The astroglial transporters EAAT1 and EAAT2 are responsible for the largest percentage of glutamate transport in forebrain. Abnormal expression/function of EAAT2 is common to sporadic ALS and to transgenic models of the disease. In addition, altered function of various molecular subtypes of this transporter family is associated with brain tumor growth, cerebellar ataxia, multiple sclerosis and epilepsy. Regulating expression of these proteins could provide powerful therapies to retard disease progression. No practical pharmacological agents exist that can activate glutamate transporters. Studies using EAAT2 transgenic mice recently provide exciting evidence that increasing EAAT2 protein/activity can retard neurodegeneration in ALS animal models;diminish seizures associated with epilepsy, and retard brain tumor growth. A recent NINDS-organized screen of FDA approved drugs, identified beta-lactam antibiotics as modulators of EAAT2. We have accumulated preliminary data that several screened antibiotics can activate EAAT2 gene expression, leading to increased brain protein up to seven fold. The in vitro and in vivo actions of these drugs have been validated- they can protect against excitotoxic injury to cultured neurons/motor neurons. Finally one beta-lactam, ceftriaxone, can delay loss of muscle strength and increase survival in the ALS transgenic mouse model-even when given at disease onset. In this translational research proposal we will systematically evaluate non-antibiotic beta-lactam compounds and beta-lactam antibiotics as modulators of EAAT1 or EAAT2 expression. We will then go on to identify the most potent agent(s) and thoroughly evaluate the drugs in an in vitro-relevant and animal model of ALS. These sequential phases will set the stage for future practical translation towards rational clinical trial design.
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