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 | 
Dec 06, 2012
 |  BC Innovations  |  Cover Story

A current affair in MS

A European team has used the diabetes drug glibenclamide to block inflammation-induced neurodegeneration in mice.1 The team plans to test the nonspecific inhibitor of the cationic channel TRPM4 in an investigator-led clinical trial in multiple sclerosis and is looking for pharmas to develop more specific antagonists of the target.

Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a widely expressed Ca2+-activated, voltage-dependent cation channel that depolarizes the plasma membrane by increasing sodium influx.

A group of German and Swiss researchers hypothesized that TRPM4 might be a key player in MS because disease-associated inflammation leads, in part, to elevated glutamate levels, which promote excitotoxic neurodegeneration by inducing Na+ and Ca2+ influx.2

Indeed, the ion channels NaV1.6 (PN4; SCN8A), Na+-Ca2+ exchanger and acid-sensing ion channel-1 (ASIC1) are dysregulated in MS,3-5 but nothing was known about the role TRPM4 might play in the disease.

In Trpm4 knockout mice with experimental autoimmune encephalomyelitis (EAE), compared with wild-type EAE mice, the team saw an overall decrease in disease severity-despite similar immune cell activation and infiltration.

Brain samples from both EAE wild-type mice and patients with MS showed that TRPM4 expression was greater within active demyelinating brain lesions than inactive lesions or tissue adjacent to active lesions.

The unanswered question was if-and how-Trpm4 affected the way in which neurons responded to toxic insults.

In assays to...

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