Connexin43 inhibition attenuated dopaminergic neuronal loss in the lipopolysaccharide-induced mice model of Parkinson's disease.

Studies using in vitro Parkinson's disease (PD) models have found that lipopolysaccharide (LPS) induced reduction of connexin 43 (Cx43) gap junction communication and elevation of hemichannel function, which could cause neurotoxicity directly and indirectly via excessive ATP and glutamate release. However, in vivo study about Cx43 expression and function, as well as the efficacy of Cx43 inhibition for neuronal survival in PD is lacking. This study aimed to unravel the role of Cx43 in PD and understand the underlying mechanisms using an in vivo PD model. Male C57BL/6 mice received intranigral injection of LPS (5 µg) and 43Gap27 (4 µg), a Cx43 inhibitor, simultaneously. Results showed that following LPS treatment, total Cx43 expression decreased by about 60%, but the relative level of phosphorylated Cx43 increased to about double that controls (all p < 0.05). The administration of 43Gap27 significantly attenuated the loss of dopaminergic neurons and restored dopamine and its metabolites levels. Moreover, 43Gap27 treatment inhibited intense microgliosis and astrogliosis in nigrostriatal system induced by LPS and also ameliorated elevated levels of inflammatory mediators. Interestingly, Cx43 inhibition also increased nerve growth factors. In conclusion, Cx43 inhibition was able to prevent LPS-mediated dopaminergic neuronal death, possibly via neuroinflammation reaction reduction and neurotrophic factors elevation. Therefore, Cx43 may be a promising therapeutic target for degenerative neurological disorders such as PD.

Benzo(a)pyrene exposure in utero exacerbates Parkinson's Disease (PD)-like α-synucleinopathy in A53T human alpha-synuclein transgenic mice.

BACKGROUND: Previous work indicated that benzo[a]pyrene (B(a)P) exposure in utero might adversely affect neurodevelopment and cause Parkinson's Disease (PD)-like symptoms. However, the effect of utero exposure to B(a)P on PD-like α-synucleinopathy and the mechanism under are unclear. OBJECTIVE: The A53T human alpha-synuclein (α-syn) transgenic mice (M83+/-) were used in this study to gain insights into the role of B(a)P exposure in utero in the onset of α-syn pathology and neuronal damage. METHOD: Timed-pregnant M83+/- dams were exposed to 1) corn oil (vehicle) or 2) 5 mg/kg bw/d B(a)P or 3) 20 mg/kg bw/d B(a)P at gestational day 10-17 by oral gavage and then the SNCA transcription, α-syn accumulation and aggregation, neuroinflammation and nigral dopaminergic neurodegeneration of 60-day-old pups were evaluated. RESULT: SNCA mRNA and α-syn protein expression in the midbrain of 60 days adult mice were found to be remarkably elevated after B(a)P exposure in utero, the protein degradation capacity was injured (in 20 mg/kg dose group) and α-syn aggregation could be observed in the substantia nigra (SN); Enhanced Iba1 expression in the midbrain and microglial activation (in 20 mg/kg dose group) in the SN were also figured out; Besides, dopaminergic neurons in the SN of 60 days adult mice were significantly decreased. CONCLUSIONS: Our findings demonstrated that B(a)P exposure in utero could exacerbate α-syn pathology and induce activation of microglia which might further lead to dopaminergic neuronal loss in the SN.

Double-stranded RNA-induced dopaminergic neuronal loss in the substantia nigra in the presence of Mac1 receptor.

BACKGROUND: The underlying mechanism of viral infection as a risk factor for Parkinson's disease (PD), the second most common neurodegenerative disease, remains unclear. OBJECTIVE: We used Mac-1-/- and gp91phox-/- transgene animal models to investigate the mechanisms by which poly I:C, a mimic of virus double-stranded RNA, induces PD neurodegeneration. METHOD: Poly I:C was stereotaxically injected into the substantia nigra (SN) of wild-type (WT), Mac-1-knockout (Mac-1-/-) and gp91 phox-knockout (gp91 phox-/-) mice (10 µg/µl), and nigral dopaminergic neurodegeneration, α-synuclein accumulation and neuroinflammation were evaluated. RESULT: Dopaminergic neurons in the nigra and striatum were markedly reduced in WT mice after administration of poly I:C together with abundant microglial activation in the SN, and the expression of α-synuclein was also elevated. However, these pathological changes were greatly dampened in Mac-1-/- and gp91 phox-/- mice. CONCLUSIONS: Our findings demonstrated that viral infection could result in the activation of microglia as well as NADPH oxidase, which may lead to neuron loss and the development of Parkinson's-like symptoms. Mac-1 is a key receptor during this process.

Benzo(a)pyrene exposure induced neuronal loss, plaque deposition, and cognitive decline in APP/PS1 mice.

BACKGROUND: Exposure to benzo(a)pyrene (BaP) was associated with cognitive impairments and some Alzheimer's disease (AD)-like pathological changes. However, it is largely unknown whether BaP exposure participates in the disease progression of AD. OBJECTIVES: To investigate the effect of BaP exposure on AD progression and its underlying mechanisms. METHODS: BaP or vehicle was administered to 4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and wildtype (WT) mice for 2 months. Learning and memory ability and exploratory behaviors were evaluated 1 month after the initiation/termination of BaP exposure. AD-like pathological and biochemical alterations were examined 1 month after 2-month BaP exposure. Levels of soluble beta-amyloid (Aß) oligomers and the number of Aß plaques in the cortex and the hippocampus were quantified. Gene expression profiling was used to evaluate alternation of genes/pathways associated with AD onset and progression. Immunohistochemistry and Western blot were used to demonstrate neuronal loss and neuroinflammation in the cortex and the hippocampus. Treatment of primary neuron-glia cultures with aged Aß (a mixture of monomers, oligomers, and fibrils) and/or BaP was used to investigate mechanisms by which BaP enhanced Aß-induced neurodegeneration. RESULTS: BaP exposure induced progressive decline in spatial learning/memory and exploratory behaviors in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer behavioral deficits than WT mice. Moreover, BaP exposure promoted neuronal loss, Aß burden and Aß plaque formation in APP/PS1 mice, but not in WT mice. Gene expression profiling showed most robust alteration in genes and pathways related to inflammation and immunoregulatory process, Aß secretion and degradation, and synaptic formation in WT and APP/PS1 mice after BaP exposure. Consistently, the cortex and the hippocampus of WT and APP/PS1 mice displayed activation of microglia and astroglia and upregulation of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), and NADPH oxidase (three widely used neuroinflammatory markers) after BaP exposure. Furthermore, BaP exposure aggravated neurodegeneration induced by aged Aß peptide in primary neuron-glia cultures through enhancing NADPH oxidase-derived oxidative stress. CONCLUSION: Our study showed that chronic exposure to environmental pollutant BaP induced, accelerated, and exacerbated the progression of AD, in which elevated neuroinflammation and NADPH oxidase-derived oxidative insults were key pathogenic events.

Identification of potential markers for internal exposure to ambient ozone in oral cavity of healthy adults.

BACKGROUND: Ozone is a highly oxidative gaseous pollutant associated with adverse health outcomes, but markers for internal exposure to ambient ozone are not well-established. METHODS: We aimed to evaluate the feasibility and suitability of the markers in oral microbiome for ambient ozone exposure. Between March and May in 2018, 97 healthy adults were examined on 2 or 3 occasions for oral swab sampling. Hourly concentrations of ambient ozone 1-7 days preceding sampling were collected. Mixed-effect models were fitted to examine the associations between ambient ozone and the diversity and taxon abundances of oral microbiome. Receiver operating characteristic (ROC) curves estimated the accuracies of markers to delineate between samples exposed to different concentrations of ambient ozone. The associations between the makers and lung function were further examined by linear mixed effect models. RESULTS: The averages of daily mean concentrations of ambient ozone (O3-daily), maximum 8-h means (O3-8hmax) and 1-h maximums (O3-1hmax) were respectively 72 µg/m³, 123 µg/m³ and 144 µg/m³. O3-daily was positively associated with α-diversity of oral microbiome, but the exposure-response curves only yielded positive associations in the range of O3-daily from 60 µg/m³ to 75 µg/m³. Results of O3-8hmax and O3-1hmax were consistent with these of O3-daily. With an interquartile range increase in O3-daily at lag04, the abundance of Proteobacteria decreased by 3.1% (95% CI: -4.0%, -2.2%) and Firmicutes increased by 3.3% (95% CI: 2.3%, 4.3%), whilst the Proteobacteria:Firmicutes ratio (P/F) decreased by 0.9 (95% CI: -1.5, -0.4). The areas under ROC curves for Proteobacteria, Firmicutes and P/F were 0.8535, 0.7569 and 0.8929, respectively. Proteobacteria and P/F were associated with forced expiratory volume in the first second and fractional exhaled nitric oxide significantly. CONCLUSION: Ambient ozone disturbs oral microbial homeostasis. Proteobacteria, Firmicutes and their ratio may be potential markers for short-term ambient ozone exposure, and indicators of airway inflammation or lung function decline.