Abbreviations used: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; LNC, LN cell; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein.The online version of this article contains supplemental material. Most autoimmune diseases are more common in women than in men. This may be caused by differences in sex hormones, sex chromosomes, or both. In this study, we determined if there was a contribution of sex chromosomes to sex differences in susceptibility to two immunologically distinct disease models, experimental autoimmune encephalomyelitis (EAE) and pristane-induced lupus. Transgenic SJL mice were created to permit a comparison between XX and XY within a common gonadal type. Mice of the XX sex chromosome complement, as compared with XY, demonstrated greater susceptibility to both EAE and lupus. This is the fi rst evidence that the XX sex chromosome complement, as compared with XY, confers greater susceptibility to autoimmune disease.
Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal, or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized, and hormone-replaced gonadectomized animals were used. These groups were subjected to cuprizone diet-induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol-supplemented ovariectomized females was significantly increased during normal myelination less attenuated during demyelination and increased beyond placebo-treated ovariectomized or intact female levels during remyelination. In castrated males, the non-aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to bring forth efficient CC myelination and axon conduction in both sexes.
Matrix metalloproteinases (MMPs) play a crucial role in migration of inflammatory cells into the central nervous system (CNS). Levels of MMP-9 are elevated in multiple sclerosis (MS) and predict the occurrence of new active lesions on magnetic resonance imaging (MRI). This translational study aims to determine whether in vivo treatment with the pregnancy hormone estriol affects MMP-9 levels from immune cells in patients with MS and mice with experimental autoimmune encephalomyelitis (EAE). Peripheral blood mononuclear cells (PBMCs) collected from three female MS patients treated with estriol and splenocytes from EAE mice treated with estriol, estrogen receptor (ER) α ligand, ERβ ligand or vehicle were stimulated ex vivo and analyzed for levels of MMP-9. Markers of CNS infiltration were assessed using MRI in patients and immunohistochemistry in mice. Supernatants from PBMCs obtained during estriol treatment in female MS patients showed significantly decreased MMP-9 compared to pre treatment. Decreases in MMP-9 coincided with a decrease in enhancing lesion volume on MRI. Estriol treatment of mice with EAE reduced MMP-9 in supernatants from autoantigen stimulated splenocytes, coinciding with decreased CNS infiltration by T cells and monocytes. Experiments with selective ER ligands revealed that this effect was mediated via ERα. In conclusion, estriol acting via ERα to reduce MMP-9 from immune cells is one mechanism potentially underlying the estriol-mediated reduction in enhancing lesions in MS and inflammatory lesions in EAE.
Aim: To evaluate the plasma glucose levels in normal, term infants who were appropriate size for gestational age (AGA) and exclusively breast fed, and to assess the influence of parity of the mother, mode of delivery, and time of feed on the glucose levels. Method: A total of 200 healthy, term, AGA infants were longitudinally evaluated at 3, 6, 24, and 72 hours of life. Plasma glucose was estimated from heel prick capillary samples. The influence of mode of delivery, parity, and interval between feeds on plasma glucose was analysed. Results: There was no significant difference between the plasma glucose levels of the cohorts at any of the sampling time points. Parity, mode of delivery, and time since the last feed did not affect plasma glucose. Satisfactory glucose levels were maintained even when infants remained unfed up to 6 hours of age. Infants with plasma glucose concentrations less than 2.2 mmol/l at 3 hours of age were more likely to have low sugar concentration (< 2.5 mmol/l) at 72 hours (RR = 6.55, 95% confidence interval 3.93 to 10.92). Conclusions: A term, breast fed infant may have its own distinct plasma glucose levels, showing no significant variation between 3 and 72 hours of age. Plasma glucose levels are satisfactorily maintained in normal term infants without resort to prelacteal feeds. Mode of delivery, parity of the mother, and interval between feeds did not influence plasma glucose. Biochemical thresholds for hypoglycaemia do not seem to be of practical importance in asymptomatic, normal, term, breast fed infants.T he assessment of blood glucose has become an inherent part of basic neonatal care in many centres. Therapeutic interventions, with fairly elaborate protocols for "low blood sugar", are meticulously adhered to in most neonatal units. However, normal blood sugar is not precisely defined. [1][2][3][4] Parity, mode of delivery, timing of plasma sugar evaluation with respect to previous feed, etc are all relevant when commenting on the euglycaemic status of the infant. We therefore evaluated 200 normal, term, exclusively breast fed neonates, and monitored their plasma glucose at 3, 6, 24, and 72 hours of life with the aim of clarifying some of these issues. MATERIALS AND METHODSTwo hundred normal, term, appropriate for gestational age (AGA) infants delivered at the Kasturba Hospital, Manipal were included in the study. We defined "term" as delivered at 37-42 weeks gestation, based on maternal dates. Birth weight was defined as AGA on the basis of Usher's chart. 5 The mean birth weight was 2650 g (range 2300-4290), with a male to female ratio of 104:96. Ninety seven infants were born to primiparous mothers, and 103 were born to multipara. A total of 130 of the infants were born vaginally, and 70 were delivered by lower segment caesarean section. Infants with respiratory distress, perinatal asphyxia, meconium aspiration syndrome, or polycythaemia (capillary packed cell volume > 70), infants receiving antibiotics, and those born to mothers with a history of hypertension, anaemia, or diab...
BackgroundTherapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile.AimsWe aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS.Materials and methodsActive EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed.ResultsProphylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers.DiscussionEven when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects.ConclusionsOur results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.