ammonium-trichloro(dioxoethylene-o-o--)tellurate and Inflammation

AS101 is a non-toxic organotellurium-IV compound with demonstrated immunomodulating activity in vitro and in vivo. Inflammatory responses are attributed to the pathophysiology of numerous ocular diseases. In this study, we wished to elucidate whether AS101 could mitigate pro-inflammatory activity in human retinal pigment epithelial (RPE) cells, which are heavily involved in ocular immune responses, induced by pro-inflammatory IL-β activity.. Primary and transformed RPE cells treated with varying concentrations of AS101 were used in this study. Real-time PCR and ELISA assays were used to detect cytokine/chemokine mRNA expression and protein production. Western blot was used to detect changes in the NFκB pathway. Cell viability and proliferation were detected using a Vi-Cell XR cell counter. To measure the cytoprotective capacity of AS101, cell numbers were compared between cells treated with IL-1β or lipopolysaccharide (LPS) and cells treated with IL-1β or LPS in the presence of AS101.. AS101 inhibited IL-1β-induced mRNA expression and protein production of IL-6 and IL-8 in RPE cells. The viability of RPE cells treated with IL-1β and LPS was unaffected. AS101 slightly inhibited RPE cell growth in the presence of higher levels of IL-1β. Also, AS101 downregulated the IL-1β activity by inhibiting the phosphorylation of p65, an NFκB subunit.. The results demonstrate that AS101 reduces IL-1β-induced inflammatory responses in the RPE. In previous studies, AS101 exhibited therapeutic effects in various disease models and was a safe profile in clinical trials. These results suggest that AS101 may have potent anti-inflammatory potential in the eye and confer the downregulation of RPE inflammatory responses in a pathological environment.

Topics: Adjuvants, Immunologic; Adult; Angiogenesis Inhibitors; Blotting, Western; Cell Count; Cell Line, Transformed; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Ethylenes; Humans; Inflammation; Interleukin-1beta; NF-kappa B; Oxidation-Reduction; Real-Time Polymerase Chain Reaction; Retinal Pigment Epithelium; RNA, Messenger; Tissue Donors

In Parkinson's disease (PD) dopaminergic neurons in the substantia nigra (SN) become dysfunctional and many ultimately die. We report that the tellurium immunomodulating compound ammonium trichloro(dioxoethylene-O,O'-)tellurate (AS101) protects dopaminergic neurons and improves motor function in animal models of PD. It is effective when administered systemically or by direct infusion into the brain. Multifunctional activities of AS101 were identified in this study. These were mainly due to the peculiar Tellur(IV)-thiol chemistry of the compound, which enabled the compound to interact with cysteine residues on both inflammatory and apoptotic caspases, resulting in their inactivation. Conversely, its interaction with a key cysteine residue on p21(ras), led to its activation, an obligatory activity for AS101-induced neuronal differentiation. Furthermore, AS101 inhibited IL-10, resulting in up-regulation of GDNF in the SN. This was associated with activation of the neuroprotective kinases Akt and mitogen-activated protein kinases, and up-regulation of the antiapoptotic protein Bcl-2. Inhibition of caspase-1 and caspase-3 activities were associated with decreased neuronal death and inhibition of IL-1beta. We suggest that, because multiple mechanisms are involved in the dysfunction and death of neurons in PD, use of a multifunctional compound, exerting antiapoptotic, anti-inflammatory, and neurotrophic-inducing capabilities may be potentially efficacious for the treatment of PD.

Topics: Adjuvants, Immunologic; Animals; Apoptosis; Cells, Cultured; Disease Models, Animal; Dopamine; Ethylenes; Inflammation; Male; Mice; Mice, Inbred C57BL; Motor Activity; Neurons; Parkinson Disease; Protective Agents; Rats; Rats, Sprague-Dawley; Tellurium

The purpose of this study was to investigate the effect of a novel immunomodulator, AS101 [ammonium trichloro(dioxyethelene-O-O') tellurate], in the eye. Lewis rats were injected intravitreally with AS101 at a concentration of 13 micrograms/ml in one eye and BSS in the contralateral eye. Control animals were injected with BSS into the central vitreous of both eyes. Ocular inflammation was evaluated at 20 hours by histology, immunopathology, and by cell count, protein and cytokine measurement in the aqueous humor. At 20 hours, eyes injected with AS101 developed iridocyclitis and mild vitritis versus minimal inflammation and/or protein in contralateral eyes or eyes of control animals (p = 0.0121). The inflammatory infiltrate was mixed in character. Major Histocompatibility Complex (MHC) class II antigens and intercellular adhesion molecules (ICAM-1) were expressed in the anterior segment of eyes injected with AS101. In the aqueous humor of these eyes there were significant quantities of inflammatory cells, protein (mean +/- SEM = 11.2 +/- 2.3 mg/ml) and the cytokine interleukin 6 (IL-6) (450 units/ml) compared with contralateral eyes (p = 0.0005 for inflammatory cells; protein, mean +/- SEM = 1.6 +/- 0.17 mg/ml; IL-6 = 12 units/ml) and both eyes of control animals injected with BSS (p = 0.8955 for inflammatory cells; protein, OD = 1.5 mg/ml, OS = 0.7 mg/ml; IL-6, OD = 8 units/ml, OS = 13 units/ml). AS101 has a local inflammatory effect in the eye. This compound may activate ocular inflammation by releasing cytokines such as IL-6.

Topics: Adjuvants, Immunologic; Animals; Anterior Eye Segment; Ethylenes; Eye Diseases; Female; Histocompatibility Antigens Class II; Inflammation; Injections; Intercellular Adhesion Molecule-1; Interleukin-6; Iridocyclitis; Rats; Rats, Inbred Lew; Vitreous Body