enhanced in neurons pretreated with interleukin-1␤ or lipopolysaccharide, which elevated expression of COX-2 and mPGES-1 and produced PGE2, and this enhancement was inhibited by a COX-2 inhibitor that inhibited production of PGE2. Our results suggest that PGE2 synthesized by postsynaptically localized COX-2 functions as a retrograde messenger in hippocampal synaptic signaling via a presynaptic EP2 receptor.

Epidemiological literatures show an association between air pollution and ischemic stroke, and effective pollutants may include SO(2), NO(x), O(3), CO, and particulates. However, existing experimental studies lack evidence as to the presence of effects for SO(2), which has been the focus in developing countries with increasing use of coal as the main resource. In the present study, we treated Wistar rats with SO(2) at various concentrations and determined endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and intercellular adhesion molecule 1 (ICAM-1) messenger RNA (mRNA) and protein expression in the cortex. The results show that SO(2) elevated the levels of ET-1, iNOS, COX-2, and ICAM-1 mRNA and protein in a concentration-dependent manner. Then, we set up rat model of ischemic stroke using middle cerebral artery occlusion (MCAO) and further treated the model rats with filtered air and lower concentration SO(2) for the same period. As expected, elevated expression of ET-1, iNOS, COX-2, and ICAM-1 occurred in the cortex of MCAO model rats exposed to filtered air, followed by increased activation of caspase-3 and cerebral infarct volume. Interestingly, SO(2) inhalation after MCAO significantly amplified above effects. It implies that SO(2) inhalation caused brain injuries similar to that of cerebral ischemia, and its exposure in atmospheric environment contributed to the development and progression of ischemic stroke.

The oxygenation of endogenous cannabinoids (eCBs) 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide by cyclooxygenase-2 (COX-2) produces novel types of prostanoids: prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs). However, the physiological function of COX-2 oxidative metabolites of eCBs is still unclear. Here we demonstrate that PGE 2 -G, a COX-2 oxidative metabolite of 2-AG, induced a concentration-dependent increase in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in primary cultured hippocampal neurons, an effect opposite to that of 2-AG. This increase was not inhibited by SR141716, a CB 1 receptor antagonist, but was attenuated by an IP 3 or MAPK inhibitor. In addition, we also examined the effects of other prostanoids derived from COX-2 oxygenation of eCBs on mIPSCs. PGD 2 -G, PGF 2α -G and PGD 2 -EA, but not PGE 2 -EA or PGF 2α -EA, also increased the frequency of mIPSCs. The eCB-derived prostanoid-induced responses appeared to be different from those of corresponding arachidonic acid-derived prostanoids, implying that these effects are not mediated via known prostanoid receptors. We further discovered that the inhibition of COX-2 activity reduced inhibitory synaptic activity and augmented depolarization-induced suppression of inhibition (DSI), whereas the enhancement of COX-2 augmented the synaptic transmission and abolished DSI. Our results, which show that COX-2 oxidative metabolites of eCBs exert opposite effects to their parent molecules on inhibitory synaptic transmission, suggest that alterations in COX-2 activity will have significant impact on endocannabinoid signalling in hippocampal synaptic activity.

Lipids are essential components of plasma- and organelle-membranes, not only providing a frame for embedded proteins (e.g., receptors and ion channels) but also functioning as reservoirs for lipid mediators. Increasing evidence indicates that bioactive lipids such as eicosanoids, endocannabinoids, and lysophospholipids serve as intercellular and intracellular signaling molecules participating in physiological and pathological functions in the brain. The discovery of some of these lipid receptors and novel lipid signaling mediators has sparked an intense interest in lipidomic neurobiology research. Classic prostaglandins (PGD(2), PGE(2), PGF(2alpha), PGI(2), and TXA(2)), catalyzed by cyclooxygenases (COX), are synthesized from arachidonic acid (AA). Experimental studies demonstrate that prostaglandin E(2) (PGE(2)), mainly derived from the COX-2 reaction, is an important mediator, acting as a retrograde messenger via a presynaptic PGE(2) subtype 2 receptor (EP(2)) in modulation of synaptic events. Novel prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides) are COX-2 oxidative metabolites of endogenous cannabinoids (2-arachidonyl glycerol and arachidonyl ethanolamide). Recent evidence suggests that these new types of prostaglandins are likely novel signaling mediators involved in synaptic transmission and plasticity. This means that COX- 2 plays a central role in metabolisms of AA and endocannabinoids (eCBs) and productions of AA- and eCB- derived prostaglandins. Thus, in the present review article, the authors will mainly discuss COX-2 regulation of prostaglandin signaling in modulation of hippocampal synaptic transmission and plasticity.

Neuroinflammation has been implicated in the pathogenesis of neurodegenerative diseases. Cyclooxygenase-2 (COX-2), an inducible enzyme converting arachidonic acid (AA) to prostaglandins, is the key player in neuroinflammation. It has been long thought that the COX-2-mediated neuronal injury/degeneration is attributed to the increased production of AA-derived prostaglandins. Recent studies show that endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is a natural substrate for COX-2, and it can be oxygenated by COX-2 to form prostaglandin glyceryl esters. In this study, we demonstrate that prostaglandin E(2) glyceryl ester (PGE(2)-G), a major COX-2 oxidative metabolite of 2-arachidonoylglycerol, enhanced hippocampal glutamatergic synaptic transmission indicated by the increased frequency of miniature excitatory post-synaptic currents, and induced neuronal injury/death revealed by the terminal transferase dUTP nick end labeling staining and caspase 3 activation. The actions of PGE(2)-G are not mediated via a cannabinoid receptor 1, but mediated through ERK, p38 mitogen-activated protein kinase, IP(3), and NF-kappaB signal transduction pathways. In addition, the PGE(2)-G-induced neurotoxicity is attenuated by blockade of the NMDA receptors. Our results suggest that the COX-2 oxidative metabolism of endocannabinoids is an important mechanism contributing to the inflammation-induced neurodegeneration.

On the basis of the close relationship between human exposure to high concentrations of small particulate matter (PM) and increased lung cancer mortality, PM was recently designated as a Group I carcinogen. Considering that PM is highly heterogeneous, the potential health risks of PM promoting tumor metastasis in lung cancer, as well as its chemical characteristics, remain elusive. In the present study, we collected PM2.5 and PM10 in a peri-urban residential site of Taiyuan and determined the concentration and source of polycyclic aromatic hydrocarbons (PAHs). The results indicated that 18 PAHs, ranging from 38.21 to 269.69 ng/m(3) (for PM2.5) and from 44.34 to 340.78 ng/m(3) (for PM10), exhibited seasonal variations, and the PAHs in winter PM mainly originated from coal combustion. We calculated the benzo(a)pyrene-equivalent (BaPeq) and found that the PAH-bound PM in winter exhibited higher carcinogenic risks for humans. Following this result, in vitro bioassays demonstrated that PM2.5 and PM10 induced A549 cell migration and invasion, and the mechanism involved reactive oxygen species (ROS)-mediated epithelial-to-mesenchymal transition (EMT) activation and extracellular matrix (ECM) degradation. Our data indicate the potential risk for winter PAH-bound PM from peri-urban North China promoting lung cancer cell metastasis and reveal a mechanistic basis for treating, ameliorating, or preventing outcomes in polluted environments.

BackgroundPM2.5 (particulate matter ≤ 2.5 μm) is one of the leading environmental risk factors for the global burden of disease. Whereas increasing evidence has linked the adverse roles of PM2.5 with cardiovascular and respiratory diseases, limited but growing emerging evidence suggests that PM2.5 exposure can affect the nervous system, causing neuroinflammation, synaptic dysfunction and cognitive deterioration. However, the molecular mechanisms underlying the synaptic and cognitive deficits elicited by PM2.5 exposure are largely unknown.MethodsC57BL/6 mice received oropharyngeal aspiration of PM2.5 (1 and 5 mg/kg bw) every other day for 4 weeks. The mice were also stereotaxically injected with β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1) shRNA or LV-miR-574-5p lentiviral constructs in the absence or presence of PM2.5 aspiration at 5 mg/kg bw every other day for 4 weeks. Spatial learning and memory were assessed with the Morris water maze test, and synaptic function integrity was evaluated with electrophysiological recordings of long-term potentiation (LTP) and immunoblot analyses of glutamate receptor subunit expression. The expression of α-secretase (ADAM10), BACE1, and γ-secretase (nicastrin) and the synthesis and accumulation of amyloid β (Aβ) were measured by immunoblot and enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA) expression was screened with a microRNA microarray analysis and confirmed by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Dual-luciferase reporter gene and chromatin immunoprecipitation (ChIP) analyses were used to detect the binding of miR-574-5p in the 3’UTR of BACE1 and NF-κB p65 in the promoter of miR-574-5p, respectively.ResultsPM2.5 aspiration caused neuroinflammation and deteriorated synaptic function integrity and spatial learning and memory, and the effects were associated with the induction of BACE1. The action was mediated by NF-κB p65-regulated downregulation of miR-574-5p, which targets BACE1. Overexpression of miR-574-5p in the hippocampal region decreased BACE1 expression, restored synaptic function, and improved spatial memory and learning following PM2.5 exposure.ConclusionsTaken together, our findings reveal a novel molecular mechanism underlying impaired synaptic and cognitive function following exposure to PM2.5, suggesting that miR-574-5p is a potential intervention target for the prevention and treatment of PM2.5-induced neurological disorders.Electronic supplementary materialThe online version of this article (10.1186/s12989-017-0215-3) contains supplementary material, which is available to authorized users.

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