Browsing by Author "Gonzalez-Madrid, Enrique"

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    Asymptomatic herpes simplex virus brain infection elicits cellular senescence phenotypes in the central nervous system of mice suffering multiple sclerosis-like disease
    (2024) Duarte, Luisa F.; Villalobos, Veronica; Farias, Monica A.; Rangel-Ramirez, Ma. Andreina; Gonzalez-Madrid, Enrique; Navarro, Areli J.; Carbone-Schellman, Javier; Dominguez, Angelica; Alvarez, Alejandra; Riedel, Claudia A.; Bueno, Susan M.; Kalergis, Alexis M.; Caceres, Monica; Gonzalez, Pablo A.
    Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.
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    Gestational hypothyroxinemia induces ASD-like phenotypes in behavior, proinflammatory markers, and glutamatergic protein expression in mouse offspring of both sexes
    (2024) Gonzalez-Madrid, Enrique; Rangel-Ramirez, Ma. Andreina; Opazo, Maria C.; Mendez, Luis; Bohmwald, Karen; Bueno, Susan M.; Gonzalez, Pablo A.; Kalergis, Alexis M.; Riedel, Claudia A.
    Background The prevalence of autism spectrum disorder (ASD) has significantly risen in the past three decades, prompting researchers to explore the potential contributions of environmental factors during pregnancy to ASD development. One such factor of interest is gestational hypothyroxinemia (HTX), a frequent condition in pregnancy associated with cognitive impairments in the offspring. While retrospective human studies have linked gestational HTX to autistic traits, the cellular and molecular mechanisms underlying the development of ASD-like phenotypes remain poorly understood. This study used a mouse model of gestational HTX to evaluate ASD-like phenotypes in the offspring.Methods To induce gestational HTX, pregnant mice were treated with 2-mercapto-1-methylimidazole (MMI), a thyroid hormones synthesis inhibitor, in the tap-drinking water from embryonic days (E) 10 to E14. A separate group received MMI along with a daily subcutaneous injection of T4, while the control group received regular tap water during the entire pregnancy. Female and male offspring underwent assessments for repetitive, anxious, and social behaviors from postnatal day (P) 55 to P64. On P65, mice were euthanized for the evaluation of ASD-related inflammatory markers in blood, spleen, and specific brain regions. Additionally, the expression of glutamatergic proteins (NLGN3 and HOMER1) was analyzed in the prefrontal cortex and hippocampus.Results The HTX-offspring exhibited anxious-like behavior, a subordinate state, and impaired social interactions. Subsequently, both female and male HTX-offspring displayed elevated proinflammatory cytokines in blood, including IL-1 beta, IL-6, IL-17A, and TNF-alpha, while only males showed reduced levels of IL-10. The spleen of HTX-offspring of both sexes showed increased Th17/Treg ratio and M1-like macrophages. In the prefrontal cortex and hippocampus of male HTX-offspring, elevated levels of IL-17A and reduced IL-10 were observed, accompanied by increased expression of hippocampal NLGN3 and HOMER1. All these observations were compared to those observed in the Control-offspring. Notably, the supplementation with T4 during the MMI treatment prevents the development of the observed phenotypes. Correlation analysis revealed an association between maternal T4 levels and specific ASD-like outcomes.Discussion This study validates human observations, demonstrating for the first time that gestational HTX induces ASD-like phenotypes in the offspring, highlighting the need of monitoring thyroid function during pregnancy.
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    Risk Factors from Pregnancy to Adulthood in Multiple Sclerosis Outcome
    (2022) Gonzalez-Madrid, Enrique; Rangel-Ramirez, Ma. Andreina; Mendoza-Leon, Maria Jose; Alvarez-Mardones, Oscar; González Muñoz, Pablo Alberto; Kalergis Parra, Alexis Mikes; Opazo, Ma. Cecilia; Riedel, Claudia A.
    Multiple sclerosis (MS) is an autoimmune disease characterized by a robust inflammatory response against myelin sheath antigens, which causes astrocyte and microglial activation and demyelination of the central nervous system (CNS). Multiple genetic predispositions and environmental factors are known to influence the immune response in autoimmune diseases, such as MS, and in the experimental autoimmune encephalomyelitis (EAE) model. Although the predisposition to suffer from MS seems to be a multifactorial process, a highly sensitive period is pregnancy due to factors that alter the development and differentiation of the CNS and the immune system, which increases the offspring's susceptibility to develop MS. In this regard, there is evidence that thyroid hormone deficiency during gestation, such as hypothyroidism or hypothyroxinemia, may increase susceptibility to autoimmune diseases such as MS. In this review, we discuss the relevance of the gestational period for the development of MS in adulthood.