Corrigendum: Neuroprotection in metabolic syndrome by environmental enrichment. A lifespan perspective.

[This corrects the article DOI: 10.3389/fnins.2023.1214468.].

Neuroprotection in metabolic syndrome by environmental enrichment. A lifespan perspective.

Metabolic syndrome (MetS) is defined by the concurrence of different metabolic conditions: obesity, hypertension, dyslipidemia, and hyperglycemia. Its incidence has been increasingly rising over the past decades and has become a global health problem. MetS has deleterious consequences on the central nervous system (CNS) and neurological development. MetS can last several years or be lifelong, affecting the CNS in different ways and treatments can help manage condition, though there is no known cure. The early childhood years are extremely important in neurodevelopment, which extends beyond, encompassing a lifetime. Neuroplastic changes take place all life through - childhood, adolescence, adulthood, and old age - are highly sensitive to environmental input. Environmental factors have an important role in the etiopathogenesis and treatment of MetS, so environmental enrichment (EE) stands as a promising non-invasive therapeutic approach. While the EE paradigm has been designed for animal housing, its principles can be and actually are applied in cognitive, sensory, social, and physical stimulation programs for humans. Here, we briefly review the central milestones in neurodevelopment at each life stage, along with the research studies carried out on how MetS affects neurodevelopment at each life stage and the contributions that EE models can provide to improve health over the lifespan.

Palmitoylethanolamide attenuates neurodevelopmental delay and early hippocampal damage following perinatal asphyxia in rats.

Impaired gas exchange close to labor causes perinatal asphyxia (PA), a neurodevelopmental impairment factor. Palmitoylethanolamide (PEA) proved neuroprotective in experimental brain injury and neurodegeneration models. This study aimed to evaluate PEA effects on the immature-brain, i.e., early neuroprotection by PEA in an experimental PA paradigm. Newborn rats were placed in a 37°C water bath for 19 min to induce PA. PEA 10 mg/kg, s.c., was administered within the first hour of life. Neurobehavioral responses were assessed from postnatal day 1 (P1) to postnatal day 21 (P21), recording the day of appearance of several reflexes and neurological signs. Hippocampal CA1 area ultrastructure was examined using electron microscopy. Microtubule-associated protein 2 (MAP-2), phosphorylated high and medium molecular weight neurofilaments (pNF H/M), and glial fibrillary acidic protein (GFAP) were assessed using immunohistochemistry and Western blot at P21. Over the first 3 weeks of life, PA rats showed late gait, negative geotaxis and eye-opening onset, and delayed appearance of air-righting, auditory startle, sensory eyelid, forelimb placing, and grasp reflexes. On P21, the hippocampal CA1 area showed signs of neuronal degeneration and MAP-2 deficit. PEA treatment reduced PA-induced hippocampal damage and normalized the time of appearance of gait, air-righting, placing, and grasp reflexes. The outcome of this study might prove useful in designing intervention strategies to reduce early neurodevelopmental delay following PA.

Multidimensional overview of neurofilament light chain contribution to comprehensively understanding multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease characterized by demyelination, progressive axonal loss, and varying clinical presentations. Axonal damage associated with the inflammatory process causes neurofilaments, the major neuron structural proteins, to be released into the extracellular space, reaching the cerebrospinal fluid (CSF) and the peripheral blood. Methodological advances in neurofilaments' serological detection and imaging technology, along with many clinical and therapeutic studies in the last years, have deepened our understanding of MS immunopathogenesis. This review examines the use of light chain neurofilaments (NFLs) as peripheral MS biomarkers in light of the current clinical and therapeutic evidence, MS immunopathology, and technological advances in diagnostic tools. It aims to highlight NFL multidimensional value as a reliable MS biomarker with a diagnostic-prognostic profile while improving our comprehension of inflammatory neurodegenerative processes, mainly RRMS, the most frequent clinical presentation of MS.

Corrigendum: Palmitoylethanolamide attenuates neurodevelopmental delay and early hippocampal damage following perinatal asphyxia in rats.

[This corrects the article DOI: 10.3389/fnbeh.2022.953157.].

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.

Adipokines, Cardiovascular Risk, and Therapeutic Management in Obesity and Psoriatic Arthritis.

Psoriatic arthritis is a chronic inflammatory disease with skin and joint pathology as the dominant characteristics. Scientific evidence supports its systemic nature and relevant relationship with obesity, metabolic syndrome, and associated conditions. Metabolic syndrome and obesity share common signaling pathways with joint inflammation, reinforcing the idea that adipose tissue is a major contributor to disease development and severity. The adipose tissue is not a mere energy store but also an endocrine organ participating in the immune response. In the search for the best therapeutic strategy for a patient, we should appraise the adipose tissue as an endocrine and immune organ responsible for mild chronic inflammation. Today, our challenge is not only to achieve disease remission but to control the associated comorbidities as well. In light of the high prevalence of obesity in psoriatic arthritis patients and the importance of the adipose tissue in the development of chronic inflammation, we aimed to identify the most relevant articles in this regard published in English until June 2020 using the PubMed database. Search terms included psoriatic arthritis, in combination with metabolic syndrome, obesity, adipokines, cardiovascular disease, and treatment. This review summarizes the current evidence regarding the role of adipose tissue as an adipokine-secreting endocrine organ, discussing its influence on disease development and severity, and ultimately in meeting successful disease management.

Long-Term Effects of Hypoxia-Reoxygenation on Thioredoxins in Rat Central Nervous System.

BACKGROUND: Oxidative stress induced by the oxidative pathway dysregulation following ischemia/ reperfusion has been proposed as an important cause of neuronal death and brain damage. The proteins of the thioredoxin (Trx) family are crucial mediators of protein function regulating the intracellular hydrogen peroxide levels and redox-sensitive post-translational protein changes. AIM: To analyze the expression and distribution of fourteen members of the Trx family, potentially essential for the regeneration upon long-term brain damage, in a perinatal hypoxia-ischemia rat model induced by common carotid artery ligation. METHODS: The right common carotid artery (CCA) was exposed by an incision on the right side of the neck, isolated from nerve and vein, and permanently ligated. Sham-surgery rats underwent right CCA surgical exposure but no ligation. Euthanasia was administered to all rats at 30, 60, and 90 days of age. Protein expression and distribution of fourteen members of the Trx family and related proteins (Grx1, Grx2, Grx3, Grx5, Prx1, Prx2, Prx3, Prx4, Prx5, Prx6, Trx1, Trx2, TrxR1, TrxR2) was examined in the most hypoxia susceptible rat brain areas, namely, cerebellum, corpus striatum, and the hippocampus. RESULTS: The thioredoxin proteins displayed a complex, cell-type, and tissue-specific expression pattern following ischemia/reperfusion. Even 60 days after ischemia/reperfusion, Western blot analysis showed a persistent expression of Trx1 and Grx2 in several brain areas. CONCLUSION: The Trx family of proteins might contribute to long-term survival and recovery supporting their therapeutic use to curtail ischemic brain oxidative damage following an ischemia/reperfusion insult. Characterization of ischemia/reperfusion oxidative brain damage and analysis of the involved mechanisms are required to understand the underneath processes triggered by ischemia/reperfusion and to what extent and in what way thioredoxins contribute to recovery from brain hypoxic stress.

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.

Partial Reversal of Striatal Damage by Palmitoylethanolamide Administration Following Perinatal Asphyxia.

Perinatal asphyxia (PA) is a clinical condition brought by a birth temporary oxygen deprivation associated with long-term damage in the corpus striatum, one of the most compromised brain areas. Palmitoylethanolamide (PEA) is a neuromodulator well known for its protective effects in brain injury models, including PA, albeit not deeply studied regarding its particular effects in the corpus striatum following PA. Using Bjelke et al. (1991) PA model, full-term pregnant rats were decapitated, and uterus horns were placed in a water bath at 37°C for 19 min. One hour later, the pups were injected with PEA 10 mg/kg s.c., and placed with surrogate mothers. After 30 days, the animals were perfused, and coronal striatal sections were collected to analyze protein-level expression by Western blot and the reactive area by immunohistochemistry for neuron markers: phosphorylated neurofilament-heavy/medium-chain (pNF-H/M) and microtubule-associated protein-2 (MAP-2), and the astrocyte marker, glial fibrillary acidic protein (GFAP). Results indicated that PA produced neuronal damage and morphological changes. Asphyctic rats showed a decrease in pNF-H/M and MAP-2 reactive areas, GFAP+ cells number, and MAP-2 as well as pNF-H/M protein expression in the striatum. Treatment with PEA largely restored the number of GFAP+ cells. Most important, it ameliorated the decrease in pNF-H/M and MAP-2 reactive areas in asphyctic rats. Noticeably, PEA treatment reversed the decrease in MAP-2 protein expression and largely prevented PA-induced decrease in pNF-H/M protein expression. PA did not affect the GFAP protein level. Treatment with PEA attenuated striatal damage induced by PA, suggesting its therapeutic potential for the prevention of neurodevelopmental disorders.

Immune-Mediated Inflammation Promotes Subclinical Atherosclerosis in Recent-Onset Psoriatic Arthritis Patients without Conventional Cardiovascular Risk Factors.

Studies on the inflammatory burden in recent-onset psoriatic arthritis (PsA) patients without conventional cardiovascular risk factors (CVRFs) are not available. This preliminary study focuses on cardiovascular risk in cutaneous psoriasis (CPs) and recent-onset PsA patients. Blood biochemistry (glucose, cholesterol, uric acid, lipid profile and apolipoprotein B) was analyzed using standard kits. Proatherogenic inflammation markers, C-reactive protein (CRP) and interleukin-6 (IL-6), and endothelial activators monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1 (sICAM-1), were determined by enzyme-linked immunosorbent assay. Ultrasound images allowed measuring carotid intima-media thickness (cIMT). Our study first shows an increase in cIMT, and in serum levels of sICAM-1 and CRP in recent-onset PsA patients not presenting conventional CVRFs over the non-medicated time-period, from disease diagnosis to the beginning of pharmacological treatment, compared with healthy subjects. The outcome highlights the importance of monitoring serum level of sICAM1, CRP, and cIMT, and the value of primary prevention in psoriatic patients even with no history of cardiovascular events.

Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration.

The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

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.

Chagas disease prevalence in pregnant women: migration and risk of congenital transmission.

INTRODUCTION: Argentina has been a preferential target for Bolivian immigrants for decades. The relatively recent migratory flux includes Germany, France, the United States, Australia, Japan, and some Latin American countries. The aim of this cross-sectional study was to describe the prevalence of Chagas disease in pregnant women, analyzing the Bolivian-specific Chagas prevalence as the main contributor of migratory populations from Chagas disease-endemic areas to Buenos Aires city, Argentina, and to evaluate the impact of these migrant influxes on the process of the "urbanization" of the disease in reference hospital José Maria Ramos Mejia (JMRM). METHODOLOGY: Overall, 21,332 pregnant women (100%) between 15 and 49 years of age derived from the public maternity service of JMRMH were studied. Serology data was obtained from registered serological diagnosis data, consisting of three different serological tests performed at the Public Parasitology Unit. RESULTS: Although general prevalence decreased during the analyzed period, the specific prevalence of pregnant women from Bolivian origin showed a sustained growth during 1983-2013. Solely 5% of the total pregnant women population from Bolivia contributed to one third of the total Chagas prevalence. CONCLUSIONS: This study showed that a cohort of pregnant women from Bolivia who attended JMRMH during the period 1983-2007 constituted a population at risk for congenital transmission. Increased migration from endemic areas of Bolivia might potentially increase the prevalence of Chagas disease among pregnant women. In addition, this study highlights the importance to analyze specific prevalence according to endemic areas to determine the profiles of potential hidden prevalence.

Glial Modulation by N-acylethanolamides in Brain Injury and Neurodegeneration.

Neuroinflammation involves the activation of glial cells and represents a key element in normal aging and pathophysiology of brain damage. N-acylethanolamides (NAEs), naturally occurring amides, are known for their pro-homeostatic effects. An increase in NAEs has been reported in vivo and in vitro in the aging brain and in brain injury. Treatment with NAEs may promote neuroprotection and exert anti-inflammatory actions via PPARα activation and/or by counteracting gliosis. This review aims to provide an overview of endogenous and exogenous properties of NAEs in neuroinflammation and to discuss their interaction with glial cells.

Antiproliferative effect of sera from chagasic patients on Trypanosoma cruzi epimastigotes. Involvement of xanthine oxidase.

Serum from asymptomatic or symptomatic (with cardiovascular manifestations) chagasic patients depleted of the complement system displayed an antiproliferative effect on Trypanosoma cruzi epimastigotes, RA strain, when added to the growth medium. This effect was also observed when patient's serum was depleted of specific antibodies. The antiproliferative effect was both time and concentration dependent. It was confined to the non-dialyzable, high molecular weight, fraction of the serum. This effect was abrogated by allopurinol and catalase, and enhanced by N-ethylmaleimide. Xanthine oxidoreductase and xanthine oxidase activities were increased in the chagasic sera, while catalase activity remained unchanged. Parasites exposed to chagasic sera showed a decrease in Fe/superoxide dismutase activity as well as an increase in membrane lipoperoxidation. Our data provides evidence to support the idea that the antiproliferative activity observed in sera from chagasic patients may be due, at least partially, to a direct effect of hydrogen peroxide on the epimastigotes of T. cruzi. The increase of hydrogen peroxide to antiproliferative levels might result from an increase in xanthine oxidase activity in the serum of patients infected with the parasite.