Apoptosis Signal-Regulating Kinase 1 Mediates MPTP Toxicity and Regulates Glial Activation

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase 3 family, is activated by oxidative stress. The death-signaling pathway mediated by ASK1 is inhibited by DJ-1, which is linked to recessively inherited Parkinson's disease (PD). Considering that DJ-1 deficiency exacerbates the toxicity of the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we sought to investigate the direct role and mechanism of ASK1 in MPTP-induced dopamine neuron toxicity. In the present study, we found that MPTP administration to wild-type mice activates ASK1 in the midbrain. In ASK1 null mice, MPTP-induced motor impairment was less profound, and striatal dopamine content and nigral dopamine neuron counts were relatively preserved compared to wild-type littermates. Further, microglia and astrocyte activation seen in wild-type mice challenged with MPTP was markedly attenuated in ASK1−/− mice. These data suggest that ASK1 is a key player in MPTP-induced glial activation linking oxidative stress with neuroinflammation, two well recognized pathogenetic factors in PD. These findings demonstrate that ASK1 is an important effector of MPTP-induced toxicity and suggest that inhibiting this kinase is a plausible therapeutic strategy for protecting dopamine neurons in PD

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Neuroprotective And Anti-Inflammatory Properties Of A Coffee Component In The Mptp Model Of Parkinson\u27S Disease

Consumption of coffee is associated with reduced risk of Parkinson\u27s disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP+-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. © 2013 The American Society for Experimental NeuroTherapeutics, Inc

Meta-Analysis Comparing Complete or Culprit Only Revascularization in Patients With Multivessel Disease Presenting With Cardiogenic Shock

The optimal strategy for patients with an acute myocardial infarction (MI) and multivessel (MV) coronary artery disease complicated by cardiogenic shock (CS) remains unknown. We conducted a meta-analysis of all randomized controlled trials and observational studies that reported adjusted effect measures to evaluate the association of MV-PCI (percutaneous coronary intervention), compared with culprit only (C)-PCI, with cardiovascular events in patients admitted for CS and MV disease. We identified 12 studies (n = 1 randomized controlled trials, n = 11 observational) that included 7,417 patients (n = 1,809 treated with MV-PCI and n = 5,608 with C-PCI). When compared with C-PCI, MV-PCI was not associated with an increased risk of short-term death (odds ratio [OR] 1.14, 95% confidence interval [CI] 0.87 to 1.48, p = 0.35 and adjusted OR [ORadj] 1.00, 95% CI 0.70 to 1.43, p = 1.00). In-hospital and/or short-term mortality tended to be higher with MV-PCI, when compared with C-PCI, for CS patients needing dialysis (ß 0.12, 95% CI from 0.049 to 0.198; p= 0.001), whereas MV-PCI was associated with lower in-hospital and/or short-term mortality in patients with an anterior MI (ß −0.022, 95% CI −0.03 to −0.01; p <0.001). MV-PCI strategy was associated with a more frequent need for dialysis or contrast-induced nephropathy after revascularization (OR 1.36, 95% CI 1.06 to 1.75, p = 0.02). In conclusion, MV-PCI seems not to increase risk of death during short- or long-term follow-up when compared with C-PCI in patients admitted for MV coronary artery disease and MI complicated by CS. Furthermore, it appears a more favorable strategy in patients with anterior MI, whereas the increased risk for AKI and its negative prognostic impact should be considered in decision-making process. Further studies are needed to confirm our hypothesis on in these subpopulations of CS patients

Indices of dopamine nerve terminal integrity in the striatum show protection against MPTP in ASK1^−/− mice.

<p>(A) Striatal dopamine content following MPTP or saline administration. * p<0.05. (B) TH content measured by ELISA in striatal tissue. ** p<0.01. Saline-WT (n = 5), Saline-ASK1^−/− (n = 5), MPTP-WT (n = 4), MPTP-ASK1^−/− (n = 5). (C) Representative images of immunohistochemical images for TH in striatum. Scale bar = 200 µm.</p

MPTP induced astrogilal activation is suppressed in ASK1^−/− mice.

<p>(A, B) Immunohistochemistry for GFAP in nigral (SNc) and striatal (ST) sections. Scale bar = 100 µm. (C) Quantification of nigral GFAP immunopositivity. * p<0.01; **<0.001. (D) Quantification of striatal GFAP immunopositivity. ** p<0.001. Quantifications were done using ImageJ. WT-Saline (n = 4), WT-MPTP-1 day (n = 4), WT-MPTP-3 day (n = 4); ASK1^−/−-Saline (n = 3), ASK1^−/−-MPTP-1 day (n = 4), ASK1^−/−-MPTP-3 day (n = 3).</p

MPTP induced microglia activation is suppressed in ASK1^−/− mice.

<p>(A, B) Immunohistochemistry with the microglial marker Iba1 (polyclonal, 1∶2,000) of nigral (SNc) and striatal (ST) sections. Scale bar = 100 µm. (C) Quantification of nigral Iba1 immunopositivity. * p<0.001. (D) Quantification of striatal Iba1 immunopositivity. * p<0.001. Quantifications were done using ImageJ. (E) MPTP-induced COX-2 expression is attenuated in ASK1^−/− mice. Midbrains containing substantia nigra were homogenized and lysed for Western blotting for COX-2. Samples from two different mice per group are shown. * p<0.001. WT-Saline (n = 4), WT-MPTP-1 day (n = 4), WT-MPTP-3 day (n = 4); ASK1^−/−-Saline (n = 3), ASK1^−/−-MPTP-1 day (n = 4), ASK1^−/−-MPTP-3 day (n = 3).</p

Nigral dopaminergic neurons are protected against MPTP in ASK1^−/− mice.

<p>(A) Western blot for ASK1 in substantia nigra tissue lysates from wild-type and ASK1^−/− mice shows loss of the specific band in the latter group (arrow). The asterisk marks a nonspecific band. (B) Stereological counting of TH positive nigral dopamine neurons following MPTP or saline administration. * p<0.05. (C) Number of Nissl stained TH negative neurons. Saline-WT (n = 5), Saline-ASK1^−/− (n = 5), MPTP-WT (n = 4), MPTP-ASK1^−/− (n = 5). (D) Representative images of TH immunohistochemistry of midbrain sections from wild-type and ASK1^−/− mice treated with saline or MPTP. Scale bar = 200 µm.</p