Biomedical subjects
Publications and source records attributed to M Kubera.
Patients with treatment-resistant major depression had a significantly higher percentage of helper CD4+ T cells and immature double positive CD4+CD8+ T cells in their blood, and higher CD4+/CD8+ ratio than healthy controls. These results suggest activation of T helper immuno-response and disturbance in thymus function in these patients.
The effects of desipramine and fluoxetine on the swelling of hind paws, radiologically-detectable bone destruction of hind paws, increase in spleen and popliteal lymph node weight, increase in metabolic activity of splenocytes and increase in proliferative activity of splenocytes and popliteal lymph node cells from right adjuvant injected paw in male C57BL/6 mice were studied on the 17th day after induction of post-adjuvant arthritis. Drugs were administered once-daily ip at a dose of 10 mg/kg. Fourteen days of desipramine administration, starting on the third day after injection of the adjuvant, significantly increased edema and radiologically assessed bone destruction, spleen and popliteal lymph node weight whereas fluoxetine induced an opposite effect, but it did not reduce edema in comparison with saline-treated control. Two-week desipramine administration significantly increased metabolic activity of splenocytes and proliferative activity of popliteal lymph node cells from the right adjuvant-injected paw, whereas 14 days of fluoxetine injection reduced proliferative activity of splenocytes in comparison with the saline-treated mice. Desipramine administration 30 days before and 17 days after adjuvant injection did not change these parameters in spite of reduction of proliferative activity of splenocytes. These findings indicate that: 1) fluoxetine has a suppressive effect on some of the local and systemic changes which occur in adjuvant-induced arthritis in mice, 2) two-week desipramine administration significantly increases whereas 47-day desipramine treatment does not change most of local and systemic parameters of post-adjuvant disease in C57BL/6 mice, 3) the action of fluoxetine differs from that of desipramine in this model of autoimmunodisease probably as a result of the distinct effect of these two drugs on corticoids levels and on the activity of a sympathetic nervous system.
There is now some evidence that major depression is accompanied by an immune response with an increased production of pro-inflammatory cytokines. The aim of the present study was to examine serum level of cytokines: interleukin-6 (IL-6), which is considered pro-inflammatory one and anti-inflammatory cytokines: interleukin 10 (IL-10), and interleukin-1 receptor antagonist (IL-1Ra) in acute clinical state of depression and after 6-week antidepressant treatment. Serum IL-6, IL-10, IL-1Ra levels were higher in the subjects with major depression than in normal controls although these results were not statistically significant. The mean score according to the Hamilton Depression Rating Scale (HDRS) in the patients significantly decreased during the 6 weeks of the study, demonstrating an overall improvement. Successful antidepressant treatment had no significant effect on serum level of this cytokines.
It has been established that thyrotropin-releasing hormone (TRH) affects several aspects of immunoreactivity, e.g. production of pro-inflammatory cytokines, and enhances therapeutic efficiency of classic tricyclic antidepressants. On the other hand, it has been suggested that pro-inflammatory cytokines play a role in the etiology of depression, whereas the therapeutic efficacy of antidepressants is related to their negative immunoregulatory effect. In order to verify the hypothesis that the TRH-induced increase in the therapeutic efficiency of classic tricyclic antidepressants results from synergistic inhibitory effects of those two agents on the secretion of pro-inflammatory cytokines, we studied the effect of imipramine appliedjointly with TRH on the production of IFN-gamma and IL-10 by human whole blood cells stimulated in vitro by mitogens. A significant decrease in the production of IFN-gamma and IL-10 cytokines, by 36% and 34%, respectively, was observed in cells stimulated with mitogens and co-incubated with imipramine and TRH (either given at a dose of 10(-5) M). Under the same conditions, TRH alone did not change the production of those cytokines. Furthermore, imipramine alone decreased, not statistically significantly, though, the production of IFN-gamma. Hence our data only partly support the above-mentioned hypothesis, since TRH and imipramine applied jointly suppress the production of both the pro-inflammatory IFN-gamma and the anti-inflammatory IL-10 cytokines.
Antidepressant drugs have been shown to reverse some changes evoked by glucocorticoids or stress. In the present study we attempted to find out whether imipramine, one of the most frequently used antidepressant drugs, interfered with glucocorticoids, modulating the production of IFN-gamma and IL-10, pro-inflammatory and anti-inflammatory cytokines, respectively. We observed a significant inhibitory effect of hydrocortisone, dexamethasone and the glucocorticoid receptor agonist RU 28362, used at doses of 10(-6) and 10(-5) M, on the production of IFN-gamma and IL-10 by whole blood cells stimulated by mitogens. Imipramine at doses of 10(-6) and 10(-5) M did not modulate IFN-gamma or IL-10 production, whereas at a dose of 10(-5) M it increased the production of IL- 10 and decreased that of IFN-gamma, those results being statistically insignificant, though. A combination of imipramine and dexamethasone or hydrocortisone at doses of 10(-6) or 10(-5) M significantly suppressed the production of IFN-gamma and IL-10, the level of inhibition being similar to that observed for glucocorticoids alone. The classic antidepressant imipramine was not able to modulate the suppressive effect of "stress" doses of hydrocortisone on the production of cytokines.
Seizure-related changes in function of the peripheral immune system, especially in its cell component are poorly recognized. In the present study, we examined the effect of seizures induced by intraperitoneal injection of kainate to mice and rats on weight of central and secondary immunological organs and metabolic activity of splenocytes (MTT test). In kainate-injected mice the production of cytokines: interleukin 2 (IL-2) and IL-10 was also estimated. Seventy two hours after kainate administration, the mice and rats showed a marked decrease in the thymus weight by 36% and 50%, respectively, whereas the spleen weight tended to decrease in rats only. Splenocytes of kainate-injected mice and rats showed significant increase in metabolic activity. The ability of splenocytes of kainate-injected mice to produce IL-2 and IL-10 was reduced but only the former effect reached statistical significance. The results suggest a decrease in T helper-cell dependent immunoreactivity and enhanced phagocytic activity of macrophages in kainate-treated rodents.
The effect of physiological and pharmacologically induced thymus involution was studied in 12-week-old female C57BL mice. Thymus involution was estimated by measurement of the thymus weight and the ability of thymocytes to induce a graft-versus-host (GvH) reaction at 48 h after delivery or drug administration in comparison with control (virgin, saline-treated) mice. The thymus weight and immunoreactivity of thymocytes after delivery were reduced in a statistically significant manner by ca. 80 and 75%, respectively. On the other hand, hydrocortisone administration decreased the thymus weight (by ca. 60%), but did not change the ability of thymocytes to induce a GvH reaction. Cyclophosphamide administration significantly reduced both the thymus weight and the reactivity of thymocytes. The present study suggests that the transient thymus involution observed after delivery, connected with a loss of the ability of thymocytes to induce a GvH reaction, cannot be explained merely by elimination of a steroid-sensitive cortical cell population, since the GvH reactivity of thymocytes was preserved in hydrocortisone-treated mice.
Topiramate, a new anticonvulsant, has been reported to possess neuroprotective effects in both in vivo and in vitro experiments. In the present study, the effect of topiramate (40 and 80 mg/kg ip) on the fully developed kainate-induced status epilepticus was evaluated in the rat. Injection of kainate (15 mg/kg ip) evoked recurrent limbic seizures which lasted several hours. Topiramate injected 1.5 h after kainate administration had no effect on the seizures and mortality of the animals. Biochemical study revealed that at 80 mg/kg ip, topiramate significantly attenuated the kainate-induced lipid peroxidation in the piriform cortex and showed similar tendency in the frontal cortex. Besides the central nervous system, the kainate-induced seizures evoked significant changes in immunoreactivity, such as reduction in thymus weight and the proliferative activity of splenocytes, and the splenocyte-increased production of interleukin-10, but not interferon-gamma. Topiramate did not affect the kainate-induced reduction in thymus weight, but attenuated changes in the proliferative activity of splenocytes. It is concluded that topiramate, when given during the fully developed kainate-induced status epilepticus in rats, has no effect on seizures, but attenuates lipid peroxidation in piriform cortex and prevents certain changes in immunoactivity.
Cell-mediated immunity was investigated in adult mice and rats treated with monosodium glutamate in their suckling period. Delayed-type hypersensitivity to xenogeneic cells and host-versus-graft reactivity to allogeneic cells were depressed in these mice. Their splenocytes showed reduced mitogen-induced blastogenesis in vitro which was restored by removal of nonadherent to glass spleen cells. Xenogeneic local graft-versus-host reaction induced by spleen cells taken from Wistar rats treated with monosodium glutamate was significantly decreased. Treatment with monosodium glutamate of neonatal mice and rats (possibly producing hypothalamic lesions) significantly reduced their cell-mediated immunity.
Lymphoid neonatal cells from syngeneic donors are able to modulate the reactivity of recipient rats to MHC-incompatible vascular cardiac grafts. The suppressor splenocytes, obtained from one-day-old rats, may enhance the immunosuppressive effect of chronically administered low doses of cyclosporine (CsA).
The study examined the effect of repeated amitriptyline administration to mice on the proliferative activity of lymphocytes in response to mitogen stimulation and on the ability of natural killer (NK) cells to evoke lysis of YAC-1 tumor cells in vitro. A relatively short treatment (5 days) produced an increase in the NK activity, but no change in the T cell proliferative response to mitogens. After a 2-week treatment, a transient but significant decrease in the proliferative activity of splenocytes and in the NK activity was observed. Prolonged administration of that drug for more than 3 weeks produced a return to the control level of the NK activity and the T lymphocyte responsiveness to mitogens. The obtained results show that amitriptyline modifies the immune function, and that the observed effect depends crucially on the length of drug administration.
The effects of single and repeatedly administered amitriptyline (10 mg/kg ip) on the ability of the splenocytes of the restraint-stressed (for 2.5 h) Sprague-Dawley rats to induce the Graft versus Host (GvH) reaction in vivo and to respond to the concanavalin A (Con A) stimulation in vitro were studied. In acute experiments single immobilization, amitriptyline administration, or single amitriptyline treatment of the previously stressed rats did not change the reactivity of splenocytes to both mitogen and alloantigens. On the other hand, in the "chronic" experiment, when rats were stressed 2.5 h daily for five days with or without concurrent amitriptyline treatment, a statistically significant decrease in the reactivity of splenocytes to Con A and increase in the reactivity to alloantigens were visible only in the stressed, but not in stressed, amitriptyline treated animals.
A depression-like state was induced by chronic (3-week) exposure of Wistar rats to a very mild, unpredictable stress which is a model of depression, developed by Willner's group. Five-week daily administration of imipramine reversed the stress-induced deficit in sucrose consumption. Eight-week stress induced an increase in the ability of splenocytes to produce interleukin 1 (IL-1) and interleukin 2 (IL-2) and to proliferate after stimulation with concanavalin A. Antidepressant effects of imipramine were accompanied by a decrease in the ability of splenocytes to produce IL-1 and IL-2 and to proliferate. Administration of imipramine alone did not modify the activity of those cells.
Syngeneically-pregnant CBA mice were stressed by injecting them with saline, sc twice daily, on days 10-18 of their pregnancy. Pups born to these mothers exhibited disturbances in their immuno-regulatory cell development. Splenocytes harvested from these pups, when one day old, failed to suppress xenogeneic Graft-versus-Host reaction and proliferative response of syngeneic mature cells to concanavalin-A, as control splenocytes did. Also, thymocytes of 4-6-day-old mice, born to stressed mothers, did not exert an inhibitory effect on neonatal suppression, as control thymocytes did. These results demonstrate that neonatal stress is an useful physiological model for studying interactions between some regulatory systems of the organism, in its early stages of development.