This study tests the hypothesis that in chronic Toxoplasma gondii infection communication among immune cells promotes neuroinflammation through cytokine networks and potentiate cognitive impairments in BALB/c mice with Alzheimer's disease (AD). The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from the Tehran strain of T. gondii . We injected amyloid-beta 1-42 peptide (Aβ, 1 and 2 μl) into the hippocampus of BALB/c mice to establish an animal model of AD. The behavioral experiments such as spatial learning and memory were performed using the Morris water maze test. The mRNA levels of TNF-α, IL-1β, IFN-γ, and inducible nitric oxide synthase (iNOS) were examined by real-time PCR. We found that T. gondii infection caused AD-like symptoms and impaired learning and memory functions of the infected BALB/c mice. We also found that in Toxoplasma infection + Aβ (1 μl) group, T. gondii infection could potentiate AD in infected mice receiving subdoses of Aβ (1 μl) and caused considerable impairment in learning and memory functions similar to AD group. Comparison of the results demonstrated that mRNA levels of IL-1β, TNF-α, IFN-γ, and iNOS significantly (P < 0.001) increased in T. gondii + Aβ (1 μl) in comparison with the other tested groups. The obtained results showed that chronic T. gondii infection communication among immune cells promotes neuroinflammation through cytokine networks and induces pathological progression of AD in the mice brain, whereas the presence of neuroanatomical Toxoplasma tissue cysts in the brain could also affect the behavioral functions in T. gondii -infected mice.
Leishmaniasis is one of the diverse and neglected tropical diseases. Embryo-toxicity of drugs has always been a major concern. Chick embryo is a preclinical model relevant in the assessment of adverse effects of drugs. The current study aimed to assess embryonic histopathological disorders and amniotic fluid biochemical changes following meglumine antimoniate treatment. The alteration of vascular branching pattern in the chick’s extra-embryonic membrane and exploration of molecular cues to early embryonic vasculogenesis and angiogenesis were also quantified. Embryonated chicken eggs were treated with 75 or 150 mg/kg of meglumine antimoniate. Embryo malformations, growth retardation and haemorrhages on the external body surfaces were accompanied by histopathological lesions in the brain, kidney, liver and heart in a dose-dependent manner. Significant rise occurred in the biochemical indices of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and amylase in the amniotic fluid. Quantification of the extra-embryonic membrane vasculature showed that the anti-angiogenic and anti-vasculogenic effects of the drug were revealed by a significant decrease in fractal dimension value and mean capillary area. The relative expression levels of vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 mRNA also significantly reduced. Concerns of a probable teratogenicity of meglumine antimoniate were established by data presented in this study. It is concluded that tissue lesions, amniotic fluid disturbance, altered early extra-embryonic vascular development and gene expression as well as the consecutive cascade of events, might eventually lead to developmental defects in embryo following meglumine antimoniate treatment. Therefore, the use of meglumine antimoniate during pregnancy should be considered as potentially embryo-toxic. Hence, physicians should be aware of such teratogenic effects and limit the use of this drug during the growing period of the fetus, particularly in rural communities. Further pharmaceutical investigations are crucial for planning future strategies.
Background: Leishmaniasis is a serious health problem in some parts of the world. In spite of the many known leishmaniasis control measures, the disease has continued to increase in endemic areas, and no effective vaccine has been discovered. Methods: In this study, Leishmania tarentulae was used as a living factory for the production of two LACK and KMP11 immunogenic antigens in the mice body, and safety profiles were investigated. The sequences of the KMP11 and LACK L. major antigens were synthesized in the pLEXSY-neo 2.1 plasmid and cloned into E. coli strain Top10, and after being linearized with the SwaI enzyme, they were transfected into the genome of L. tarentolae. The L. tarentolae-LACK/ KMP11/EGFP in the stationary phase with CpG ODN as an adjuvant was used for vaccination in BALB/c mice. Vaccination was performed into the left footpad. Three weeks later, the booster was injected in the same manner. To examine the effectiveness of the injected vaccine, pathogenic L. major (MRHO/IR/75/ER) was injected into the right footpad of all mice three weeks following the booster vaccination. In order to assess humoral immunity, the levels of IgG1, and IgG2a antibodies before and 6 weeks after the challenge were studied in the groups. In addition, in order to investigate cellular immunity in the groups, the study measured IFN-γ, IL-5, TNF-α, IL-6 and IL-17 cytokines before, 3 weeks and 8 weeks after the challenge, and also the parasite load in the lymph node with real-time PCR. Results: The lowest level of the parasitic load was observed in the G1 group (mice vaccinated with L. tarentolae-LACK/KMP11/EGFP with CpG) in comparison with other groups (L. tarentolae-LACK/KMP11/EGFP +non-CpG (G2); L. tarentolae-EGFP + CpG (G3, control); L. tarentolae-EGFP + non-CpG (G4, control); and mice injected with PBS (G5, control). Moreover, the evaluation of immune response showed a delayed-type hypersensitivity towards Th1. Conclusions: According to the results of this study, the live recombinant vaccine of L. tarentolae-LACK/KMP11/EGFP with the CpG adjuvant reduced the parasitic load and footpad induration in infected mice. The long-term effects of this vaccine can be evaluated in volunteers as a clinical trial in future planning.
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