Nitrogen dioxide (NO2) pollution as a potential risk factor for developing vascular dementia and its synaptic mechanisms

doi:10.1016/j.chemosphere.2013.02.061

Chemosphere

Volume 92, Issue 1, June 2013, Pages 52-58

https://doi.org/10.1016/j.chemosphere.2013.02.061 Get rights and content

Highlights

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NO₂ exposure weakened synaptic plasticity in stroke model rats.
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NO₂ exposure induced excitotoxicity in healthy rats.
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NO₂ exposure increased the risk of VaD after ischemic stroke.

Abstract

Recent epidemiological literatures reported that NO₂ is a potential risk factor of ischemic stroke in polluted area. Meanwhile, our previous in vivo study found that NO₂ could delay the recovery of nerve function after stroke, implying a possible risk of vascular dementia (VaD) with NO₂ inhalation, which is often a common cognitive complication resulting from stroke. However, the effect and detailed mechanisms have not been fully elucidated. In the present study, synaptic mechanisms, the foundation of neuronal function and viability, were investigated in both model rats of ischemic stroke and healthy rats after NO₂ exposure. Transmission electron microscope (TEM) observation showed that 5 mg m⁻³ NO₂ exposure not only exacerbated the ultrastructural impairment of synapses in stroke model rats, but also induced neuronal damage in healthy rats. Meantime, we found that the expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), two structural markers of synapses in ischemic stroke model were inhibited by NO₂ inhalation; and so it was with the key proteins mediating long-term potentiation (LTP), the major form of synaptic plasticity. On the contrary, NO₂ inhalation induced the expression of nearly all these proteins in healthy rats in a concentration-dependent manner. Our results implied that NO₂ exposure could increase the risk of VaD through inducing excitotoxicity in healthy rats but weakening synaptic plasticity directly in stroke model rats.

Introduction

VaD is the acquired chronic and progressive cognitive impairments caused by cerebrovascular diseases (CVDs), and the main type of senile dementia (Knopman, 2007). According to various estimates reported in the scientific literatures, vascular dementia may account for 5–20% of all cases of dementia, while the dementia affects nearly 35.6 million worldwide people presently (Igoumenou and Ebmeier, 2012, World Health Organization, 2012). VaD occurs when brain tissue is damaged because of reduced blood flow to the brain. The brain cells, in effect, have difficulty working together to process information, consequently lead to cognitive impairment including memory loss, confusion, and decreased attention span, in addition to problems with activities of daily living (National Stroke Association, 2012).

Environmental NO₂ is a potential risk factor for ischemic stroke. Recently, increasing epidemiological studies from Danish, Italy, Canada and other different geographic regions found significant correlation between level of NO₂ pollution and acute ischemic stroke (Villeneuve et al., 2006, Vidale et al., 2010, Andersen et al., 2012). We further confirmed this relevance through conducting NO₂ exposure to animals in a relatively independent environment to exclude the influence of other pollutants existed in epidemiological studies. Especially, we found that NO₂ exposure could not only cause ischemic stroke-like changes of hemorrheology in healthy rat, but also time-dependently delayed the neurological structure and function recovery of stroke model rats (Zhu et al., 2012), which implied a possible risk of vascular dementia (VaD) after NO₂ inhalation. However, no report has addressed the relationship between NO₂ exposure and VaD.

Cognitive function is postulated to be represented by vastly interconnected networks of synapses in the brain, so synaptic plasticity is considered to be one of the important neurochemical foundations of cognition, such as learning and memory (Kaiser and Peters, 2009). Several proteins associated with structural and functional plasticity join in the regulation of cognition. SYP and PSD-95 have been widely used for the visualization of the pre- and postsynaptic membranes as structural markers of synapses (Glantz et al., 2007). SYP has a role in the biogenesis of secretory vesicles, stabilizing and modifying the function of other synaptic proteins (Cao et al., 2011), while PSD-95 expression enhances postsynaptic clustering and activity of glutamate receptors and plays important roles in signal integration (Changeux and Edelstein, 2001). As one form of synaptic plasticity, LTP is essential for learning and memory and for activity-dependent regulation of synapse formation in the developing brain (Vara et al., 2003). It is suggested that formation and maintenance of LTP involves: (1) repeated intense synaptic activation that engages α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–type glutamate receptors (GluR), N-methyl D-aspartate (NMDA) receptors and Ca²⁺ influx; (2) activation of kinase cascades (major including protein kinase A (PKA), protein kinase C (PKC), calcium/calmodulin-dependent protein kinase II (CaMKII)) that trigger the initial increase in synaptic efficacy; (3) phosphorylation of extracellular regulated protein kinase (ERK1/2) and translocation of p-ERK into the nucleus; and (4) activation of gene expression, including cAMP response element-binding (CREB) transcription factor capable of activating secondary response genes and IEG “effectors” (like c-Fos and c-Jun protein) capable of modulating protein synthesis required by LTP maintenance (Akaneya and Tsumoto, 2006, Escobar and Derrick, 2007). It was demonstrated that cognitive impairment is not only the clinical manifestations of many neurological diseases including VaD, but also possibly a prodromal stage happened in the pre-clinical phase (Zhang and Wang, 2005). Therefore, how these synaptic factors will change in both stroke patients and healthy people when exposure to NO₂ environment becomes the key issue for we exploring the pathogenesis of VaD induced by NO₂.

NO₂ is the major component of automobile exhaust. In recent years, as the auto possession increases rapidly, the healthy impact caused by NO₂ pollution has caused more and more attention. Meantime, the number of dementia is expected to double by 2030 (65.7 million) and more than triple by 2050 (115.4 million) (World Health Organization, 2012), while environmental pollution was considered to be the potential cause. In the present study, we aimed to determine the relationship between NO₂ inhalation and VaD through investigating the pathological, molecular changes of synapses. The results of this study will reveal some clues for exploring the cause of VaD from the perspective of environment pollution, and provide basic information on prevention and clinical treatment for human populations.

Section snippets

Animal exposure and treatment protocols

Male healthy Wistar rats, 280–300 g, were purchased from Experimental Animal Center, Academy of Military Medical Sciences of Chinese PLA (Beijing, China). Rats were acclimatized (24 ± 2 °C, 50 ± 5% relative humidity, and 12-h light–dark cycle) for one week in a stainless steel cages, and given food and water ad libitum. Use of animals in this study was approved by the Institutional Animal Care and Use Committee of Shanxi University. The animals were treated humanely and with regard for alleviation of

Results

Compared to naïve control group, the mean body weight, morbidity, and related protein expression in the cortex of negative control rats did not show significant difference.

Discussion

NO₂ is a major pollutant of outdoor traffic exhaust and indoor secondhand smoke (SHS). Prior studies have found that NO₂ is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, especially VaD, so the interactions between NO₂ and VaD should be paid attention. However, up to now, no direct evidence has link NO₂ pollution to the increased morbidity and mortality of VaD, but there are some reports about the relevance of traffic exhaust and secondhand

Acknowledgment

This study was supported by Graduate Student Innovation Program of Shanxi (20103018).

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For example, it has been suggested that NO2 may induce the neurological disorders by damaging mitochondrial energy metabolism and impaired biogenesis in rat brain (Yan et al., 2015). In human research, epidemiological evidence and recent toxicological studies have been proved that higher level of air pollution exposure (especially NO2) may increasing risk of neurological disorders s and mental disorders, such as ischemic stroke, autism spectrum disorder, neurodevelopmental impairment and cognitive deficit (Li and Xin, 2013; Pelgrims et al., 2021; Kim et al., 2014; Jung et al., 2013). The special group of children and adolescents are more sensitive to environmental pollution components and are more susceptible to the adverse effects.
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Citation Excerpt :
SYP and PSD-95 are markers of synapse structures and their expression levels can represent the roughly numbers of synapse. What's more, they are key proteins mediating in the long-term potentiation (LTP) [37]. From immunohistochemistry, the lowest expression levels of SYP and PSD-95 in Model Group indicate drastic damage and loss of synapse owing to CCH.
Chronic Cerebral Hypoperfusion (CCH) is a common, crucial and tough problem for old people. It easily leads to Lacunar Infarction and even Vascular Dementia (VD). Western medicine has the advantage to relieve some VD symptoms but fails to cure it. Some classic Chinese medicines have good efficacies to treat and delay the cerebral functional decline resulted from CCH. Among them Modified Dioscorea Pills (MDP) has been proven to have a convincing effect in curing VD. So far the knowledge about neuroplasticity in CCH is little known and the underlying interfered mechanism by MDP on neuroplasticity has not yet been explored. This study explores the changes of neuroplasticity involving neurogenesis, angiogenesis and synaptogenesis in CCH and interfered by MDP.
40 male SD rats were divided into the Sham operated Group, the Model Group and the MDP Group according to a Random Number Table. Bilateral Common Carotid Arteries Occlusion (BCCAO) was adopted to prepare CCH models. MDP condense decoction had been administered by gavage to rats in the MDP Group (10g·Kg-1·d-1) for 45 days; Rats in the other two groups were accepted normal salts as substitution with same dosage and course. Through Morris Water Maze (MWM) test, pathological observation of hippocampus, ultrastructural study on synapse, Real Time Polymerase Chain Reaction (RT-PCR) and immunohistochemistry detection, the capacities of intelligence of rats, the morphological character of hippocampus CA1 zone and the synapse associated protein and gene such as Growth Associated Protein (GAP-43) mRNA, Vascular Endothelial Growth Factor (VEGF) mRNA, Microtubule-associated Protein (MAP)-2, Synaptophysin (SYP), Postsynaptic Density protein (PSD)-95 and Micro Vessel Density (MVD) were determined. Through one-way ANOVA the data was analyzed and when P＜0.05 the result was considered significant.
Compared to the Model Group, rats in the MDP Group achieved much better behavioral performance (P＜0.05); more neurons and more synapses regenerated; the expression of SYP, PSD-95and MAP-2 up-regulated (P＜0.05); The expressions of GAP-43 mRNA and VEGF mRNA in the Model Group were higher than those in the Sham operated Group (P＜0.05), but they reached the highest in the MDP Group (P＜0.05); The count of MVD in the Sham operated Group is the lowest, it is higher in the MDP Group and it reaches highest in the Model Group (P＜0.05).
Some key genes promoting neuroplasticity such as GAP-43 mRNA and VEGF mRNA remarkably up-regulated in CCH, they only boost angiogenesis but fail to facilitate neurogenesis and synaptogenesis in CCH. However, accompanied by furtherly up-regulation of these two key genes, MDP obviously improves neurogenesis, synaptogenesis and temperate angiogenesis in CCH which may be underlying its good efficacy.
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2019, Environment International
Evidence regarding the association of specific air pollutants with vascular dementia (VaD) risk is limited. In this nested case–control study, we enrolled 831 adults aged >65 years with VaD (International Classification of Diseases, Ninth Revision, Clinical Modification code 290.4x) newly diagnosed during 2005–2013; 3324 controls were age-, sex-, and VaD diagnosis year–matched with the study patients. Both patients with VaD and controls were selected from among a cohort of one million beneficiaries of Taiwan’s National Health Insurance program, all of whom were registered in 2005. Exposure to the mean daily air pollutant concentration, derived from 76 fixed air quality monitoring stations, in 3, 5, and 7 years before VaD diagnosis was assessed using the spatial analysis method (i.e., ordinary kriging) on ArcGIS. A logistic regression model was used to calculate covariate-adjusted odds ratios (ORs) of VaD in relation to specific air pollutants. After potential confounders and other air pollutants were controlled for, high concentrations of coarse particulate matter (10 µm or less in diameter) and carbon monoxide (CO) were sporadically associated with higher OR of VaD. The most prominent association was observed for nitrogen dioxide (NO₂) exposure within 5 and 7 years before diagnosis. Compared with the <25th percentile of NO₂ exposure, the 25th–50th, 50th–75th, and >75th percentiles of NO₂ exposure significantly increased ORs (95% confidence intervals): 1.62 (1.28–2.23), 1.61 (1.11–2.33), and 2.22 (1.35–3.65) within 5 years before diagnosis, respectively, and 1.59 (1.20–2.11), 1.65 (1.15–2.37), and 2.05 (1.28–3.28) within 7 years before diagnosis, respectively. We found that higher NO₂ exposure in the past was significantly associated with an elevated risk of VaD. Although less consistent, higher exposure to CO was also associated with a higher risk of VaD. Most NO₂ in cities originates from motor vehicle exhaust; other sources of NO₂ are petrol and metal refining, electricity generation from coal-fired power stations, other manufacturing industries, and food processing. Future studies should investigate associations of VaD with specific sources of NO₂.

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Nitrogen dioxide (NO2) pollution as a potential risk factor for developing vascular dementia and its synaptic mechanisms

Highlights

Abstract

Introduction

Section snippets

Animal exposure and treatment protocols

Results

Discussion

Acknowledgment

Neurosci. Lett.

Curr. Opin. Neurobiol.

Neuroscience

Mol. Cell Proteomics

Neurotoxicology

Brain Res. Bull.

Neuron

Pharmacol. Biochem. Behav.

Neuroscience

Toxicol. Lett.

Bidirectional trafficking of prostaglandin E2 receptors involved in long-term potentiation in visual cortex

J. Neurosci.

Stroke and long-term exposure to outdoor air pollution from nitrogen dioxide: a cohort study

Stroke

Secondhand smoke, vascular disease, and dementia incidence: findings from the cardiovascular health cognition study

Am. J. Epidemiol.

PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex

J. Physiol.

Effects of ulinastatin, a urinary trypsin inhibitor, on synaptic plasticity and spatial memory in a rat model of cerebral ischemia/reperfusion injury

Chin. J. Physiol.

Cerebral ischemia causes dysregulation of synaptic adhesion in mouse synaptosomes

J. Cereb. Blood Flow Metab.

CAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors

J. Neurosci.

Nitrogen dioxide (NO₂) pollution as a potential risk factor for developing vascular dementia and its synaptic mechanisms

Bidirectional trafficking of prostaglandin E₂ receptors involved in long-term potentiation in visual cortex