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GLT-1 enhancers for the treatment of cerebral palsey

Cerebral Palsy (CP) is an umbrella term that describes abnormal motor movements that is caused by damage in the brain and, depending on the region(s) of the brain affected, can cause additional deficits. The underlying insults that cause brain damage in CP are not fully understood. Research has shown that neonatal hypoxia-ischemia combined with intrauterine infection are the most common underlying causes of white matter damage (periventricular leukomalacia) and CP. Most research to date has focused on the role of oligodendrocytes due to the correlation of PVL (oligodendrocyte loss) and the development of CP. Although oligodendroctye loss is the prevalent brain damage observed in CP, this research has not lead to a cure. We have elected to focus our efforts on a different cell type, the astrocyte. These cells maintain glutamate homeostasis through the sodium dependent glutamate transporters, primarily GLT-1, protecting the neurons in the brain from excitotoxic injury.

Our underlying hypothesis is that cellular changes, beginning with loss of astrocytes and their glutamate uptake functions through GLT-1, sets the stage for the development of CP. It has been demonstrated that astrocyte loss is caused by excitotoxicity that is caused by loss of GLT-1 function, and we have therefore further hypothesized that compounds capable of up-regulating GLT-1 expression and function may be capable of preventing neuronal damage that leads to CP.  Several FDA approved beta-lactam containing compounds (e.g. ceftriaxone, clavulanic acid) have been shown to up-regulate GLT-1.  We used these compounds as starting points to develop novel GLT-1 expression modulators that are capable of preventing CP-like disease progression in a hypoxia/ischemia/inflammation mouse model of CP.

Temple University
Moulder Center for Drug Discovery Research

Temple University School of Pharmacy
3307 N Broad Street
Philadelphia, PA 19140