Epidemiological literatures show an association between air pollution and ischemic stroke, and effective pollutants may include SO₂, NO_x, O₃, CO, and particulates. However, existing experimental studies lack evidence as to the presence of effects for SO₂, 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 SO₂ 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 SO₂ 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 SO₂ 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, SO₂ inhalation after MCAO significantly amplified above effects. It implies that SO₂ 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.

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-1β 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.

PM2.5 (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. C57BL/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. PM2.5 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. Taken 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.