AUTHOR=Morris Catherine E., Boucher Pierre A., Joos Bela 

TITLE=Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 3 - 2012

YEAR=2012

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2012.00019

DOI=10.3389/fphar.2012.00019

ISSN=1663-9812

ABSTRACT=In sodium channel (Nav)-rich axon initial segments and nodes of Ranvier, mechanical,  ischemic  and inflammatory injuries render these voltage-gated channels  dangerously leaky.    Extrapolating from recombinant Nav1.6 behavior (Wang et al 2009 Am J Physiol 297:C823),  we postulate that the structural degradation of axolemmal bilayer, a common feature of neuoropathologic conditions,  fosters   ENa dissipation by favoring left-shifted Nav channel operation.  This “sick excitable cell Nav-leak” would encompass left-shifted Itransient and Ipersistent components (fast-mode Iwindow, slow-mode Ipersistent).  Ideally, bilayer damage-induced malfunction of Nav channels could be studied in Nav-rich  myelinated axon nodes, exploiting the INa(v,t) hysteresis of sawtooth  ramp voltage clamp.   We hypothesize that protective lipophilic Nav antagonists (e.g., ranolazine, riluzole) partition more avidly into disorderly bilayers of traumatically (ischemically, etc) damaged axons than into well-packed undamaged bilayers.  Whereas inhibitors using aqueous routes would access all Navs equally,  differential partitioning  into “sick bilayer” would co-localize lipophilic antagonists with “sick Nav channels”,  allowing for more specific targeting of  impaired cells.  Molecular fine-tuning effective antagonists for maximal partitioning into damaged-membrane milieus (thereby avoiding healthy cells) could help reduce Nav antagonist side-effects.  In potentially salvageable neurons of traumatic and/or ischemic penumbra, in inflammatory neuropathies,  in muscular dystrophy,  in myocytes of cardiac infarct borders,  Nav-leak driven excitotoxicity too easily overwhelms  cellular repair mechanisms.  Precision-tuned Nav antagonist variants that preferred mildly,  as opposed to  severely, damaged Nav-rich axolemma or sarcolemma might be suitable for the prolonged continuous administration needed to allow for excitable cell remodeling and hence for improved functional recovery.