B Grembecka

Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats.

Intracerebroventricular (ICV) injection of streptozotocin (STZ) is a widely-accepted animal model of sporadic Alzheimers disease (sAD). The present study evaluated the ability of dimethyl fumarate (DMF), an agent with antioxidant and anti-inflammatory properties, to prevent spatial memory impairments and hippocampal neurodegeneration mediated by ICV injection of STZ in 4-month-old rats. Rodent chow containing DMF (0.4%) or standard rodent chow was made available on day 0. Rat body weight and food intake were measured daily for whole the experiment (21days). STZ or vehicle (SHAM) ICV injections were performed on days 2 and 4. Spatial reference and working memory were evaluated using the Morris water maze on days 14-21. Cells containing Fluoro-Jade B (neurodegeneration marker), IL-6, IL-10 were quantified in the hippocampus and choline acetyltransferase (ChAT) in the basal forebrain. The disruption of spatial memory and a high density of hippocampal CA1-3 cells labeled with Fluoro-Jade B or containing IL-6 or IL-10 were observed in the STZ group but not in the STZ+DMF group, as compared to the SHAM or SHAM+DMF groups. STZ vs. STZ+DMF differences were found: worse reference memory acquisition, fewer ChAT-positive neurons in the medial septum (Ch1), more Fluoro-Jade-positive CA1 hippocampal cells in STZ rats. DMF therapy in a rodent model of sAD prevented the disruption of spatial reference and working memory, loss of Ch1 cholinergic cells and hippocampal neurodegeneration as well as the induction of IL-6 and IL-10 in CA1. These beneficial cognitive and molecular effects validate the anti-inflammatory and neuroprotective properties of DMF in the hippocampus.

Effects of chronic desipramine pretreatment on open field-induced suppression of blood natural killer cell activity and cytokine response depend on the rat's behavioral characteristics

Effects of 14 consecutive day exposure to desipramine (10mg/kg i.p.), by itself or following chronic open field (OF) exposure, on subsequent neuroimmunological effects of acute (30 min) OF stress and the involvement of individual differences in response to novelty or social position in the anti-depressive responsiveness were investigated. Chronic desipramine pretreatment did not protect against OF stress-induced suppression of blood anti-tumor natural killer cell activity but increased plasma interleukin-10 and decreased interferon-γ and corticosterone concentration. These effects were particularly dangerous for the animals with increased responsivity to stress (desipramine alone) or with low behavioral activity (desipramine after chronic stress).

Stress-induced differences in the limbic system Fos expression are more pronounced in rats differing in responsiveness to novelty than social position

We determined the interaction between such individual behavioural profiles as locomotor response to novelty or social position and the activation (Fos expression) of the brains limbic regions following chronic laboratory and social interaction stress. Male Wistar rats (n=45), housed separately and handled for 2 weeks, were divided into high (HR) and low (LR) responders to novelty. Seven days later, 12 HRs and 12 LRs were subjected to a chronic 23 consecutive day social interaction test (Nov/SocI group), 5 HRs and 5 LRs were subjected to chronic laboratory stress: carrying from the vivarium to the laboratory for 23 consecutive days (Nov/Carr group) while the remaining rats stayed in the vivarium in their home cages (Nov/Home group). The highest limbic system activation was found 7 days later in the Nov/SocI rats. In comparison with the LRs, the HRs showed a higher number of Fos(+) cells in most of the limbic prosencephalic structures (24 areas) in the Nov/SocI group, and in 12 areas, especially in the amygdala and the hypothalamus, in the Nov/Carr group. There were no HR/LR differences in the limbic systems activity in the Nov/Home group. Within dominance/submission differences, a higher Fos expression was found in 6 structures, especially in the limbic cortex, in the dominant rather than the subordinate HRs. We conclude that chronic social and laboratory stress persistently activates the limbic system, with the largest effects in the brains of rats responding maximally to novelty. Social position was less predictive of Fos expression than was activity to novelty.

Changes in blood CD4 + T and CD8 + T lymphocytes in stressed rats pretreated chronically with desipramine are more pronounced after chronic open field stress challenge

The present study examines the influence of a chronic (14 consecutive days) desipramine (10mg/kg i.p.) pretreatment by itself vs. after chronic (7 consecutive day) open-field (OF) on immune system alterations in response to acute (30 min) OF in Wistar rats (n=60). Opposing to the effect of desipramine injected alone, the combined pretreatment after chronic OF challenge exerts suppressive effects on peripheral blood T/B, CD4(+)T-helper/inducer and CD8(+)T-cytotoxic/suppressor but not NK cell number, decreased interferon-γ/interleukin-10 ratio and thymus weight in the stressed rats. It suggests that chronic stress exposure is important for the immunomodulatory effects of pretreatment with antidepressants.

Chronic antidepressant desipramine treatment increases open field-induced brain expression and spleen production of interleukin 10 in rats

In the present study, we established a role of individual differences in locomotor response to novelty or social position in modulatory effect of chronic (14 consecutive days) antidepressant drug desipramine pretreatment (10mg/kg i.p.) on acute (30 min), white and illuminated open field (OF)-induced changes in spleen anti-tumor activity of natural killer (NK) cells (chromium release assay) in parallel to the brain anti-inflammatory interleukin 10 (IL-10) and Fos expression (immunohistochemistry), splenocytic pro-inflammatory interferon γ (IFN-γ) and IL-10 production (ELISA), and plasma corticosterone concentration (RIA) in rats. The involvement of individual differences (high (HR) and low (LR) responders to novelty or dominants (D) and subordinates (S)) in the anti-depressive responsiveness, was investigated in the desipramine treated by itself (DES) or following 7 consecutive days of OF exposure (ChS-DES) group. In the desipramine pretreated groups, OF stress decreased spleen NKCC, behavioral activity, the Con A-stimulated splenocyte IFN-γ response and plasma corticosterone concentration whereas it increased the brain and splenocyte IL-10 response. The percentage of OF-induced IL-10/Fos(+) cells was increased in the CA1 and dentate gyrus of the hippocampus and amygdaloid nucleus, particularly in the LR-D (DES) and LR-S (ChS-DES) rats. Moreover, a decreased splenocytic ability to produce IFN-γ and IL-10, particularly in the HR-S (DES) and LR-S (ChS-DES) rats, was noted. There were no significant differences in the OF-induced NKCC suppression between the behavioral groups. These studies emphasize that chronic desipramine pretreatment had anti-inflammatory but not immunoprotective properties against OF stress-induced neuroimmunological effects which depend on the animals behavioral characteristics and treatment.

Age-dependent effects of dimethyl fumarate on cognitive and neuropathological features in the streptozotocin-induced rat model of Alzheimer’s disease

We previously demonstrated that dimethyl fumarate (DMF), an anti-oxidative and immunosuppresive compound, prevents intracerebroventricular (ICV) streptozotocin-induced disruption of spatial memory and neurodegeneration in 4-month-old rats. The present study evaluated the influence of age on DMFs therapeutic effect. Aged rats (22-months-old, n = 40) were provided rodent chow containing DMF (0.4%) and given ICV injections of streptozotocin (STZ) or vehicle (Sham) on days 2 and 4. Spatial memory was evaluated using the Morris water maze (MWM) on days 14-21. Hippocampal samples from young (4-month-old, n = 36, collected previously) and aged rats were assessed for presence of activated (CD68-positive) microglia, IL-10 and oxidative/nitrative stress marker nitrotyrosine. Aged rat samples were also stained with Fluoro-JadeB marker for neurodegeneration. Previously obtained MWM and Fluoro-JadeB data from young rats served as a reference for assessing impact of age. Aged Sham DMF-fed rats exhibited better spatial memory and less neurodegeneration in the CA3 region of the hippocampus compared to corresponding young rats. Aged STZ rats displayed greater memory impairment and increased CA2 neurodegeneration, CA1 nitrotyrosine immunoreactivity, and microglial activation in the dentate gyrus (DG), compared to young STZ rats. Notably, within aged STZ-injected rats, DMF treatment was associated with improved performance in MWM, reduced neurodegeneration in all hippocampal areas, reduced DG microglia activation, and reduced CA1 nitrotyrosine labeling compared to age-matched rats without DMF treatment. This beneficial age-related effect of DMF treatment after STZ ICV injections may result from reduced microglial activation in the hippocampus that leads to an alleviation of oxidative stress, neurodegeneration, and memory impairments.