Sunday, 24 August 2014

Sodium channels are a new target for therpy


Pappalardo LW, Liu S, Black JA, Waxman SG. Dynamics of sodium channel Nav1.5 expression in astrocytes in mouse models of multiple sclerosis. Neuroreport. 2014 Aug 20. [Epub ahead of print]

Astrocytes actively participate in the response of the central nervous system to injury, including in multiple sclerosis. Astrocytes can play both beneficial and detrimental roles in response to neuroinflammation; however, in extreme cases, astrogliosis can result in the formation of a glial scar, which can impede the regeneration of injured neurons. Although astrocytes do not express the voltage-gated sodium channel Nav1.5 in the nonpathological human brain, they exhibit robust upregulation of Nav1.5 within acute and chronic multiple sclerosis lesions. Recent work has indicated that Nav1.5 contributes to the pathways that regulate glial scar formation in vitro through modulation of intracellular Ca levels. However, the temporal dynamics of astrocytic Nav1.5 channel expression in response to neuroinflammatory pathologies has not been investigated. We examined astrocytes from mice with monophasic and chronic-relapsing (CR) experimental autoimmune encephalomyelitis (EAE) by immunohistochemical analysis to determine whether Nav1.5 is expressed in these cells, and whether the expression correlates with the severity of disease and/or phases of relapse and remission. Our results demonstrate that Nav1.5 is upregulated in astrocytes in situ in a temporal manner that correlates with disease severity in both monophasic and CR EAE. Further, in CR EAE, Nav1.5 expression is upregulated during relapses and subsequently attenuated during periods of remission. These observations are consistent with the suggestion that Nav1.5 can play a role in the response of astrocytes to inflammatory pathologies in the central nervous system and suggest Nav1.5 may be a potential therapeutic target to modulate reactive astrogliosis in vivo.

There are over nine different isoforms of sodium channels such as Nav 1.1 to Nav1.9. Nav 1.8 gets upregulated on nerves during EAE and MS and may contribute to or be expressed in response to to neuroinflammation. Nav 1.6 is the sodium channel that many people want to control. This study indicates that Nav 1.5 may be expressed on astrocytes and suggests it may be a target for control of immunity. However, this idea may be a dead duck as Nav1.5 is expressed on heart muscle and blocking this channel is going to be dangerous. Drug companies screen their drugs for binding to Nav 1.5 and potassium channel called hERG and chuck them away if they bind to these targets, so don't build up your  hopes

2 comments:

  1. It seems Na channel blocking drugs have been studied for a long, long time in EAE. What therapies have come from this? Do researchers think " I need to pad my CV, I think I'll publish another paper on a Na channel blocker"? So Na channel blockers my be an important target but it'll never happen because as you say it is too dangerous. Another example of "if you're a mouse with EAE we have good news for you" story.

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    1. It seems these drugs were studied for a long long time...indeed and it shows how slow the drug development is.

      The waxman group has been studying sodium channels for some time.

      A number have gone to clinical trial...the lamotrigine trial was the first and deemed a failure,,but when you looked who was taking the drug (this was done years after the trial) only 50% of the people on the trial were taking their medications so how was it every going to work?

      In those that did do it properly, it worked and slowed nerve loss! However it is not going to be done again...so no point blaming EAE here...you need to blame the drug as it was not sufficiently tolerable in the group of MSers it was tried on.

      As to be being dangerous...they need not be

      http://multiple-sclerosis-research.blogspot.co.uk/2014/03/targeting-drugs-to-lesions-chemical.html

      Furthermore they are sometimes used in MSers to tret things such as epilepsy

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