Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied sickness behavior, by assessing daily body weight, open field behavior, and TNF-α plasmatic levels. Anxiety-like behavior (light-dark test), depressive-like behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced sickness behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like behavior in rats. Propentofylline prevented sickness behavior after four days of consecutive treatment, as well as prevented the depressive-like behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced sickness behavior and depressive-like behavior in rats. Propentofylline prevented both sickness behavior and depressive-like behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases.

A programmed turnover of pancreatic beta cells occurs in the neonatal rat involving a loss of beta cells by apoptosis, and their replacement by islet cell replication and neogenesis. The timing of apoptosis is associated with a loss of expression of a survival factor, insulin-like growth factor-II (IGF-II), in the pancreatic islets. Offspring from rats chronically fed a low protein isocalorific diet (LP) exhibit a reduced pancreatic beta cell mass at birth and a reduced insulin secretion in later life. This study therefore investigated the impact of LP on islet cell ontogeny in the late fetal and neonatal rat, and any associated changes in the presence of IGFs and their binding proteins (IGFBPs). Pregnant Wistar rats were fed either LP (8% protein) or normal (C) (20% protein) chow from shortly after conception until the offspring were 21 days postnatal (PN). Bromo-deoxyuridine (BrdU) was administered 1 h before rats were killed and pancreata removed from animals between 19.5 days fetal life and postnatal day 21. Offspring of rats given LP diet had reduced birthweight, pancreatic beta cell mass, and pancreas insulin content, with smaller islets compared with control fed animals, which persisted to weaning. Histological analysis showed that islets from pups given LP diet had a lower nuclear labeling index with BrdU in the beta cells, although, paradoxically, more beta cells showed immunoreactivity for proliferating cell nuclear antigen (PCNA). Because PCNA is present in G1 as well as S phase of the cell cycle, we quantified the number of beta cells immunopositive for cyclin D1, a marker of G1, and NEK2, an indicator of cells in G2 and mitosis. More beta cells in islets from LP-fed animals contained cyclin D1, but less contained NEK2 than did those in controls. This suggests that the beta cell cycle may have a prolonged G1 phase in LP-fed animals in vivo. Offspring of rats given C diet had a low rate of islet cell apoptosis detected by the TUNEL method in fetal and neonatal life (1-2%), with a transient increase to 8% at PN day 14. Offspring of rats receiving LP diet demonstrated a significantly greater level of islet cell apoptosis at every age, rising to 15% at PN 14. IGF-II mRNA was quantified in whole pancreas and was significantly reduced in LP-fed animals at ages up to PN day 10. IGF-II immunoreactivity within the islets of LP-fed rats was also less apparent, but no changes were seen in immunoreactive IGF-I or IGFBPs-2 to -5. These findings show that LP diet changes the balance of beta cell replication and apoptosis in fetal and neonatal neonatal life, which may involve an altered length of beta cell cycle, and contribute to the smaller islet size and impaired insulin release seen in later life. A reduced pancreatic expression of IGF-II may contribute to the lower beta cell proliferation rate and increased apoptosis seen in the fetus and neonate after feeding LP diet.

The present study analyzed the immune modulation mechanisms of thymulin 5CH in a granuloma experimental model. Male adult Balb/c mice were inoculated with BCG into the footpad to induce granuloma, which was quantitatively evaluated. The phenotypic characterization of phagocyte, T- and B-lymphocyte populations in the peritoneum, and local lymph node was done by flow cytometry. During all experimental periods, thymulin 5CH and vehicle (control) were given ad libitum to mice, diluted into the drinking water (1.6 × 10−17 M). After 7 days from inoculation, thymulin-treated mice presented reduction in the number of epithelioid cytokeratine-positive cells (P = 0.0001) in the lesion, in relation to young phagocytes. After 21 days, the differentiation of B1 peritoneal stem cells into phagocytes reached the peak, being higher in thymulin-treated mice (P = 0.0001). Simultaneously, the score of infected phagocytes in the lesion decreased (P = 0.001), and the number of B1-derived phagocytes, CD4+ and CD8+ T lymphocytes in the local lymph node increased in relation to control (P = 0.0001). No difference was seen on the CD25+ Treg cells. The results show that thymulin 5CH treatment is able to improve the granuloma inflammatory process and the infection remission, by modulating local and systemic phagocyte differentiation.

The treatment of mice with Antimonium crudum 30cH induced a predominantly B cell pattern of immune response in Leishmania (L.) amazonensis experimental infection, alongside the increase of free amastigote forms number in the infection site. The clinical significance of this study is discussed, further studies are suggested.

The effects of a maternal hypercaloric diet (HD) during puberty and early adulthood on neuroimmune aspects in offspring were investigated. In female rats of the F generation and male rats of the F generation, bodyweight (BW) gain, retroperitoneal fat (RPF) weight, the number of hypodermic adipocytes (HAs) and expression of glial fibrillary acidic protein (GFAP) were measured in hypothalamic astrocytes. On Postnatal Day 50, the F pups were challenged with lipopolysaccharide (LPS, 100µgkg, s.c.) or an equal volume of saline (S), and behaviour in the open field test was evaluated, as were plasma neuropeptide and cytokine concentrations. The maternal HD caused the female F rats to become overweight. The F offspring of dams fed the HD and challenged with saline (HDS group) exhibited increases in BW gain, RPF weight and in the number of large HAs and a decrease in GFAP immunoreactivity. F offspring of dams fed the HD and challenged with LPS (HDLPS group) exhibited decreases in BW gain, RPF weight and GFAP immunoreactivity, but no differences were observed in the number of larger and small HAs. Plasma tumour necrosis factor-α concentrations were high in the HDS and HDLPS groups. Thus, the maternal HD during puberty and early adulthood caused the F generation to become overweight despite the fact that they received a normocaloric diet. These results indicate a transgenerational effect of the HD that may occur, in part, through permanent changes in immune system programming. The attenuation of neuroinflammation biomarkers after LPS administration may have resulted in a decrease in the number of adipocytes, which, in turn, reduced cytokine, adipokine and chemokine levels, which are able to recruit inflammatory cells in adipose tissue.

Introduction Encephalitozoon cuniculi (E. cuniculi), a fungus that acts as an intracellular pathogen, causes a marked neurological syndrome in many host species and is a zoonotic concern. Although no well-established treatment for this syndrome is known, previous successful clinical experience using homeopathic phosphorus has been described in which symptom remission with no mortality occurred in 40/42 animals by means of unknown immunological mechanisms. The latter observation was the main motivation for this study. Objective To verify, in an in-vitro model, if macrophages infected with E. cuniculi can change in function after treatment with different potencies of phosphorus. Materials and Methods RAW 264.7 macrophages were infected with E. cuniculi in-vitro and treated with various homeopathic potencies of phosphorus. The vehicle was used as a control solution (0.06% succussed ethanol). After 1 and 24 hours, the following parameters were analyzed: parasite internalization (by the Calcofluor staining method), lysosome activity (by the acridine orange method), cytokine/chemokine production (by the MAGPIX system), and cell ultrastructure. Automatic image analysis was used when applicable, and the experiments were performed in triplicate. Results Treatment with vehicle alone increased interleukin (IL)-6, tumor necrosis factor alpha and monocyte chemotactic protein -1 production (p ≤ 0.05) and reduced the number of internalized parasites (p ≤ 0.001). A progressive and time-dependent increase in RANTES (regulated on activation, normal T-cell expressed and secreted) and lysosome activity (p ≤ 0.002) was observed only after treatment with the highest potency of phosphorus (Phos 200cH), together with decreased apoptosis rate, intense parasite digestion, and the presence of non-internalized spores. Conclusions Phos 200 cH has a modulatory action on the activity of infected macrophages, especially a specific increase in RANTES, a key element in the prognosis of E. cuniculi-infected and of immunosuppressed patients bearing infections.

Background Highly diluted and succussed solutions interact with solvatochromic dyes, indicating that changes in solvent and solute polarity could be related to their mechanism of action. It is not known, however, how the activity associated with succussed high dilutions is transferred to untreated water and what the limits of this process are. Aims The aims of the present study were to ascertain whether a succussed high dilution of phosphorus (1.5 × 1−59 M; Phos 30cH) seeded into a natural water source that fed a fjord and two connected lakes could propagate itself through the lake system (total volume 2200 m3) and, moreover, whether the process could be tracked using solvatochromic dyes. Methods Samples of water were collected before and after seeding, at different times and places throughout the lake system. Controls comprised water taken from an untreated and adjacent, but independent, lake (1385 m3). Results Water samples taken up to 72 hours after the source treatment produced significant increases (p ≤ 0.03) in the absorbance of the solvatochromic dye methylene violet (MV), while samples from the control lake produced no changes. Conclusions The study indicates that activity associated with Phos 30c can propagate itself through large volumes of water, causing changes throughout a whole connected lake system, and that these changes can be tracked using the solvatochromic dye MV. This in turn means the use of homeopathic medicines in large volumes of drinking water, in farming and ecological contexts, now has the potential to be assessed with physico-chemical monitoring.

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