Biomedical subjects

B Sakic

Publications and source records attributed to B Sakic.

6 recordsLinked to original sources

PubMed2001

Neurotoxic properties of cerebrospinal fluid from behaviorally impaired autoimmune mice.

The chronic, lupus-like autoimmune disease in MRL-lpr mice is associated with leucocyte infiltration into the choroid plexus, brain cell death, and deficits in motivated behavior. The presence of lymphoid cells in the ventricular lumen and the increased number of TUNEL-positive cells in periventricular areas led to the hypothesis that immune cells enter into the cerebrospinal fluid (CSF) and induce primary neuronal damage in regions bordering the cerebral ventricles. Using an in vitro approach, we presently examine the possibility that CSF from autoimmune mice is neurotoxic and/or gliotoxic. The CSF and serum from diseased MRL-lpr mice, less symptomatic MRL +/+ controls, and healthy Swiss/Webster mice (non-autoimmune controls) were frozen until their effects on the viability of pyramidal neurons and astrocytes were assessed in a two-color fluorescence assay. Significant reduction in neuronal viability (in some cases as low as 67%) was observed in the co-cultures of hippocampal neurons and astrocytes incubated for 24 h with CSF from autoimmune MRL-lpr mice. The viability of astrocytes did not differ among the groups, and the CSF from autoimmune mice appeared more toxic than the serum. The behavior of MRL-lpr mice differed significantly from the control groups, as indicated by impaired exploration, reduced intake of palatable food, and excessive immobility in the forced swim test. The present results suggest that CSF from the behaviorally impaired lupus-prone mice is neurotoxic and are consistent with the hypothesis that neuroactive metabolites are produced intrathecally in neuropsychiatric lupus erythematosus.

Animals↗

PubMed2000

Immunosuppression prevents neuronal atrophy in lupus-prone mice: evidence for brain damage induced by autoimmune disease?

An early onset of systemic, lupus-like disease in MRL-lpr mice is accompanied by deterioration in their behavioral performance and atrophy of pyramidal neurons in the parietal cortex and the hippocampal CA1 area. Using the immunosuppressive drug cyclophosphamide (CY) to attenuate the disease, we have tested the hypothesis that the autoimmune/inflammatory process is responsible for changes in brain morphology. A modified Golgi impregnation method revealed that, in comparison to saline-treated controls, immunosuppressive treatment with CY (100 mg/kg/week i.p. over 8 weeks) increased dendritic branching and spine numerical density in the CA1 region of MRL-lpr mice and MRL +/+ mice, which develop less severe manifestations of the disease. More interestingly, CY selectively prevented the atrophy and aberrant morphology of pyramidal neurons in the parietal cortex of MRL-lpr mice. The neuropathological measures (in particular reduced dendritic spine density) significantly correlated with increased serum levels of antinuclear antibodies and splenomegaly. The present results support the hypothesis that chronic autoimmune disease induces functionally important changes in neuronal morphology, and provide an empirical basis for understanding the behavioral dysfunction in systemic lupus erythematosus and autoimmune phenomena reported in some forms of mental illness.

Animals↗

PubMed2000

Increased TUNEL staining in brains of autoimmune Fas-deficient mice.

Profound changes in brain morphology and behavior coincide with the spontaneous development of systemic autoimmune/inflammatory disease in Fas-deficient MRL-lpr mice. The dendrites atrophy, the density of hippocampal and cortical neurons decreases, and an anxious/depressive-like behavior emerges while lymphoid cells infiltrate into the choroid plexus of MRL-lpr mice. We hypothesized that the inherited lack of the Fas-dependent anti-inflammatory mechanism would lead to unsuppressed immune activity, characterized by reduced apoptosis in the MRL-lpr brain. Using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeled (TUNEL) method as an indicator of apoptosis, a surprisingly high incidence of TUNEL-positive cells was observed in the hippocampus, choroid plexus and periventricular regions of MRL-lpr mice, 5-10-fold higher than that found in the MRL +/+ control brain. Immunostaining with anti-CD3, CD4 and CD8 monoclonal antibodies showed limited overlap between CD-positive and TUNEL-positive cells, suggesting that the dying cells are for the most part (approximately 70%) not T-lymphocytes. Although further characterization of the phenotype of the dying cells and the mechanism of cell death are required, the present results suggest the involvement of a Fas-independent apoptotic process in neurodegeneration induced by systemic autoimmune disease.

Animals↗

PubMed1997

Animal models for nervous system disease in systemic lupus erythematosus.

Animal models have much to teach us about nervous system dysfunction in SLE. It should be stressed that the murine strains described in this review have variable expression in the onset and severity of clinical and serological features, perhaps making them more like a heterogeneous human population with SLE. With this in mind, studies involving animal models like those involving human subjects should use a sample size that ensures adequate power. It is not surprising that studies that use sample sizes as low as four to five animals per group would find discrepant results, especially in outcomes that are measured prior to the terminal phases of the disease. Similar to human SLE patients, murine models have systemic autoimmune as well as neurological manifestations. Studies with murine models must continue to consider some type of SLE disease activity measures in order to control for the effects of systemic disease on nervous system dysfunction. Because of the short time window between the earliest evidence of neurologic dysfunction and severe autoimmune disease manifestations, especially in MRL/lpr mice, the disease acceleration model may allow a more careful dissection of how immunological events are related to nervous system dysfunction. Alternatively, the study of MRL/lpr mice ultraearly (e.g., 3 weeks of age) could also provide invaluable information about the first events leading to nervous system dysfunction in SLE. Both approaches promise to identify predictors of specific nervous system manifestations that may suggest novel and more specific therapeutic interventions.

Animals↗

PubMed1990

Self-stimulation behavior: consequences upon immunity?

A variety of behavioral and emotional factors can affect the immune response by changing the brain immunoregulatory mechanisms, resulting in immunosuppression or immunopotentiation. This experiment deals with the effect of chronic self-stimulation behavior on the immune response and lymphoid tissue. Male rats were stereotaxically implanted with bipolar electrodes into the lateral hypothalamus and 7 days after surgery were screened for self-stimulation behavior. Lateral hypothalamus self-stimulating rats (LH-SS) were allowed to self-stimulate for 60 min/day for a period of 9 consecutive days: 5 days before and 4 days after immunization with 5 x 10(9) sheep red blood cells (SRBC). The animals were sacrificed and plaque-forming cell assay (PFC), microhaemmagglutination reaction with SRBC, and differential blood leucocyte counts were performed. The thymus, spleen, and inguinal lymph nodes were weighed and processed for histological examination. In the LH-SS group, an enhanced PFC response and increased anti-SRBC antibody titer were observed when compared to controls. The thymus and spleen of LH-SS rats were smaller in size in comparison with controls, but only with moderate changes in splenic cellular make-up. The relative number of lymphocytes was increased in peripheral blood of LH-SS rats when compared to intact animals. The results obtained suggest that chronic self-stimulation behavior can modulate some parameters of humoral immune response and affect the relative weight of lymphoid organs in the rat.

Animals↗

PubMed1989

Electro-acupuncture modifies humoral immune response in the rat.

The immunomodulating properties of "Shangqiu" (LP-5), "Ququan" (H-8), and "Rangu" (R-2) points were studied in several experiments performed on male Wister rats treated bilaterally by acupuncture (A) or electro-acupuncture (EA). On the stimulation day 3, the sheep-red-blood cells (SRBC) antigen was injected intraperitoneally and four days later, the immunological tests (plaque forming cells-PFC, direct microhemagglutination) were performed. Also, the relative weights of lymphoid organs (spleen and thymus) and adrenal gland were derived after sacrifice. The results obtained suggest pronounced immunomodulating properties of 200 Hz cathodal current stimulation at H-8 point. The immunosuppression observed reflected in a decreased number of PFC and reduced relative weights of adrenal gland revealed in all A- or EA-treated groups.

Acupuncture Analgesia↗