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Perspective of synaptic protection after post-infarction treatment with statins.

ABSTRACT: Stroke is the second most common cause of death in people over 45 years of age in Colombia and is the leading cause of permanent disability worldwide. Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments. The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal models. However, in clinical trials, most of these drugs do not reproduce the previously demonstrated neuroprotective property, and some even have adverse effects that had not previously been detected in animal experimentation.Statins are drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Several studies have shown that statin therapy in an animal model of focal cerebral ischemia reduces infarct volume, as well as markers of neurodegeneration, activates neuronal survival pathways, and improves performance on learning and memory tests. Given the implied therapeutic benefit and the limited understanding of the mechanism of action of statins in brain repair, it is necessary to address the biochemical and tissue effects of these drugs on synaptic proteins, such as NMDA receptors, synaptic adhesion proteins, and cytoskeletal proteins; these proteins are highly relevant therapeutic targets, which, in addition to giving a structural account of synaptic connectivity and function, are also indicators of cellular communication and the integrity of the blood-brain barrier, which are widely affected in the long term post-cerebral infarct but, interestingly, are protected by statins when administered during the acute phase.

SUBMITTER: Gutierrez-Vargas JA

PROVIDER: S-EPMC4403706 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Perspective of synaptic protection after post-infarction treatment with statins.

Gutiérrez-Vargas Johanna Andrea JA Cespedes-Rubio Angel A Cardona-Gómez Gloria Patricia GP

Journal of translational medicine 20150413

Stroke is the second most common cause of death in people over 45 years of age in Colombia and is the leading cause of permanent disability worldwide. Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments. The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal mode ...[more]

PMID: 25884826

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Project description:AimTo examine the contribution of treatment resistant depression (TRD) to mortality in depressed post-myocardial infarction (MI) patients independent of biological and social predictors.MethodsThis secondary analysis study utilizes the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial data. From 1834 depressed patients in the ENRICHD study, there were 770 depressed post-MI patients who were treated for depression. In this study, TRD is defined as having a less than 50% reduction in Hamilton Depression (HAM-D) score from baseline and a HAM-D score of greater than 10 in 6 mo after depression treatment began. Cox regression analysis was used to examine the independent contributions of TRD to mortality after controlling for the biological and social predictors.ResultsTRD occurred in 13.4% (n = 103) of the 770 patients treated for depression. Patients with TRD were significantly younger in age (P = 0.04) (mean = 57.0 years, SD = 11.7) than those without TRD (mean = 59.2 years, SD = 12.0). There was a significantly higher percentage of females with TRD (57.3%) compared to females without TRD (47.4%) [χ(2) (1) = 4.65, P = 0.031]. There were significantly more current smokers with TRD (44.7%) than without TRD (33.0%) [χ(2) (1) = 7.34, P = 0.007]. There were no significant differences in diabetes (P = 0.120), history of heart failure (P = 0.258), prior MI (P = 0.524), and prior stroke (P = 0.180) between patients with TRD and those without TRD. Mortality was 13% (n = 13) in patients with TRD and 7% (n = 49) in patients without TRD, with a mean follow-up of 29 mo (18 mo minimum and maximum of 4.5 years). TRD was a significant independent predictor of mortality (HR = 1.995; 95%CI: 1.011-3.938, P = 0.046) after controlling for age (HR = 1.036; 95%CI: 1.011-1.061, P = 0.004), diabetes (HR = 2.912; 95%CI: 1.638-5.180, P < 0.001), heart failure (HR = 2.736; 95%CI: 1.551-4.827, P = 0.001), and smoking (HR = 0.502; 95%CI: 0.228-1.105, P = 0.087).ConclusionThe analysis of TRD in the ENRICHD study shows that the effective treatment of depression reduced mortality in depressed post-MI patients. It is important to monitor the effectiveness of depression treatment and change treatments if necessary to reduce depression and improve cardiac outcomes in depressed post-MI patients.

Project description:BackgroundProinflammatory cytokine cascades play crucial roles in the onset and progression of myocardial ischemia and infarction. Clinically, elevated serum levels of pro-inflammatory cytokine interleukin-6 is a poor prognostic indicator for future cardiac events and cardiac morbidity. Despite several reports, there is no clear evidence of cardiac benefits of inhibiting IL-6 in pre-clinical and clinical settings.ObjectiveTo analyze the available data systematically and perform a meta-analysis to show the evidence of effects of IL-6 inhibition on cardiac remodeling and mortality in ischemic animal models.MethodsWe used PICO framework and the quality of the studies was assessed using SYRCLE's risk of bias tool. Studies with interventions i.e., genetic deletion or pharmacological inhibition of IL-6/IL-6R were included for the meta-analysis. Systematic review was synthesized by including pre-clinical as well as randomized clinical trials involving myocardial infarction patients treated with IL-6 inhibitors. The effect size of the pooled data was determined using standard mean difference and 95% confidence intervals.ResultsA total of 12 pre-clinical studies were included in the review for analysis. Most of the studies showed an unclear risk of bias as the selection and reporting criteria were poorly described. We observed high heterogeneity in the included studies due to the varying duration of myocardial infarction and the dosage of IL-6 antibodies used in the studies. Overall inhibition of IL-6 significantly increased area at risk [p = 0.001, SMD = 0.49 (95% CI: -0.36, 1.35)] and significantly reduced ejection fraction [p = 0.001, SMD = -0.19 (95% CI: -1.39, 1.01)] and end-diastolic diameter [p = 0.02, SMD = -0.25 (95% CI: -0.87, 0.36)] of left ventricle post-MI, but no effects on infarct size [p < 0.01, SMD = 0.00; 95% CI: -1.34, 0.58). In randomized clinical trials, the overall effect on C-reactive protein remains significantly unchanged on CRP levels (SMD = -0.38; 95% CI: -1.94, 0.55) post-treatment with IL-6R inhibitor tocilizumab. The meta-regression demonstrates a significant positive correlation (p = 0.058) between the increase in ischemic area and duration of ischemia post-surgery in the absence of IL-6. This meta-analysis indicates mixed effect of IL-6 inhibition on cardiac remodeling post-MI, particularly in protecting the myocardium viability from damaging acute inflammation but not significant on cardiac function of ischemic animal models.ConclusionDespite the well-established pro-inflammatory nature of IL-6 in myocardial ischemia, our meta-analysis reports a limited contribution of IL-6 in the cardiac remodeling of hearts in animal models of myocardial ischemia. Moreover, genetically deleted IL-6 murine models produced contrasting results. Additional pre-clinical studies exploring the pharmacological inhibition of IL-6R are required to determine the beneficial effects of IL-6 inhibitors in regulating cardiac remodeling. The findings from IL-6R inhibition have better clinical relevance compared to genetically inhibited IL-6.

Project description:A hexanucleotide repeat expansion in a noncoding region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Reduction of select or total C9orf72 transcript and protein levels is observed in postmortem C9-ALS/FTD tissue, and loss of C9orf72 orthologues in zebrafish and C. elegans results in motor deficits. However, how the reduction in C9orf72 in ALS and FTD might contribute to the disease process remains poorly understood. It has been shown that C9orf72 interacts and forms a complex with SMCR8 and WDR41, acting as a guanine exchange factor for Rab GTPases. Given the known synaptosomal compartmentalization of C9orf72-interacting Rab GTPases, we hypothesized that C9orf72 localization to synaptosomes would be required for the regulation of Rab GTPases and receptor trafficking. This study combined synaptosomal and post-synaptic density preparations together with a knockout-confirmed monoclonal antibody for C9orf72 to assess the localization and role of C9orf72 in the synaptosomes of mouse forebrains. Here, we found C9orf72 to be localized to both the pre- and post-synaptic compartment, as confirmed by both post-synaptic immunoprecipitation and immunofluorescence labelling. In C9orf72 knockout (C9-KO) mice, we demonstrated that pre-synaptic Rab3a, Rab5, and Rab11 protein levels remained stable compared with wild-type littermates (C9-WT). Strikingly, post-synaptic preparations from C9-KO mouse forebrains demonstrated a complete loss of Smcr8 protein levels, together with a significant downregulation of Rab39b and a concomitant upregulation of GluR1 compared with C9-WT mice. We confirmed the localization of Rab39b downregulation and GluR1 upregulation to the dorsal hippocampus of C9-KO mice by immunofluorescence. These results indicate that C9orf72 is essential for the regulation of post-synaptic receptor levels, and implicates loss of C9orf72 in contributing to synaptic dysfunction and related excitotoxicity in ALS and FTD.

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Perspective of synaptic protection after post-infarction treatment with statins.

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Perspective of synaptic protection after post-infarction treatment with statins.

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