HIV-1 Tat protein attenuates the clinical course of experimental autoimmune encephalomyelitis (EAE).

A growing body of evidence has shown that the human immunodeficiency virus (HIV) infection is associated with a significantly decreased risk of developing multiple sclerosis (MS) in patients with acquired immunodeficiency virus (AIDS). It is thought that two mechanisms are in charge of protection against MS, which include immunosuppression induced by chronic HIV infection (depletion of CD4 + T cells) and antiretroviral medications. HIV-1 encodes several regulatory (Tat and Rev) and accessory (Vpr, Vif, Vpu, and Nef) proteins that have immunosuppressive and immunomodulatory properties. HIV-1 Tat protein is a strongly immunosuppressive agent and can cross the blood-brain barrier (BBB). In this study, we examined the effect of HIV-1 Tat, which is classified into clade B and C, on inflammation, gliosis, apoptosis, and behavioral function in a murine model of MS called experimental autoimmune encephalomyelitis (EAE). For this aim, mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), followed by pertussis toxin to induce paralysis in EAE mice. After the induction of EAE in mice, the animals intraperitoneally received serial doses of HIV-1 Tat clade B and C (5, 10, and 20 µg/kg body weight) when the early clinical manifestations of EAE were initiated. The results showed that the administration of both clades of the Tat protein led to a marked decrease in the clinical score of EAE mice, as well as improvement in motor-neuron functions. In line with this, Tat considerably reduced the number of apoptotic cells in the sacral region of the spinal cord through the upregulation expression of the Bcl-2 protein. Besides, proinflammatory cytokines such as, IFN-γ, TNF-α, IL-6, and IL-17 were significantly diminished in the serum and spinal cord of EAE mice receiving HIV-1 Tat clade B and C. Conversely, anti-inflammatory cytokines, including IL-10 and IL-4 were elevated in the serum and spinal cord of EAE mice receiving HIV Tat clade B and C when compared with the control group. The immunohistochemical analysis indicated that HIV-1 Tat clade B and C mitigated microgliosis and astrogliosis. The flow cytometry analysis demonstrated that the number of Th1 and Th17cells was significantly decreased in response to TAT administration while the frequency of Th2 cells was markedly increased in the peripheral blood of mice with EAE without influencing the number of T regulatory cells (CD4 + CD25 + forkhead box protein 3 + ). It seems that HIV-1 Tat could be a bona fide therapeutic protein for the alleviation of MS since it has beneficial roles in the suppression of neuroinflammation in MS pathology.

2-(Bipiperidin-1-yl)-5-(nitroaryl)-1,3,4-thiadiazoles: Synthesis, evaluation of in vitro leishmanicidal activity, and mechanism of action.

The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4'-bipiperidin]-1'-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (IIc) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of L. major cells to IIa and IIc led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of IIa and IIc is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.

Novel 5-(nitrothiophene-2-yl)-1,3,4-Thiadiazole Derivatives: Synthesis and Antileishmanial Activity against promastigote stage of Leishmania major.

In this study, a series of novel compounds based on 5-(5-nitrothiophene-2-yl)-1,3,4-thiadiazole possessing (het) aryl thio pendant at C-2 position of thiadiazole ring is developed and evaluated as antileishmanial agents using MTT colorimetric assay. 10 New compounds containing aryl and heteroaryl derivatives, started from thiophene-2-carbaldehyde in five steps, were synthesized in good to excellent yields and characterized by 1H-NMR, 13C-NMR, and IR spectroscopy. Through the compounds 6a-j, methylimidazole containing derivative 6e was recognized as the most active compound against L. major promastigotes exhibiting IC50 values of 11.2µg/mL and 7.1µg/mL after 24 and 48 h, respectively. This compound is > 4 fold more effective than Glucantime as a standard drug (IC50 = 50 µg/mL after 24 h and 25 µg/mL after 48 h).

The protective effect of rifampicin on behavioral deficits, biochemical, and neuropathological changes in a cuprizone model of demyelination.

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) in which both neuroinflammation and neurodegeneration play critical roles in the pathogenesis of the disease. A growing body of evidence indicates that some antibiotics have anti-inflammatory and neuroprotective properties. Rifampicin, commonly used for the treatment of mycobacteria, has been shown to exert neuroprotective activities in neurodegenerative diseases. In this study, we examined the efficacy of rifampicin on demyelination, gliosis, apoptosis, inflammation, behavioral dysfunction, and biochemical alterations in the cuprizone model of demyelination. For this aim, male C57BL/6J mice were fed a chow containing 0.2% cuprizone (w/w) for 6 weeks to induce reversible demyelination in the corpus callosum. Mice intraperitoneally received serial doses of rifampicin (10, 20, or 40 mg/kg body weight) in the last 7 days of a 6-week period of cuprizone treatment. The results showed that the administration of rifampicin led to the improvement in motor behavioral deficits. In line with this, rifampicin decreased the number of apoptotic cells in the corpus callosum thereby diminishing the expression of cleaved caspase-3 and Bax, as well as increasing Bcl-2. Moreover, rifampicin significantly lowered the levels of interleukin-6, interleukin-1ß, caspase-12 activity, heme oxygenase-1(HO-1), nitric oxide (NO), and malondialdehyde (MDA) in mice treated with cuprizone. Conversely, the activity of glutathione peroxidase (GPx) and the level of ferric reducing ability of plasma (FRAP) were increased in response to the treatment with rifampicin. Histopathological findings demonstrated that rifampicin statistically promoted remyelination and mitigated microgliosis and astrogliosis. It seems that rifampicin is able to be added to the armamentarium of therapies for multiple sclerosis.