Rethinking a drug treatment failure on a traditional ALS target.
Exp Neurol. 2009 Apr;216(2):254-7.
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Overall, the data now show that loss of neuronal glutamate release leads to downregulation of glutamate transporters in astrocytes. This makes a lot of sense for a homeostatic mechanism. It implies that the previously noted downregulation of astrocyte glt1 was a consequence of the neurodegenerative process rather than necessarily being part of the disease process. Drugs like riluzole have had only weak effects and conceivably their actions could relate to some other effect of this drug rather than any effect on glutamate transport.
The drug resistance problem caused by upregulation of P-glycoprotein at the blood-brain barrier is well documented and comes as no surprise. Getting drugs across the CNS is a big problem. The current findings showing that glial downregulation of glt1 is caused by loss of neurons suggest that even if high riluzole levels could be maintained in the CNS, this still would not be much more helpful for treating ALS. Many other genes are likely to turn off or on in astrocytes as a result of neuron degeneration and quite possibly these will turn out to be more relevant.