Abstract
Neuroinflammation appears to involve some degree of excitotoxicity promulgated by microglia, which release glutamate via the system Xc- cystine-glutamate antiporter. With the aim of mitigating this source of neuronal stress and toxicity, we have developed a panel of inhibitors of the Xc- antiporter. The compounds were based on L-tyrosine, as elements of its structure align with those of glutamate, a primary physiological substrate of the Xc- antiporter. In addition to 3,5-dibromotyrosine, ten compounds were synthesized via amidation of that parent molecule with a selection of acyl halides. These agents were tested for the ability to inhibit release of glutamate from microglia activated with lipopolysaccharide (LPS), an activity exhibited by eight of the compounds. Two of these were further tested for the ability to inhibit death of primary cortical neurons in the presence of activated microglia. While both showed some neuroprotective activity, they were quantitatively distinct with a compound we refer to as "35DBTA7" showing the greatest effi cacy. This agent may hold promise in reducing the neurodegenerative effects of neuroinflammation in conditions such as encephalitis, traumatic brain injury, stroke, or neurodegenerative diseases.