Rethinking a drug treatment failure on a traditional ALS target.
In a recent issue of Experimental Neurology, Boston-Howes and colleagues used an assay of glutamate transport to screen 1040 FDA approved drugs in an attempt to identify compounds that would increase glutamate transport, a central function of astrocytes, and a potential biological target for neuroprotection for a variety of neurological disorders. They identified the compound nordihydroguaiaretic acid (NDGA) as a particularly good candidate for inducing glutamate transport. Pharmacological increases in glutamate transport could have a number of potential applications to diseases of the nervous system where glutamate excitotoxicity is thought to be a contributing factor to pathogenesis including Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, stroke, and epilepsy among others. They chose to test this compound in a model of Amyotrophic Lateral Sclerosis (ALS)--the SOD1G93A mouse. In both human ALS and rodent models of the disease, glutamate excitotoxicity and abnormalities in glutamate transporter biology more specifically, have been implicated in ALS disease propagation. Interestingly, while the authors nicely demonstrate that NDGA has a biological effect on glutamate transport in normal (wild type) central nervous system tissues both in vitro and in vivo, it was the somewhat unexpected (and often overlooked) findings in the ALS mouse model that makes this manuscript notable and suggests that rethinking translational approaches to drug therapies in ALS may be on the horizon.
Maragakis
Nicholas J
NJ
Department of Neurology, Johns Hopkins University, School of Medicine, 600 N. Wolfe St., Meyer 6-119, Baltimore, MD 21287, USA. nmaragak@jhmi.edu
D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology / Q000627:therapeutic use; D017211:Treatment Failure
D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D009637:Masoprocol