Neuroprotection from protein misfolding in cerebral hypoperfusion concurrent with metabolic syndrome. A translational perspective.

Based on clinical and experimental evidence, metabolic syndrome (MetS) and type 2 diabetes (T2D) are considered risk factors for chronic cerebral hypoperfusion (CCH) and neurodegeneration. Scientific evidence suggests that protein misfolding is a potential mechanism that explains how CCH can lead to either Alzheimer's disease (AD) or vascular cognitive impairment and dementia (VCID). Over the last decade, there has been a significant increase in the number of experimental studies regarding this issue. Using several animal paradigms and different markers of CCH, scientists have discussed the extent to which MetSor T2D causes a decrease in cerebral blood flow (CBF). In addition, different models of CCH have explored how long-term reductions in oxygen and energy supply can trigger AD or VCID via protein misfolding and aggregation. Research that combines two or three animal models could broaden knowledge of the links between these pathological conditions. Recent experimental studies suggest novel neuroprotective properties of protein-remodeling factors. In this review, we present a summarized updated revision of preclinical findings, discussing clinical implications and proposing new experimental approaches from a translational perspective. We are confident that research studies, both clinical and experimental, may find new diagnostic and therapeutic tools to prevent neurodegeneration associated with MetS, diabetes, and any other chronic non-communicable disease (NCD) associated with diet and lifestyle risk factors.

Salud mental materna en el posparto y apoyo social percibido durante la pandemia por COVID-19 / Postpartum maternal mental health and perceived social support during the covid-19 pandemic

Introducción: La presente investigación tuvo como propósito describir la salud mental materna y su relación con el apoyo social percibido en mujeres cuyo parto ocurrió durante la pandemia por COVID-19 en Argentina durante los meses de mayo a agosto del año 2020. Métodos: Se realizó un estudio cuantitativo de alcance descriptivo correlacional. La población de estudio estuvo compuesta por 83 mujeres de nacionalidad y residencia argentina. Las edades de las participantes oscilaron entre 20 y 53 años, siendo la media de 32,86 (DE: 4,73). Se utilizó el Cuestionario de Salud General de Goldberg GHQ-12 (Goldberg, 1978; Burrone, 2015) y el Cuestionario de Apoyo Social Percibido MOS (Sherbourne & Stewart, 1991; Rodríguez Espínola & Enrique, 2007). Resultados: El 48,2% de las madres no presentó indicadores de psicopatología, 14,5% presentó indicadores de riesgo o sospecha de psicopatología y el 37,3% presentó indicadores de psicopatología. En la percepción de apoyo social total presentaron una puntuación correspondiente a un nivel bajo, en apoyo emocional informacional, apoyo afectivo y apoyo instrumental presentaron una puntuación correspondiente a un nivel bajo . Se encontraron asociaciones significativas negativas entre indicadores de salud mental y percepción de apoyo social total y apoyo afectivo, en cuanto a apoyo instrumental los valores indicarían tendencia de asociación; entre apoyo emocional, informacional no se encontró asociación con indicadores de salud mental. No se encontraron diferencias significativas en la percepción de apoyo social e indicadores de salud mental en el período postparto, en relación al hecho de haber sido acompañadas o no durante el parto. Discusión: La mayor parte de la evidencia sobre la salud mental materna en tiempos de Covid-19 informa la prevalencia de problemas de salud mental, además de la amenaza al apoyo social debido a los protocolos de aislamiento.(AU)

Introduction: The purpose of this research was to describe maternal mental health and its relationship with perceived social support in mothers whose birth occurred during the COVID-19 pandemic in Argentina during the months of May to August 2020. Methods: A quantitative study of correlational descriptive scope was conducted. The study population was composed of 83 women of Argentine nationality and residence. The ages of the participants ranged from 20 and 53 years, with the mean of 32.86 (SD: 4.73). The Goldberg GHQ-12 General Health Questionnaire (Goldberg, 1978; Burrone, 2015) was used and the MOS Perceived Social Support Questionnaire (Sherbourne & Stewart, 1991; Rodríguez Espínola & Enrique, 2007) were used. Results: 48.2% of the mothers did not present indicators of psychopathology, 14.5% presented indicators of risk or suspicion of psychopathology and 37.3% presented indicators of psychopathology. In total perceived social support they presented a low level score, in informational emotional support, affective support and instrumental support they presented a low level score. Significant negative associations were found between mental health indicators and perception of total social support and affective support, in tems of instrumental support the values would indicate association trend; between emotional and informational support, no association was found with mental health indicators. No significant differences were found in the perception of social support and mental health indicators in the postpartum period, in relation to the fact of having been accompanied or not during childbirth. Discussion: Most of the evidence on maternal mental health in times of Covid-19 reports the prevalence of mental health problems, in addition to the threat to social support due to isolation protocols.(AU)

Interleukin-1 Links Autoimmune and Autoinflammatory Pathophysiology in Mixed-Pattern Psoriasis.

Autoinflammatory and autoimmune diseases are characterized by an oversensitive immune system with loss of the physiological endogenous regulation, involving multifactorial self-reactive pathological mechanisms of mono- or polygenic nature. Failure in regulatory mechanisms triggers a complex network of dynamic relationships between innate and adaptive immunity, leading to coexistent autoinflammatory and autoimmune processes. Sustained exposure to a trigger or a genetic alteration at the level of the receptors of the natural immune system may lead to abnormal activation of the innate immune system, adaptive system activation, loss of self-tolerance, and systemic inflammation. The IL-1 family members critically activate and regulate innate and adaptive immune responses' diversity and plasticity in autoimmune and/or autoinflammatory conditions. The IL-23/IL-17 axis is key in the communication between innate immunity (IL-23-producing myeloid cells) and adaptive immunity (Th17- and IL-17-expressing CD8+ T cells). In psoriasis, these cytokines are decisive to the different clinical presentations, whether as plaque psoriasis (psoriasis vulgaris), generalized pustular psoriasis (pustular psoriasis), or mixed forms. These forms reflect a gradient between autoimmune pathophysiology with predominant adaptive immune response and autoinflammatory pathophysiology with predominant innate immune response.

Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease.

The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.

Synaptoprotection in Perinatal Asphyxia: An Experimental Approach.

Perinatal asphyxia (PA) is an obstetric complication occurring when the oxygen supply to the newborn is temporally interrupted. This health problem is associated with high morbimortality in term and preterm neonates. It severely affects the brain structure and function, involving cortical, hippocampal, and striatal loss of neurons. Nearly 25% of PA survivor newborns develop several neurodevelopmental disabilities. Behavioral alterations, as well as the morphological and biochemical pathways involved in PA pathophysiology, have been studied using an animal model that resembles intrauterine asphyxia. Experimental evidence shows that PA induces synaptic derangement. Then, synaptic dysfunction embodies a putative target for neuroprotective strategies. Over the last years, therapeutic hypothermia (TH), the only treatment available, has shown positive results in the clinic. Several pharmacological agents are being tested in experimental or clinical trial studies to prevent synaptopathy. Preservation of the synaptic structure and function, i.e., "synaptoprotection," makes up a promising challenge for reducing incidental neurodevelopmental disorders associated with PA. Accordingly, here, we summarize and review the findings obtained from the referred experimental model and propose a renewed overview in the field.

A Pilot Cross-Sectional Study to Investigate the Biomarker Potential of Phosphorylated Neurofilament-H and Immune Mediators of Disability in Patients With 5 Year Relapsing-Remitting Multiple Sclerosis.

Objective: To test the feasibility of conducting a full-scale project evaluating the potential value of the phosphorylated neurofilament H (pNF-H) and several cytokines as disability markers in relapsing-remitting multiple sclerosis (RRMS). Methods: Twenty-four patients with 5-year RRMS evolution and eleven healthy control subjects entered the study. None of the participants had an inflammatory systemic or metabolic disease. Disability progression was evaluated using the Expanded Disability Status Scale. Serum level of pNF-H, the anti-inflammatory cytokine transforming growth factor-ß 1 (TGF-ß1), and the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-17A (IL-17A), monocyte chemotactic protein-1 (MCP-1), and soluble intercellular cell-adhesion molecule 1 (sICAM-1) were quantified using enzyme-linked immunosorbent assay (ELISA). Results: The patients had higher serum level of TGF-ß1, IL-6, sICAM-1, and pNF-H. Based on these findings, a sample of at least 49 controls and 89 recent-onset RRMS patients is required to find an at least 1-point between-group difference in pNF-H with a power of 80% and an α error = 0.05. The progression of the disease was correlated with the level of pNF-H (Spearman rho = 0.624, p = 0.006), but not with the cytokines'. Conclusions: The serum level of pNF-H, EDSS score-correlated, might stand for a potential biomarker of disability in RRMS reflecting progressive axonal damage and cumulative neurological deterioration. The novelty of these results warrants conducting a larger confirmatory trial.

Neuroprotective Role of Hypothermia in Hypoxic-ischemic Brain Injury: Combined Therapies using Estrogen.

Hypoxic-ischemic brain injury is a complex network of factors, which is mainly characterized by a decrease in levels of oxygen concentration and blood flow, which lead to an inefficient supply of nutrients to the brain. Hypoxic-ischemic brain injury can be found in perinatal asphyxia and ischemic-stroke, which represent one of the main causes of mortality and morbidity in children and adults worldwide. Therefore, knowledge of underlying mechanisms triggering these insults may help establish neuroprotective treatments. Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators exert several neuroprotective effects, including a decrease of reactive oxygen species, maintenance of cell viability, mitochondrial survival, among others. However, these strategies represent a traditional approach of targeting a single factor of pathology without satisfactory results. Hence, combined therapies, such as the administration of therapeutic hypothermia with a complementary neuroprotective agent, constitute a promising alternative. In this sense, the present review summarizes the underlying mechanisms of hypoxic-ischemic brain injury and compiles several neuroprotective strategies, including Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators, which represent putative agents for combined therapies with therapeutic hypothermia.

Neuroprotection in Hypoxic-Ischemic Brain Injury Targeting Glial Cells.

Brain injury constitutes a disabling health condition of several etiologies. One of the major causes of brain injury is hypoxia-ischemia. Until recently, pharmacological treatments were solely focused on neurons. In the last decades, glial cells started to be considered as alternative targets for neuroprotection. Novel treatments for hypoxia-ischemia intend to modulate reactive forms of glial cells, and/or potentiate their recovery response. In this review, we summarize these neuroprotective strategies in hypoxia-ischemia and discuss their mechanisms of action.

Could Perinatal Asphyxia Induce a Synaptopathy? New Highlights from an Experimental Model.

Birth asphyxia also termed perinatal asphyxia is an obstetric complication that strongly affects brain structure and function. Central nervous system is highly susceptible to oxidative damage caused by perinatal asphyxia while activation and maturity of the proper pathways are relevant to avoiding abnormal neural development. Perinatal asphyxia is associated with high morbimortality in term and preterm neonates. Although several studies have demonstrated a variety of biochemical and molecular pathways involved in perinatal asphyxia physiopathology, little is known about the synaptic alterations induced by perinatal asphyxia. Nearly 25% of the newborns who survive perinatal asphyxia develop neurological disorders such as cerebral palsy and certain neurodevelopmental and learning disabilities where synaptic connectivity disturbances may be involved. Accordingly, here we review and discuss the association of possible synaptic dysfunction with perinatal asphyxia on the basis of updated evidence from an experimental model.