Inflammatory molecules have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. Resveratrol is an anti-fungal compound found in the skins of red grapes and other fruits and nuts. We examined the ability of resveratrol to inhibit lipopolysaccharide (LPS)-induced production of inflammatory molecules from primary mouse astrocytes. Resveratrol inhibited LPS-induced production of nitric oxide (NO); the cytokines tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and IL-6; and the chemokine monocyte chemotactic protein-1 (MCP-1), which play critical roles in innate immunity, by astrocytes. Resveratrol also suppressed astrocyte production of IL-12p40 and IL-23, which are known to alter the phenotype of T cells involved in adaptive immunity. Finally resveratrol inhibited astrocyte production of C-reactive protein (CRP), which plays a role in a variety of chronic inflammatory disorders. Collectively, these studies suggest that resveratrol may be an effective therapeutic agent in neurodegenerative diseases initiated or maintained by inflammatory processes.

Mitoxantrone has been approved by the FDA for the treatment of multiple sclerosis (MS). However, the mechanisms by which mitoxantrone modulates MS are largely unknown. Activated astrocytes produce nitric oxide (NO), TNF-α, and IL-1β, molecules which can be toxic to central nervous system (CNS) cells including oligodendrocytes, thus potentially contributing to the pathology associated with MS. MCP-1 is a chemokine believed to modulate the migration of monocytes to inflammatory lesions present in the CNS of MS patients. IL-12 and IL-23 have been demonstrated to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by contributing to the development of CD4+ T cell lineages termed Th1 and Th17, respectively. The current study demonstrates that mitoxantrone inhibits lipopolysachharide (LPS) induction of NO, TNF-α, IL-1β, and MCP-1 production by primary astrocytes. Mitoxantrone also inhibited IL-12 and IL-23 production by these cells. Furthermore, mitoxantrone suppressed the expression of C-reactive protein (CRP). Finally, we demonstrate that mitoxantrone suppressed LPS induction of NF-κB DNA-binding activity, suggesting a novel mechanism by which mitoxantrone suppresses the expression of proinflammatory molecules. Collectively, these studies demonstrate that mitoxantrone represses astrocyte production of potentially cytotoxic molecules, as well as molecules capable of altering T-cell phenotype. These in vitro studies suggest mechanisms by which mitoxantrone may modulate inflammatory diseases including MS.

Ewing's Sarcoma is a bone cancer that primarily affects children and teenagers. With a five‐year survival rate of approximately 30%, improved treatment options are needed. Our research has focused on the ability of the synthetic cannabinoid, ajulemic acid, to induce death in Ewing's sarcoma cells in vitro. We find ajulemic acid induces apoptosis in Ewing's sarcoma cells and several other tumor types in the Ewing family of tumors. In order to test the efficacy of ajulemic acid in vivo, we developed Ewing's sarcoma cells that express a firefly luciferase expression system as a handle by which to monitor tumor growth and drug response in living mice. SK‐ES Ewing's sarcoma cells were transiently transfected with firefly luciferase and then injected into the tibiae of nude mice. Tumors were allowed to develop and the growth of the bioluminescent tumors tracked using in vivo imaging techniques. The effect of different doses of ajulemic acid (and other potential therapies) can be used in these mice and tumor responses in individual mice can be monitored and measured. We hypothesize that these experiments provide the rationale for the development of improved therapies for this devastating cancer. The project described was supported by NIH Grant Number P20 RR‐16460 from the IDeA Networks of Biomedical Research Excellence (INBRE) Program of the National Center for Research Resources.

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