Anahí Chavarría

MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIAL EFFECTS OF SEX STEROIDS ON THE REPRODUCTION AND INFECTIVITY OF TAENIA CRASSICEPS

The in vitro exposure of Taenia crassiceps cysticerci to 17-β estradiol (E2) and progesterone (P4) stimulated their reproduction and infectivity. Testosterone (T4) and dihydrotestosterone (DHT) inhibited their reproduction and reduced their motility and infectivity. E2 and P4 increased, whereas T4 and DHT reduced, the expression of parasite c-fos and c-jun and DNA synthesis. In vitro exposure of cysticerci to sex steroids before their inoculation into recipient noninfected mice resulted in large parasite loads when pretreated with E2 and P4 and in smaller loads when pretreated with T4 and DHT. To determine the possible molecular mechanisms by which sex steroids affect T. crassiceps, sex steroid receptors were amplified. Taenia crassiceps expressed estrogen receptors (both α and β isoforms) and androgen receptors but no P4 receptors. These results demonstrate that sex steroids act directly on parasite reproduction by binding to a classic and specific sex steroid receptor on the parasite. The differential response of cysticerci to sex steroids may also be involved in their ability to grow faster in the murine female or feminized male host. This is the first report of direct sex steroid effects on the parasite possibly through sex steroid receptors in the cysticerci.

TH2 profile in asymptomatic Taenia solium human neurocysticercosis

Neurocysticercosis (NC), a parasitic disease caused by Taenia solium, may be either asymptomatic or have mild to severe symptoms due to several factors. In this study, the immunological factors that underlie NC pleomorphism were studied. Ten of the 132 inhabitants of a rural community in Mexico (Tepez) had a computerized tomography (CT) scan compatible with calcified NC, and all were asymptomatic. Their immunological profiles were compared with those of 122 CT scan negative (non-NC) subjects from the same village. NC was associated with a TH2 response (IgG4, IL-4, IL-5, IL-13). Subjects from Tepez had higher levels of specific antibodies (IgG1, IgG2, IgG4, IgE) and specific cell proliferation than subjects from an area with low exposure (Ensenada). This suggests that non-NC subjects from Tepez had been exposed to T. solium and resisted infection in the brain. Distinct immunological profiles in equally exposed individuals differing in outcome of infection support the hypothesis of host-related factors in resistance to and pathogenesis of NC. This is the first study reporting the immunological profile associated with the asymptomatic form of NC.

The immune response in Taenia solium cysticercosis: protection and injury

This article reviews current knowledge on the innate and acquired immune responses in human Taenia solium neurocysticercosis, highlighting the conditions that appear to be favourable for the survival or destruction of the parasite and for the benefit or injury to its host.

Neuroprotective effect of silymarin in a MPTP mouse model of Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative disease secondary to the loss of dopaminergic neurons in the substantia nigra. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces in mice and primates histopathological changes similar to PD in humans. A common feature of PD and MPTP models is neuronal death and dopamine depletion. Silymarin is a complex of flavonolignans derived from the seeds of the plant Silybum marianum and has mainly antioxidant, anti-inflammatory, cytoprotective and neuroprotective effects. In order to explore whether silymarin has a neuroprotective effects in a mouse model of PD we determined the concentration of striatal dopamine by HPLC, the number of apoptotic cells by in situ Tunel assay and the number of tyrosine hydroxylase positive neurons by immunohistochemistry in substantia nigra of vehicle-treated, silymarin-treated, MPTP-intoxicated and MPTP-silymarin treated C57BL/6J male mice. MPTP (30 mg/kg) and silymarin doses (25, 50, 100, 200, 250, 300 or 400mg/kg) were administered intraperitoneally once daily for five consecutive days. Silymarin treatment showed a non-monotonic dose-response curve and only 50 and 100mg/kg doses preserved dopamine levels (62% and 69%, respectively) after MPTP intoxication. Additionally, 100mg/kg silymarin treatment significantly diminished the number of apoptotic cells and preserved dopaminergic neurons in the substantia nigra of MPTP-intoxicated mice. These results show the neuroprotective properties of 100mg/kg silymarin and may be of interest in the treatment of PD.

Central nervous system: A modified immune surveillance circuit?

Immune surveillance in the central nervous system (CNS) was considered impossible because: (i) the brain parenchyma is separated from the blood circulation by the blood-brain barrier (BBB); (ii) the brain lacks lymphatic drainage and (iii) the brain displays low major histocompatibility complex class II (MHCII) expression. In this context, the BBB prevents entry of immune molecules and effector cells to the CNS. The absence of lymphatic vessels avoids CNS antigens from reaching the lymph nodes for lymphocyte presentation and activation. Finally, the low MHCII expression hinders effective antigen presentation and re-activation of T cells for a competent immune response. All these factors limit the effectiveness of the afferent and efferent arms necessary to carry out immune surveillance. Nevertheless, recent evidence supports that CNS is monitored by the immune system through a modified surveillance circuit; this work reviews these findings.

Neuronal influence behind the central nervous system regulation of the immune cells

Central nervous system (CNS) has a highly specialized microenvironment, and despite being initially considered an immune privileged site, this immune status is far from absolute because it varies with age and brain topography. The brain monitors immune responses by several means that act in parallel; one pathway involves afferent nerves (vagal nerve) and the other resident cells (neurons and glia). These cell populations exert a strong role in the regulation of the immune system, favoring an immune-modulatory environment in the CNS. Neurons control glial cell and infiltrated T-cells by contact-dependent and -independent mechanisms. Contact-dependent mechanisms are provided by several membrane immune modulating molecules such as Sema-7A, CD95L, CD22, CD200, CD47, NCAM, ICAM-5, and cadherins; which can inhibit the expression of microglial inflammatory cytokines, induce apoptosis or inactivate infiltrated T-cells. On the other hand, soluble neuronal factors like Sema-3A, cytokines, neurotrophins, neuropeptides, and neurotransmitters attenuate microglial and/or T-cell activation. In this review, we focused on all known mechanism driven only by neurons in order to control the local immune cells.

Neurocysticercosis: local and systemic immune-inflammatory features related to severity.

Neurocysticercosis (NC) is caused by the establishment of Taenia solium cysticerci in the central nervous system. Previous studies have established that neuroinflammation plays a key role in the severity of the disease. However, the relationship between peripheral and local immune response remains inconclusive. This work studies the peripheral and local immune-inflammatory features and their relationships, toward the identification of potential peripheral immunologic features related to severity. A panel of cytokines was measured in paired cerebrospinal fluid (CSF) and in the supernatant of antigen-specific stimulated peripheral blood mononuclear cells samples (SN) in a total of 31 untreated inflammatory and non-inflammatory NC patients. Increased clinical and radiologic severity was associated with an increased cerebrospinal fluid cell count. A peripheral proliferative depression that negatively correlates with CSF cellularity and TNFα and that positively correlates with SN IL5 was observed in severe NC patients. These results provide evidences to support the systemic proliferative response as a biomarker to monitor the level of neuroinflammation, of possible value in the patients’ follow-up during treatment.

The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum

3-Hydroxykynurenine (3-HK), an intermediate metabolite of the kynurenine pathway, has been largely hypothesized as a neurotoxic molecule contributing to neurodegeneration in several experimental and clinical conditions. Interestingly, the balance in literature points to a dual role of this molecule in the CNS: in vitro studies describe neurotoxic and/or antioxidant properties, whereas in vivo studies suggest a role of this metabolite as a weak neurotoxin. This work was designed to investigate, under different experimental conditions, whether or not 3-HK is toxic to cells, and if the redox activity exerted by this molecule modulates its actions in the rat striatum. In order to evaluate these effects, 3-HK was administered in vitro to isolated striatal slices, and in vivo to the striatum of rats. In striatal slices, 3-HK exerted a concentration- and time-dependent effect on lipid peroxidation, inducing both pro-oxidant actions at low (5-20) micromolar concentrations, and antioxidant activity at a higher concentration (100µM). Interestingly, while 3-HK was unable to induce mitochondrial dysfunction in slices, at the same range of concentrations it prevented the deleterious effects exerted by the neurotoxin and related metabolite quinolinic acid (QUIN), the mitochondrial toxin 3-nitropropionic acid, and the pro-oxidant compound iron sulfate. These protective actions were related to the stimulation of glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. In addition, 3-HK stimulated the protein content of the transcription factor and antioxidant regulator Nrf2, and some of its related proteins. Accordingly, 3-HK, but not QUIN, exhibited reductive properties at high concentrations. The striatal tissue of animals infused with 3-HK exhibited moderate levels of lipid and protein oxidation at short times post-lesion (h), but these endpoints were substantially decreased at longer times (days). These effects were correlated with an early increase in glutathione reductase (GR) and GST activities. However, these changes were likely to be merely compensatory as 3-HK-infused animals did not display behavioral (rotation) alterations or morphological changes in their injected striata. Altogether, these findings suggest that, despite 3-HK might exert pro-oxidant actions under certain conditions, these changes serve to evoke a redox modulatory activity that, in turn, could decrease the risk of cell damage. In light of this evidence, 3-HK seems to be more a redox modulatory molecule than a neurotoxic metabolite.

Evaluating Stress during Pregnancy: Do We Have the Right Conceptions and the Correct Tools to Assess It?

Gestational stress is believed to increase the risk of pregnancy failure and perinatal and adult morbidity and mortality in both the mother and her child or children. However, some contradictions might arise from methodological issues or even from differences in the philosophical grounds that guide the studies on gestational stress. Biased perspectives could lead us to use and/or design inadequate/incomplete panels of biochemical determinations and/or psychological instruments to diagnose it accurately during pregnancy, a psychoneuroimmune-endocrine state in which allostatic loads may be significant. Here, we review these notions and propose a model to evaluate and diagnose stress during pregnancy.

Regulatory T Cells in Central Nervous System: in Health and Disease

Regulatory T cells participate in several immune responses including autoimmune reactions inducing self-tolerance, tumor immunity, transplantation tolerance and microbial infection. Nevertheless regulatory T cells actions seem to be different when they are in the central nervous system (CNS), since they interact with resident cells of the CNS, according to the particular conditions elicited in this compartment. This review focuses on the role of regulatory T cells in health, autoimmune and other CNS diseases, pointing out their interactions with resident CNS cells.